A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

Full access

OBJECT

Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients.

METHODS

A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as “improvement” or “no improvement” in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms.

RESULTS

Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0–2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%–200%).

CONCLUSIONS

The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

ABBREVIATIONScGMP = cyclic guanosine monophosphate; CVS = cerebrovascular vasospasm; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; DSMB = Data Safety Monitoring Board; eNOS = endothelial nitric oxide synthase; ICA = internal carotid artery; ICP = intracranial pressure; MAP = mean arterial pressure; MCA = middle cerebral artery; NNICU = Neurology/Neurosurgery ICU; NO = nitric oxide; PDE-V = phosphodiesterase-V; SAH = subarachnoid hemorrhage.

Abstract

OBJECT

Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients.

METHODS

A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as “improvement” or “no improvement” in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms.

RESULTS

Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0–2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%–200%).

CONCLUSIONS

The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

Aneurysmal subarachnoid hemorrhage (SAH) is a significant health care problem with high morbidity and mortality; up to 70% of patients will die or be permanently disabled.33 Prognosis is dependent on a number of factors such as age, presenting neurological status, and development of delayed cerebral ischemia (DCI).4,6,74 Occurring in 30%–40% of patients, DCI is the most common and potentially treatable contributor to outcome.6,57,78 Though the mechanisms underlying DCI are multifactorial, the processes considered most responsible are delayed cerebrovascular vasospasm (CVS), cerebrovascular auto-regulatory dysfunction, and cortical spreading ischemia.6,47 Unfortunately, to date few therapies have proven effective for the prevention and treatment of DCI.4,82

A significant predictor of developing DCI is angiographic CVS of intracranial vessels.6,7,47 Approximately 60%–70% of patients will have CVS on digital subtraction angiography (DSA).4,6,7,11 In those patients, 50% will develop DCI.7,8,17,61 With this strong correlation, it is recommended that CVS be used as an initial outcome measure when assessing potential treatments for DCI.13,78 However, as research continues to elucidate the multifactorial nature of DCI, future interventions will need to attack not only CVS, but other contributors to DCI as well.

We hypothesize that one such therapeutic target is phosphodiesterase-V (PDE-V) inhibition. PDE-V is the regulatory enzyme of the endothelial nitric oxide synthase→nitric oxide→cyclic guanosine monophosphate (eNOS-NO-cGMP) pathway.19,27 Decreased functionality of this pathway following SAH has been linked to the pathophysiology of DCI including CVS.58,69,71,77,85 Studies investigating the eNOS-NO-cGMP pathway have shown that inhibition of PDE-V has substantial beneficial effects. In animal SAH studies, PDE-V inhibition (mainly via administration of sildenafil, an FDA-approved selective PDE-V inhibitor) acutely reverses SAH-induced CVS,2,28,31,32,34,42 reduces neuronal cell death,32 restores impaired autoregulatory mechanisms,73 and improves neurological outcomes.32 In SAH patients, sildenafil has been shown to improve transcranial Doppler flow velocities.56 Beyond this, there are data suggesting that sildenafil beneficially affects additional contributors of brain injury after SAH. In studies of SAH in animals, sildenafil has shown to reduce plasma levels of endothelin-1, 9,25,26,44,47,55,60,64,65 limit platelet induced microthrombosis, 30,45,62,68,83 and promote cerebral angiogenesis in hypoxic areas.14,66,87–89

Sildenafil has been extensively studied and proven safe in both healthy and cardiovascularly ill patients.1,5,18,24,35,41,67,80,81,90,91 However, to date there have been no studies in humans providing rigorous data on the safety of sildenafil in the setting of SAH. The primary objective of this study is to assess the safety of intravenous sildenafil in patients with SAH-induced CVS. Second, as a proof-of-concept, we looked to determine the ability of sildenafil to reverse CVS.

Methods

Study Design and Patient Population

A Phase I prospective, nonrandomized human trial with intravenous sildenafil using a dose escalation scheme (10 mg or 30 mg) was implemented (Fig. 1). Figure 2 shows the timeline for patient enrollment and study completion. The protocol was reviewed and approved by the study institution’s human research protection office. The US Food and Drug Administration granted an exemption from investigational new drug regulations. The trial was monitored by an independent Data Safety Monitoring Board (DSMB), led by a senior neurosurgeon with expertise in SAH management and clinical trials.

FIG. 1.
FIG. 1.

Flowchart showing the study protocol with recruitment data. Twenty-four patients were enrolled, with 12 patients completing the study.

FIG. 2.
FIG. 2.

Timeline for patient enrollment and study completion.

Patients admitted within 72 hours of an aneurysmal SAH were recruited from September 2011 through May 2013. Screening criteria included 1) age ≥ 21 years, 2) surgical or endovascular repair of the ruptured aneurysm, 3) modified Fisher Grade I to IV hemorrhage23 on initial CT imaging, and 4) CVS on DSA. Exclusion criteria were 1) pregnancy, 2) SAH secondary to traumatic or mycotic aneurysm, 3) preictal sildenafil therapy, 4) contraindications to sildenafil therapy: use of nitrates and patients with left ventricular outflow obstruction, and 5) insufficient CVS on screening DSA.

Study Interventions

Per our established clinical protocol for SAH management, patients were initially evaluated using DSA to determine the etiology of the SAH. Cerebral aneurysms were treated either surgically or endovascularly within 24 hours of admission. Following treatment, patients were monitored in the Neurology/Neurosurgery ICU (NNICU) throughout the vasospasm window.

All patients were given enteral nimodipine (60 mg every 4 hours) for 21 days, and fluid status was closely monitored. If a patient developed neurological worsening concerning for DCI, hypertensive treatment was initiated and evaluation with DSA and possible endovascular intervention (i.e., intraarterial verapamil and/or balloon angioplasty) was promptly arranged. In the absence of new symptoms, each patient underwent screening DSA to assess for CVS during the peak vasospasm period (Days 7–10).

Sildenafil Dosing

Based on dosages used in previous clinical trials evaluating sildenafil for the treatment of pulmonary hypertension,24 the study was carried out using a dose escalation scheme. Twelve patients were enrolled sequentially into 2 groups. During the first phase, patients with moderate to severe CVS (determined at the time of the screening DSA) received 10 mg (low-dose) of intravenous sildenafil (bioequivalent to a 20-mg oral dose). After the planned midpoint safety review by the DSMB, the study proceeded to the high-dose phase. At this stage, patients with any degree of CVS (mild, moderate, or severe) found on their follow-up DSA study (determined at the time of the screening DSA) received 30 mg (high dose) of intravenous sildenafil (bioequivalent to a 60 mg oral dose).

