Alterations in endothelium-dependent responsiveness of the canine basilar artery after subarachnoid hemorrhage

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✓ To investigate the alteration of endothelium-dependent responses in chronic vasospasm after subarachnoid hemorrhage (SAH), experiments were carried out in the double-hemorrhage canine model. After the presence of vasospasm was confirmed by cerebral angiography on Days 0 and 7, pharmacological studies on the basilar artery were conducted in vitro on Day 8. In the SAH group, endothelium-dependent relaxation was abolished in response to arginine vasopressin and was significantly reduced in response to thrombin. Endothelium-independent relaxation in the SAH group was preserved in response to papaverine and was minimally reduced in response to sodium nitroprusside. Endothelium-dependent contraction in response to arachidonic acid, acetylcholine, the calcium ionophore A23187, adenosine diphosphate, mechanical stretching, and hypoxia persisted in the SAH group. The maximal contraction to KCl and uridine triphosphate, which is endothelium-independent, was diminished in the SAH group, but no changes in sensitivity were noted in the concentration-response relationships. A significant correlation was observed between the degree of vasospasm determined angiographically and the loss of endothelium-dependent relaxation. The loss of endothelium-dependent relaxation and the persistence of endothelium-dependent contraction suggest that the deterioration in the endothelium-dependent responses may be an important component in the pathogenesis of cerebral vasospasm.