Sildenafil was infused over 30 minutes, after which all patients were monitored for a further 30-minute interval. After this period a repeat DSA was obtained to assess for improvement of vasospasm. If CVS persisted, the patient could receive endovascular interventions as current standard of care (i.e., intraarterial verapamil or angioplasty).

Safety and Tolerability Assessment

The safety measures to be assessed were development of hypotension, elevated intracranial pressure (ICP, measured via external ventricular drain, when available), cardiac arrhythmias, or any decline in pulmonary or neurological status. Hypotension was defined as a decrease > 10% from the baseline mean arterial pressure (MAP). The duration of hypotension was also recorded as time to return to within 10% of baseline MAP. An adverse event related to hypotension was defined as either a decline in MAP < 70 mm Hg or a decline in MAP that resulted in worsened neurological examination findings. As a comparison with sildenafil’s effect on MAP, we analyzed the impact of nimodipine by measuring patients’ prenimodipine and 1-hour postnimodipine MAP. Elevated ICP was considered as pressure > 25 mm Hg for longer than 5 minutes. Further adverse events (those previously associated with sildenafil), for which patients were monitored, included priapism, visible flushing, and visual disturbances. After the procedure, monitoring of the patients continued in the NNICU with continuous vital sign monitoring and hourly neurological checks. Complete neurological and physical examinations were completed immediately prior to DSA, 1 hour post-sildenafil, and 12 hours post-sildenafil by a study physician.

Radiological CVS Assessment

At the time of the screening DSA, images were evaluated by one of the 3 neuorinterventional radiology investigators (D.T.C., C.P.D., and C.J.M.), and vasospasm was quantified as follows: comparing the screening angiogram to the admission angiogram, CVS in the internal carotid, basilar, middle, anterior, and posterior cerebral arteries was defined based on percent reduction in caliber size as none, mild (< 50% narrowing), moderate (50%–70% narrowing), and severe (> 70% narrowing).54 For each patient the most significant percent reduction of caliber size in any single vessel was the recorded degree of CVS. Vessel measurements were made using software on the Axiom Artis unit (Siemens Healthcare).

Postprocedural analyses of DSA images to determine whether patients showed any evidence of response to sildenafil were completed by 2 authors (C.P.D. and C.W.W.). In a blinded fashion, reviewers labeled images as “admission,” “pre-sildenafil,” and “post-sildenafil.” After labeling, images were compared and subjectively graded as “improvement” or “no improvement” in vasospasm.

A quantitative analysis of images was carried out to determine the magnitude of response. Unblinded measurements of vessel diameter were made on the admission, pre-sildenafil, and post-sildenafil DSA images. Measurements were made in millimeters at the highest degree of stenosis in each of the supraclinoidal segment of the internal carotid artery (ICA), A1 and A2 segments of the anterior cerebral artery, the M1 and M2 segments of the middle cerebral artery (MCA), the basilar artery, and posterior cerebral arteries. The petrous ICA or the cervical vertebral artery was used as a reference to correct for magnification. Change in stenosis was calculated in millimeters and by percent change from pre-sildenafil baseline measurements. For each patient the largest improvement in any single vessel was the recorded response.

Statistical Analysis

All statistical analyses were completed using SAS (version 9.3, SAS Institute Inc.). Comparisons of continuous patient data pre- and post-sildenafil used a paired t-test, whereas comparisons made across low-dose and highdose groups used a 2-sample t-test. Categorical variables across groups were compared using Fisher’s exact t-test. For statistical tests, significance was defined as p < 0.05.

Results

Patient Population

Twenty-four patients provided consent for the study, and 12 were excluded for not undergoing repeat DSA (n = 2) or having insufficient degree of angiographic vasospasm (n = 10). Twelve patients received sildenafil; 5 (42%) were in the low-dose (10 mg) group and 7 (58%) were in the high-dose (30 mg) group. Demographic data are provided in Table 1. Most patients (66%) were in Hunt and Hess Grade III or IV, and 92% of patients had modified Fisher Grade III or IV SAH.

TABLE 1.

Patient demographics and admitting characteristics*

VariableValue
Mean age in yrs (range)55 (38−83)
Sex
 Male6 (50)
 Female6 (50)
Hunt & Hess grade
 I0 (0)
 II3 (25)
 III4 (33)
 IV4 (33)
 V1 (8)
Hydrocephalus on admission
 Yes10 (83)
 No2 (17)
Modified Fisher grade
 I1 (8)
 II0 (0)
 III6 (50)
 IV5 (42)
Aneurysm location
 ACoA5 (42)
 MCA1 (8)
 OphA1 (8)
 PICA1 (8)
 PCoA4 (33)
Treatment
 Clip5 (42)
 Coil7 (58)

ACoA = anterior communicating artery; OphA = ophthalmic artery; PCoA = posterior communicating artery; PICA = posterior inferior cerebellar artery.

Values are number of patients (%) unless stated otherwise.

Safety and Tolerability

There were no adverse pulmonary or neurological events. All patients accessible for subjective assessment tolerated the doses without complaint of worsening headache, flushing, or visual changes. All neurological examination findings remained stable. One patient showed improvement after infusion, with resolution of a pronator drift.

Data regarding blood pressure, ICP, and heart rate can be found in Table 2. (With the following data, averages are given with standard deviations in parentheses.) Ten of 12 patients (83%) developed hypotension following sildenafil, with greatest decline in MAP an average of 17% (SD 9%) below baseline. The change was transient in all cases, with return to baseline occurring by an average of 18 (SD 15) minutes. The magnitude of this decline was not significantly different from that seen in patients following nimodipine, which was an average of 11% (SD 6). There were no differences in the degree of hypotension between low- and high-dose groups, and return to baseline MAP occurred by 16 and 20 minutes, respectively (differences all nonsignificant). No patient had a hypotension-related adverse event.

TABLE 2.

Vital sign data

Case No.Sildenafil Dose (mg)Maximum Drop in MAP (% from baseline)Time to Return to Baseline MAP (mins)Drop in MAP Post-Nimodipine (% from baseline)Pre-Sildenafil ICP (mm Hg)Post-Sildenafil ICP (mm Hg)Pre-Sildenafil Heart Rate (bpm)Post-Sildenafil Heart Rate (bpm)
11035401226209378
2101630141378375
3108087180
410161065136874
5106068482
630215022977179
730341551189693
830172091588381
930121514128104104
10301525884105110
113012523996575
12301110927244545

There was no significant change between pre- and post-sildenafil ICP or heart rate. No patient had elevated ICP within the 24-hour period following sildenafil therapy.

Angiographic CVS

Individual angiographic data for patients are shown in Table 3. Of the 12 patients completing the study, 1 (8%) had mild, 6 (50%) moderate, and 5 (42%) severe CVS on pre-sildenafil DSA. Angiography occurred on average at posthemorrhage Day 7 (range Days 5–10). Eight (67%) were found to have a positive angiographic response to sildenafil (3 [60%] in the low-dose group and 5 [71%] in the high-dose group [difference in response rate not significant]). No patient was found to have worsening CVS following sildenafil infusion. Examples of angiographic improvement are seen in Figs. 3 and 4.

FIG. 3.
FIG. 3.

A: The anteroposterior DSA image of a left carotid artery injection prior to sildenafil. B: The anteroposterior DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram, showing severe CVS of the left A1 and A2 segments of the anterior cerebral arteries (white arrows). D: Demonstrates areas of dilation in the proximal left A1(dotted arrow) and A2 (solid arrow) segments of the anterior cerebral artery post-sildenafil.

FIG. 4.
FIG. 4.

A: The lateral DSA image of a left carotid artery injection prior to sildenafil. B: Lateral DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram showing a focal area of stenosis in the superior M2 division of the middle cerebral artery (arrow). D: Improvement in the vasospasm is seen in the M2 segment of the MCA following sildenafil infusion. The focal area of stenosis has resolved (arrow).

TABLE 3.

Angiographic data

Case No.Vasospasm GradeSildenafil Dose (mg)Improve Post-SildenafilMaximum Dilatation (mm)Maximum Dilatation (%)
1Severe10Yes1.25100
2Moderate10Yes1.25100
3Moderate10NoNRNR
4Moderate10NoNRNR
5Moderate10Yes0.8325
6Moderate30NoNRNR
7Severe30Yes1.25100
8Moderate30NoNRNR
9Severe30Yes2.1200
10Severe30Yes1.25100
11Severe30Yes0.671
12Mild30Yes0.650

NR = nonresponder.

The largest degree of vessel dilation, across all patients (both low- and high-dose groups), was an average of 0.8 mm (range 0–2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%–200%). When considering only patients identified as angiographic responders, the average dilation was 1.1 mm in the low-dose group and 1.2 mm in the high-dose group.

Discussion

The data from this Phase I clinical trial investigating the use of sildenafil for the treatment of angiographic CVS provide the first evidence that sildenafil in the setting of aneurysmal SAH is both safe and well tolerated. This is the first study to demonstrate in a rigorous fashion that sildenafil has a beneficial effect on CVS in humans.

In evaluating the safety of sildenafil in this patient population, our primary concern was that it would induce unacceptable hypotension. We have seen from other promising trials that hypotension is a potential confounder affecting patient outcomes.48,49,51 We have shown that at both a low dose (10 mg) and a high dose (30 mg), the blood pressure profile is acceptable without evidence of a prolonged adverse effect. While there was a decline in MAP by an average of 17%, this was transient with a rapid return to baseline within an average of 18 minutes (Table 2). There was no evidence that this response was dose dependent. When comparing the mild hypotension after sildenafil to that encountered after nimodipine, we found no significant difference between the 2 drugs (Table 2). Furthermore, the hypotension seen after nimodipine developed 1 hour following ingestion, whereas with sildenafil all patients had returned to baseline within 1 hour. Other encouraging data suggesting the safety of sildenafil in the SAH patients are the lack of an adverse impact on ICP and/or cardiopulmonary status. Furthermore, previously described issues surrounding its tolerability (flushing, headaches, visual decline, and etc.) were not encountered.

Angiographically, 62% of patients demonstrated a positive response. There was no significant variance related to dose. Though the degree of vessel dilation was modest in absolute magnitude (average improvement of 0.8 mm; 62% increase in vessel diameter), when comparing this intravenously dosed medication to reported response rates for intraarterial papaverine and verapamil (response rates of 67%–98%; vessel diameter increases of 26%–44%),16,43,54 our observed response to sildenafil was quite promising. It should be noted that the angiographic effects reported here were focal areas of dilation in specific vasospastic vessels (Figs. 3 and 4); the response was not necessarily a global improvement in the degree of vasospasm. Therefore, we are not claiming that our results prove that sildenafil “reverses” CVS, but we do believe our findings demonstrate a “proof-of-concept” that sildenafil is acting in positive way on the pathophysiology of cerebral vasospasm.

Sildenafil as Treatment for DCI

The vasodilatory effect seen with sildenafil has been primarily attributed to its modulation of the eNOS-NO-cGMP pathway.14,27 It has long been understood that a significant component of the development of SAH-induced CVS has been the dysfunction of the eNOS-NO-cGMP pathway, and numerous interventions designed to upregulate this pathway have been shown to improve CVS in preclinical and, at times, clinical studies.12,34,38,40,59,72,76,77,84 The majority of these interventions have targeted the upstream elements of this molecular cascade (eNOS and NO). Results from these upstream therapeutic approaches, however, have been disappointing due to a lack of specific and effective eNOS agonists as well as a myriad of difficulties associated with NO-directed therapies including the short half-life of available NO donors and the substantial systemic side effects such agents often induce.15 As a result, many investigators have begun to target the downstream element of the eNOS-NO-cGMP pathway by administering PDE-V inhibitors like sildenafil as a means for inhibiting SAH-induced CVS and DCI.

In animal studies, PDE-V inhibition attenuates or acutely reverses SAH-induced CVS,2,28,31,32,34,42 reduces SAH-induced neuronal cell death,32 and improves post-SAH neurological outcome.32 PDE-V inhibition has also been shown to augment autoregulatory vasodilatation in humans without SAH10 and, in a rat model of SAH, restore impaired autoregulatory mechanisms.73 More recently in SAH patients, sildenafil has been shown to have a positive effect on transcranial Doppler flow velocities in refractory CVS.56

The hypothesized mechanism through which sildenafil and other PDE-V inhibitors exert their beneficial vascular effects has been in their ability to increase intracellular cGMP levels in vascular smooth muscle cells, and, as a result, normalize vascular tone.32 However, there are other pathways through which PDE-V inhibition may also be acting. Endothelin-1, a potent cerebral vasoconstrictor, has been strongly implicated in early brain injury, CVS, and ultimately DCI following aneurysmal SAH.3,29,36,37,39,46,48,50– 53,75,79,86 Studies evaluating endothelial function in erectile dysfunction and pulmonary hypertension have demonstrated that sildenafil substantially reduces endothelin-1 levels.44,60,64,65 The development of platelet-induced microthrombi within the microvasculature has also been implicated in DCI,20–22,63,70 and sildenafil has been shown to limit this prothrombotic cascade.30,45,62,68,83 Lastly, when cerebral blood flow to an area decreases to ischemic levels, sildenafil has demonstrated the ability to decrease the size of the infarct and improve outcomes by promoting angiogenesis in hypoxic areas.14,66,87–89 Each of these pathways represents future areas of study in determining sildenafil’s role in treating DCI.

Study Limitations

The aims of this study were to assess the safety of sildenafil in SAH patients with CVS and to determine whether sildenafil results in a positive angiographic response. With the prescribed doses (10 mg and 30 mg), we were able to achieve both goals. However, it is possible that sildenafil was under-dosed. Studies evaluating safety and efficacy in pulmonary hypertension, have determined that oral dosing up to 300 mg/day in divided doses (comparable to 150 mg/day intravenously) can be achieved safely.24,67 Our initial concern was that the systemic vasodilatation would result in an unacceptable degree of hypotension and/or an adverse impact on ICP. Since we have now demonstrated that a single infusion is well tolerated, future studies will need to increase the prescribed dosage level in combination with changing the dosing scheme to daily divided doses continuing through the vasospasm window.

Second, the relatively small number of patients included in our study precludes us from making definitive conclusions regarding sildenafil’s impact on CVS and neurological outcomes. Assessing neurological outcome was outside the scope of this Phase I trial. Also, as we have previously discussed, our angiographic analysis was a proof-of-concept, being used to demonstrate a positive physiological response in the setting of CVS. Future clinical trials will need to be randomized and adequately powered to make meaningful assessments as to the effects of sildenafil on CVS and patient outcomes.

Conclusions

The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with angiographic CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data are the first of its kind to provide evidence that sildenafil has a positive impact on CVS. This information, along with the substantial amount of preclinical data in SAH studies and sildenafil’s proven track record in treating other pathophysiologies related to vascular endothelium dysfunction, provides a strong rationale for future clinical investigations into its effectiveness in preventing and treating SAH-related DCI.

Acknowledgments

Funding was provided by Washington University Institute of Clinical and Translational Sciences grant no. UL1 TR000448 from the National Center for Advancing Translational Sciences of the National Institutes of Health, and the Neurosurgery Research and Education Foundation.

Author Contributions

Conception and design: Washington, Derdeyn, Han, Vellimana, Zipfel. Acquisition of data: Washington, Arias, Cross, Moran. Analysis and interpretation of data: Washington, Derdeyn, Dhar. Drafting the article: Washington. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Washington. Statistical analysis: Washington. Study supervision: Washington, Zipfel.

Supplemental Information

Previous Presentation

This paper was presented in abstract form at the American Heart Association/American Stroke Association 2014 International Stroke Conference and Nursing Symposium in San Diego, CA.

References

  • 1

    Abbott DComby PCharuel CGraepel PHanton GLeblanc B: Preclinical safety profile of sildenafil. Int J Impot Res 16:4985042004

  • 2

    Atalay BCaner HCekinmez MOzen OCelasun BAltinors N: Systemic administration of phosphodiesterase V inhibitor, sildenafil citrate, for attenuation of cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 59:110211082006

  • 3

    Bellapart JJones LBandeshe HBoots R: Plasma endothelin-1 as screening marker for cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care 20:77832014

  • 4

    Connolly ES JrRabinstein AACarhuapoma JRDerdeyn CPDion JHigashida RT: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43:171117372012

  • 5

    Conti CRPepine CJSweeney M: Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 83:5A29C34C1999

  • 6

    Cossu GMesserer MOddo MDaniel RT: To look beyond vasospasm in aneurysmal subarachnoid haemorrhage. Biomed Res Int 2014:6285972014

  • 7

    Crowley RWMedel RDumont ASIlodigwe DKassell NFMayer SA: Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:9199232011

  • 8

    Dankbaar JWRijsdijk Mvan der Schaaf ICVelthuis BKWermer MJHRinkel GJE: Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology 51:8138192009

  • 9

    Das AXi LKukreja RC: Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem 280:12944129552005

  • 10

    Diomedi MSallustio FRizzato BFerrante FLeone GSpera E: Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study. Neurology 65:9199212005

  • 11

    Dorsch N: A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl 110562011

  • 12

    Edwards DHByrne JVGriffith TM: The effect of chronic subarachnoid hemorrhage on basal endothelium-derived relaxing factor activity in intrathecal cerebral arteries. J Neurosurg 76:8308371992

  • 13

    Etminan NVergouwen MDIIlodigwe DMacdonald RL: Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 31:144314512011

  • 14

    Farooq MUNaravetla BMoore PWMajid AGupta RKassab MY: Role of sildenafil in neurological disorders. Clin Neuropharmacol 31:3533622008

  • 15

    Fathi ARBakhtian KDPluta RM: The role of nitric oxide donors in treating cerebral vasospasm after subarachnoid hemorrhage. Acta Neurochir Suppl 110:93972011

  • 16

    Feng LFitzsimmons BFYoung WLBerman MFLin EAagaard BD: Intraarterially administered verapamil as adjunct therapy for cerebral vasospasm: safety and 2-year experience. AJNR Am J Neuroradiol 23:128412902002

  • 17

    Fergusen SMacdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:6586672007

  • 18

    Fox KMThadani UMa PTNash SDKeating ZCzorniak MA: Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J 24:220622122003

  • 19

    Friebe AKoesling D: Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93:961052003

  • 20

    Friedrich BMüller FFeiler SSchöller KPlesnila N: Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab 32:4474552012

  • 21

    Friedrich VFlores RMuller ASehba FA: Escape of intra-luminal platelets into brain parenchyma after subarachnoid hemorrhage. Neuroscience 165:9689752010

  • 22

    Friedrich VFlores RMuller ASehba FA: Luminal platelet aggregates in functional deficits in parenchymal vessels after subarachnoid hemorrhage. Brain Res 1354:1791872010

  • 23

    Frontera JAClaassen JSchmidt JMWartenberg KETemes RConnolly ES Jr: Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery 59:21272006

  • 24

    Galiè NGhofrani HATorbicki ABarst RJRubin LJBadesch D: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:214821572005

  • 25

    García-Cardoso JVela RMahillo EMateos-Cáceres PJModrego JMacaya C: Increased cyclic guanosine monophosphate production and endothelial nitric oxide synthase level in mononuclear cells from sildenafil citrate-treated patients with erectile dysfunction. Int J Impot Res 22:68762010

  • 26

    Gebska MAStevenson BKHemnes ARBivalacqua TJHaile AHesketh GG: Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity. Cardiovasc Res 90:3533632011

  • 27

    Ghofrani HAOsterloh IHGrimminger F: Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:6897022006

  • 28

    Gokce CGulsen SYilmaz CGuven GCaner HAltinors N: The effect of the sildenafil citrate on cerebral vasospasm and apoptosis following experimental subarachnoid hemorrhage in rats. J Neurosurg Sci 54:29372010

  • 29

    Gruber ARoessler KGeorgopoulos AMissbichler ABonelli RRichling B: Evaluation of big endothelin-1 concentrations in serum and ventricular cerebrospinal fluid after early surgical compared with nonsurgical management of ruptured intracranial aneurysms. Neurosurg Focus 8:5e62000

  • 30

    Gudmundsdóttir IJMcRobbie SJRobinson SDNewby DEMegson IL: Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. Biochem Biophys Res Commun 337:3823852005

  • 31

    Gul SBahadir BHanci VBektas SCan MKalayci M: Effect of vardenafil on cerebral vasospasm following experimental subarachnoid hemorrhage in rats. J Clin Neurosci 17:103810412010

  • 32

    Han BHVellimana AKZhou MLMilner EZipfel GJ: Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage. Neurosurgery 70:1781872012

  • 33

    Hop JWRinkel GJAlgra Avan Gijn J: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:6606641997

  • 34

    Inoha SInamura TIkezaki KNakamizo AAmano TFukui M: Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model. Neurol Res 24:6076122002

  • 35

    Jackson GBenjamin NJackson NAllen MJ: Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 83:5A13C20C1999

  • 36

    Juvela S: Plasma endothelin and big endothelin concentrations and serum endothelin-converting enzyme activity following aneurysmal subarachnoid hemorrhage. J Neurosurg 97:128712932002

  • 37

    Juvela S: Plasma endothelin concentrations after aneurysmal subarachnoid hemorrhage. J Neurosurg 92:3904002000

  • 38

    Kasuya HWeir BKANakane MPollock JSJohns LMarton LS: Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage. J Neurosurg 82:2502551995

  • 39

    Kasuya HWeir BKAWhite DMStefansson K: Mechanism of oxyhemoglobin-induced release of endothelin-1 from cultured vascular endothelial cells and smooth-muscle cells. J Neurosurg 79:8928981993

  • 40

    Kim PSchini VBSundt TM JrVanhoutte PM: Reduced production of cGMP underlies the loss of endothelium-dependent relaxations in the canine basilar artery after subarachnoid hemorrhage. Circ Res 70:2482561992

  • 41

    Kloner RAZusman RM: Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 84:5B11N17N1999

  • 42

    Koktekir EErdem YAkif Bayar MGokcek CKaratay MKilic C: A new approach to the treatment of cerebral vasospasm: the angiographic effects of tadalafil on experimental vasospasm. Acta Neurochir (Wien) 152:4634692010

  • 43

    Komotar RJZacharia BEOtten MLMocco JLavine SD: Controversies in the endovascular management of cerebral vasospasm after intracranial aneurysm rupture and future directions for therapeutic approaches. Neurosurgery 62:8979072008

  • 44

    Konstantinopoulos AGiannitsas KAthanasopoulos ASpathas DPerimenis P: The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction. Expert Opin Pharmacother 10:1551602009

  • 45

    Lewis GDWitzke CColon-Hernandez PGuerrero JLBloch KDSemigran MJ: Sildenafil improves coronary artery patency in a canine model of platelet-mediated cyclic coronary occlusion after thrombolysis. J Am Coll Cardiol 47:147114772006

  • 46

    Macdonald RL: Clazosentan: an endothelin receptor antagonist for treatment of vasospasm after subarachnoid hemorrhage. Expert Opin Investig Drugs 17:176117672008

  • 47

    Macdonald RL: Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44582014

  • 48

    Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CON-SCIOUS-2). Lancet Neurol 10:6186252011

  • 49

    Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:146314692012

  • 50

    Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care 13:4164242010

  • 51

    Macdonald RLKassell NFMayer SRuefenacht DSchmiedek PWeidauer S: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:301530212008

  • 52

    Macdonald RLPluta RMZhang JH: Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:2562632007

  • 53

    Mascia LFedorko LStewart DJMohamed FterBrugge KRanieri VM: Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Stroke 32:118511902001

  • 54

    Milburn JMMoran CJCross DT IIIDiringer MNPilgram TKDacey RG Jr: Increase in diameters of vasospastic intracranial arteries by intraarterial papaverine administration. J Neurosurg 88:38421998

  • 55

    Mrozek SDumurgier JCiterio GMebazaa AGeeraerts T: Biomarkers and acute brain injuries: interest and limits. Crit Care 18:2202014

  • 56

    Mukherjee KKSingh SKKhosla VKMohindra SSalunke P: Safety and efficacy of sildenafil citrate in reversal of cerebral vasospasm: A feasibility study. Surg Neurol Int 3:32012

  • 57

    Ohman JServo AHeiskanen O: Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery. J Neurosurg 74:8131991

  • 58

    Pluta RM: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 104:1391472008

  • 59

    Pluta RMOldfield EHBoock RJ: Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. J Neurosurg 87:7467511997

  • 60

    Proietti MAversa ALetizia CRossi CMenghi GBruzziches R: Erectile dysfunction in systemic sclerosis: effects of longterm inhibition of phosphodiesterase type-5 on erectile function and plasma endothelin-1 levels. J Rheumatol 34:171217172007

  • 61

    Rabinstein AAFriedman JAWeigand SDMcClelland RLFulgham JRManno EM: Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 35:186218662004

  • 62

    Rehse KScheffler HReitner N: Interaction of Viagra with the NO donors molsidomine and RE 2047 with regard to antithrombotic and blood pressure lowering activities. Arch Pharm (Weinheim) 332:1821841999

  • 63

    Romano JGRabinstein AAArheart KLNathan SCampo-Bustillo IKoch S: Microemboli in aneurysmal subarachnoid hemorrhage. J Neuroimaging 18:3964012008

  • 64

    Rosano GMAversa AVitale CFabbri AFini MSpera G: Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 47:2142222005

  • 65

    Rossi RNuzzo ALattanzi ACoppi FModena MG: Sildenafil improves endothelial function in patients with pulmonary hypertension. Pulm Pharmacol Ther 21:1721772008

  • 66

    Sahara MSata MMorita TNakajima THirata YNagai R: A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arterioscler Thromb Vasc Biol 30:131513242010

  • 67

    Sastry BKNarasimhan CReddy NKRaju BS: Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 43:114911532004

  • 68

    Schmidt UHan RODiSalvo TGGuerrero JLGold HKZapol WM: Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition. J Am Coll Cardiol 37:198119882001

  • 69

    Sehba FAFriedrich V JrMakonnen GBederson JB: Acute cerebral vascular injury after subarachnoid hemorrhage and its prevention by administration of a nitric oxide donor. J Neurosurg 106:3213292007

  • 70

    Sehba FAMostafa GFriedrich V JrBederson JB: Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg 102:109411002005

  • 71

    Sobey CG: Cerebrovascular dysfunction after subarachnoid haemorrhage: novel mechanisms and directions for therapy. Clin Exp Pharmacol Physiol 28:9269292001

  • 72

    Sobey CGFaraci FM: Subarachnoid haemorrhage: what happens to the cerebral arteries?. Clin Exp Pharmacol Physiol 25:8678761998

  • 73

    Sobey CGQuan L: Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. Am J Physiol 277:H1718H17241999

  • 74

    Suarez JITarr RWSelman WR: Aneurysmal subarachnoid hemorrhage. N Engl J Med 354:3873962006

  • 75

    Thampatty BPSherwood PRGallek MJCrago EARen DHricik AJ: Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia. Neurocrit Care 15:19272011

  • 76

    Thomas JERosenwasser RH: Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intra-ventricular sodium nitroprusside in humans. Neurosurgery 44:48581999

  • 77

    Vellimana AKMilner EAzad TDHarries MDZhou MLGidday JM: Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhageinduced cerebral vasospasm. Stroke 42:7767822011

  • 78

    Vergouwen MDVermeulen Mvan Gijn JRinkel GJWijdicks EFMuizelaar JP: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:239123952010

  • 79

    Vergouwen MDIAlgra ARinkel GJE: Endothelin receptor antagonists for aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke 43:267126762012

  • 80

    Wallis RMCorbin JDFrancis SHEllis P: Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 83:5A3C12C1999

  • 81

    Webb DJFreestone SAllen MJMuirhead GJ: Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 83:5A21C28C1999

  • 82

    Weyer GWNolan CPMacdonald RL: Evidence-based cerebral vasospasm management. Neurosurg Focus 21:3E82006

  • 83

    Wilson LSElbatarny HSCrawley SWBennett BMMaurice DH: Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions. Proc Natl Acad Sci USA 105:13650136552008

  • 84

    Wolf EWBanerjee ASoble-Smith JDohan FC JrWhite RPRobertson JT: Reversal of cerebral vasospasm using an intrathecally administered nitric oxide donor. J Neurosurg 89:2792881998

  • 85

    Yatsushige HCalvert JWCahill JZhang JH: Limited role of inducible nitric oxide synthase in blood-brain barrier function after experimental subarachnoid hemorrhage. J Neurotrauma 23:187418822006

  • 86

    Yeung PKShen JChung SSChung SK: Targeted overexpression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage. BMC Neurosci 14:1312013

  • 87

    Zhang LZhang RLWang YZhang CZhang ZGMeng H: Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 36:8478522005

  • 88

    Zhang LZhang ZZhang RLCui YLaPointe MCSilver B: Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 1118:1921982006

  • 89

    Zhang RWang LZhang LChen JZhu ZZhang Z: Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 92:3083132003

  • 90

    Zusman RMMorales AGlasser DBOsterloh IH: Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 83:5A35C44C1999

  • 91

    Zusman RMPrisant LMBrown MJ: Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. J Hypertens 18:186518692000

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence Chad Washington, Department of Neurological Surgery, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216. email: cwashington4@umc.edu.

INCLUDE WHEN CITING Published online August 28, 2015; DOI: 10.3171/2015.2.JNS142752.

Disclosure Dr. Derdeyn reports that he has ownership in Pulse Therapeutics and is a consultant for Micro Vention and Penumbra.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flowchart showing the study protocol with recruitment data. Twenty-four patients were enrolled, with 12 patients completing the study.

  • View in gallery

    Timeline for patient enrollment and study completion.

  • View in gallery

    A: The anteroposterior DSA image of a left carotid artery injection prior to sildenafil. B: The anteroposterior DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram, showing severe CVS of the left A1 and A2 segments of the anterior cerebral arteries (white arrows). D: Demonstrates areas of dilation in the proximal left A1(dotted arrow) and A2 (solid arrow) segments of the anterior cerebral artery post-sildenafil.

  • View in gallery

    A: The lateral DSA image of a left carotid artery injection prior to sildenafil. B: Lateral DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram showing a focal area of stenosis in the superior M2 division of the middle cerebral artery (arrow). D: Improvement in the vasospasm is seen in the M2 segment of the MCA following sildenafil infusion. The focal area of stenosis has resolved (arrow).

References

1

Abbott DComby PCharuel CGraepel PHanton GLeblanc B: Preclinical safety profile of sildenafil. Int J Impot Res 16:4985042004

2

Atalay BCaner HCekinmez MOzen OCelasun BAltinors N: Systemic administration of phosphodiesterase V inhibitor, sildenafil citrate, for attenuation of cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 59:110211082006

3

Bellapart JJones LBandeshe HBoots R: Plasma endothelin-1 as screening marker for cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care 20:77832014

4

Connolly ES JrRabinstein AACarhuapoma JRDerdeyn CPDion JHigashida RT: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43:171117372012

5

Conti CRPepine CJSweeney M: Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 83:5A29C34C1999

6

Cossu GMesserer MOddo MDaniel RT: To look beyond vasospasm in aneurysmal subarachnoid haemorrhage. Biomed Res Int 2014:6285972014

7

Crowley RWMedel RDumont ASIlodigwe DKassell NFMayer SA: Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:9199232011

8

Dankbaar JWRijsdijk Mvan der Schaaf ICVelthuis BKWermer MJHRinkel GJE: Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology 51:8138192009

9

Das AXi LKukreja RC: Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem 280:12944129552005

10

Diomedi MSallustio FRizzato BFerrante FLeone GSpera E: Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study. Neurology 65:9199212005

11

Dorsch N: A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl 110562011

12

Edwards DHByrne JVGriffith TM: The effect of chronic subarachnoid hemorrhage on basal endothelium-derived relaxing factor activity in intrathecal cerebral arteries. J Neurosurg 76:8308371992

13

Etminan NVergouwen MDIIlodigwe DMacdonald RL: Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 31:144314512011

14

Farooq MUNaravetla BMoore PWMajid AGupta RKassab MY: Role of sildenafil in neurological disorders. Clin Neuropharmacol 31:3533622008

15

Fathi ARBakhtian KDPluta RM: The role of nitric oxide donors in treating cerebral vasospasm after subarachnoid hemorrhage. Acta Neurochir Suppl 110:93972011

16

Feng LFitzsimmons BFYoung WLBerman MFLin EAagaard BD: Intraarterially administered verapamil as adjunct therapy for cerebral vasospasm: safety and 2-year experience. AJNR Am J Neuroradiol 23:128412902002

17

Fergusen SMacdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:6586672007

18

Fox KMThadani UMa PTNash SDKeating ZCzorniak MA: Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J 24:220622122003

19

Friebe AKoesling D: Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93:961052003

20

Friedrich BMüller FFeiler SSchöller KPlesnila N: Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab 32:4474552012

21

Friedrich VFlores RMuller ASehba FA: Escape of intra-luminal platelets into brain parenchyma after subarachnoid hemorrhage. Neuroscience 165:9689752010

22

Friedrich VFlores RMuller ASehba FA: Luminal platelet aggregates in functional deficits in parenchymal vessels after subarachnoid hemorrhage. Brain Res 1354:1791872010

23

Frontera JAClaassen JSchmidt JMWartenberg KETemes RConnolly ES Jr: Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery 59:21272006

24

Galiè NGhofrani HATorbicki ABarst RJRubin LJBadesch D: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:214821572005

25

García-Cardoso JVela RMahillo EMateos-Cáceres PJModrego JMacaya C: Increased cyclic guanosine monophosphate production and endothelial nitric oxide synthase level in mononuclear cells from sildenafil citrate-treated patients with erectile dysfunction. Int J Impot Res 22:68762010

26

Gebska MAStevenson BKHemnes ARBivalacqua TJHaile AHesketh GG: Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity. Cardiovasc Res 90:3533632011

27

Ghofrani HAOsterloh IHGrimminger F: Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:6897022006

28

Gokce CGulsen SYilmaz CGuven GCaner HAltinors N: The effect of the sildenafil citrate on cerebral vasospasm and apoptosis following experimental subarachnoid hemorrhage in rats. J Neurosurg Sci 54:29372010

29

Gruber ARoessler KGeorgopoulos AMissbichler ABonelli RRichling B: Evaluation of big endothelin-1 concentrations in serum and ventricular cerebrospinal fluid after early surgical compared with nonsurgical management of ruptured intracranial aneurysms. Neurosurg Focus 8:5e62000

30

Gudmundsdóttir IJMcRobbie SJRobinson SDNewby DEMegson IL: Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. Biochem Biophys Res Commun 337:3823852005

31

Gul SBahadir BHanci VBektas SCan MKalayci M: Effect of vardenafil on cerebral vasospasm following experimental subarachnoid hemorrhage in rats. J Clin Neurosci 17:103810412010

32

Han BHVellimana AKZhou MLMilner EZipfel GJ: Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage. Neurosurgery 70:1781872012

33

Hop JWRinkel GJAlgra Avan Gijn J: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:6606641997

34

Inoha SInamura TIkezaki KNakamizo AAmano TFukui M: Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model. Neurol Res 24:6076122002

35

Jackson GBenjamin NJackson NAllen MJ: Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 83:5A13C20C1999

36

Juvela S: Plasma endothelin and big endothelin concentrations and serum endothelin-converting enzyme activity following aneurysmal subarachnoid hemorrhage. J Neurosurg 97:128712932002

37

Juvela S: Plasma endothelin concentrations after aneurysmal subarachnoid hemorrhage. J Neurosurg 92:3904002000

38

Kasuya HWeir BKANakane MPollock JSJohns LMarton LS: Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage. J Neurosurg 82:2502551995

39

Kasuya HWeir BKAWhite DMStefansson K: Mechanism of oxyhemoglobin-induced release of endothelin-1 from cultured vascular endothelial cells and smooth-muscle cells. J Neurosurg 79:8928981993

40

Kim PSchini VBSundt TM JrVanhoutte PM: Reduced production of cGMP underlies the loss of endothelium-dependent relaxations in the canine basilar artery after subarachnoid hemorrhage. Circ Res 70:2482561992

41

Kloner RAZusman RM: Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 84:5B11N17N1999

42

Koktekir EErdem YAkif Bayar MGokcek CKaratay MKilic C: A new approach to the treatment of cerebral vasospasm: the angiographic effects of tadalafil on experimental vasospasm. Acta Neurochir (Wien) 152:4634692010

43

Komotar RJZacharia BEOtten MLMocco JLavine SD: Controversies in the endovascular management of cerebral vasospasm after intracranial aneurysm rupture and future directions for therapeutic approaches. Neurosurgery 62:8979072008

44

Konstantinopoulos AGiannitsas KAthanasopoulos ASpathas DPerimenis P: The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction. Expert Opin Pharmacother 10:1551602009

45

Lewis GDWitzke CColon-Hernandez PGuerrero JLBloch KDSemigran MJ: Sildenafil improves coronary artery patency in a canine model of platelet-mediated cyclic coronary occlusion after thrombolysis. J Am Coll Cardiol 47:147114772006

46

Macdonald RL: Clazosentan: an endothelin receptor antagonist for treatment of vasospasm after subarachnoid hemorrhage. Expert Opin Investig Drugs 17:176117672008

47

Macdonald RL: Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44582014

48

Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CON-SCIOUS-2). Lancet Neurol 10:6186252011

49

Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:146314692012

50

Macdonald RLHigashida RTKeller EMayer SAMolyneux ARaabe A: Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care 13:4164242010

51

Macdonald RLKassell NFMayer SRuefenacht DSchmiedek PWeidauer S: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:301530212008

52

Macdonald RLPluta RMZhang JH: Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:2562632007

53

Mascia LFedorko LStewart DJMohamed FterBrugge KRanieri VM: Temporal relationship between endothelin-1 concentrations and cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Stroke 32:118511902001

54

Milburn JMMoran CJCross DT IIIDiringer MNPilgram TKDacey RG Jr: Increase in diameters of vasospastic intracranial arteries by intraarterial papaverine administration. J Neurosurg 88:38421998

55

Mrozek SDumurgier JCiterio GMebazaa AGeeraerts T: Biomarkers and acute brain injuries: interest and limits. Crit Care 18:2202014

56

Mukherjee KKSingh SKKhosla VKMohindra SSalunke P: Safety and efficacy of sildenafil citrate in reversal of cerebral vasospasm: A feasibility study. Surg Neurol Int 3:32012

57

Ohman JServo AHeiskanen O: Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery. J Neurosurg 74:8131991

58

Pluta RM: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 104:1391472008

59

Pluta RMOldfield EHBoock RJ: Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. J Neurosurg 87:7467511997

60

Proietti MAversa ALetizia CRossi CMenghi GBruzziches R: Erectile dysfunction in systemic sclerosis: effects of longterm inhibition of phosphodiesterase type-5 on erectile function and plasma endothelin-1 levels. J Rheumatol 34:171217172007

61

Rabinstein AAFriedman JAWeigand SDMcClelland RLFulgham JRManno EM: Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 35:186218662004

62

Rehse KScheffler HReitner N: Interaction of Viagra with the NO donors molsidomine and RE 2047 with regard to antithrombotic and blood pressure lowering activities. Arch Pharm (Weinheim) 332:1821841999

63

Romano JGRabinstein AAArheart KLNathan SCampo-Bustillo IKoch S: Microemboli in aneurysmal subarachnoid hemorrhage. J Neuroimaging 18:3964012008

64

Rosano GMAversa AVitale CFabbri AFini MSpera G: Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 47:2142222005

65

Rossi RNuzzo ALattanzi ACoppi FModena MG: Sildenafil improves endothelial function in patients with pulmonary hypertension. Pulm Pharmacol Ther 21:1721772008

66

Sahara MSata MMorita TNakajima THirata YNagai R: A phosphodiesterase-5 inhibitor vardenafil enhances angiogenesis through a protein kinase G-dependent hypoxia-inducible factor-1/vascular endothelial growth factor pathway. Arterioscler Thromb Vasc Biol 30:131513242010

67

Sastry BKNarasimhan CReddy NKRaju BS: Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 43:114911532004

68

Schmidt UHan RODiSalvo TGGuerrero JLGold HKZapol WM: Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition. J Am Coll Cardiol 37:198119882001

69

Sehba FAFriedrich V JrMakonnen GBederson JB: Acute cerebral vascular injury after subarachnoid hemorrhage and its prevention by administration of a nitric oxide donor. J Neurosurg 106:3213292007

70

Sehba FAMostafa GFriedrich V JrBederson JB: Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg 102:109411002005

71

Sobey CG: Cerebrovascular dysfunction after subarachnoid haemorrhage: novel mechanisms and directions for therapy. Clin Exp Pharmacol Physiol 28:9269292001

72

Sobey CGFaraci FM: Subarachnoid haemorrhage: what happens to the cerebral arteries?. Clin Exp Pharmacol Physiol 25:8678761998

73

Sobey CGQuan L: Impaired cerebral vasodilator responses to NO and PDE V inhibition after subarachnoid hemorrhage. Am J Physiol 277:H1718H17241999

74

Suarez JITarr RWSelman WR: Aneurysmal subarachnoid hemorrhage. N Engl J Med 354:3873962006

75

Thampatty BPSherwood PRGallek MJCrago EARen DHricik AJ: Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia. Neurocrit Care 15:19272011

76

Thomas JERosenwasser RH: Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intra-ventricular sodium nitroprusside in humans. Neurosurgery 44:48581999

77

Vellimana AKMilner EAzad TDHarries MDZhou MLGidday JM: Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhageinduced cerebral vasospasm. Stroke 42:7767822011

78

Vergouwen MDVermeulen Mvan Gijn JRinkel GJWijdicks EFMuizelaar JP: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:239123952010

79

Vergouwen MDIAlgra ARinkel GJE: Endothelin receptor antagonists for aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke 43:267126762012

80

Wallis RMCorbin JDFrancis SHEllis P: Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 83:5A3C12C1999

81

Webb DJFreestone SAllen MJMuirhead GJ: Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol 83:5A21C28C1999

82

Weyer GWNolan CPMacdonald RL: Evidence-based cerebral vasospasm management. Neurosurg Focus 21:3E82006

83

Wilson LSElbatarny HSCrawley SWBennett BMMaurice DH: Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions. Proc Natl Acad Sci USA 105:13650136552008

84

Wolf EWBanerjee ASoble-Smith JDohan FC JrWhite RPRobertson JT: Reversal of cerebral vasospasm using an intrathecally administered nitric oxide donor. J Neurosurg 89:2792881998

85

Yatsushige HCalvert JWCahill JZhang JH: Limited role of inducible nitric oxide synthase in blood-brain barrier function after experimental subarachnoid hemorrhage. J Neurotrauma 23:187418822006

86

Yeung PKShen JChung SSChung SK: Targeted overexpression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage. BMC Neurosci 14:1312013

87

Zhang LZhang RLWang YZhang CZhang ZGMeng H: Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 36:8478522005

88

Zhang LZhang ZZhang RLCui YLaPointe MCSilver B: Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke. Brain Res 1118:1921982006

89

Zhang RWang LZhang LChen JZhu ZZhang Z: Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 92:3083132003

90

Zusman RMMorales AGlasser DBOsterloh IH: Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 83:5A35C44C1999

91

Zusman RMPrisant LMBrown MJ: Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. J Hypertens 18:186518692000

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 690 690 119
PDF Downloads 861 861 652
EPUB Downloads 0 0 0

PubMed

Google Scholar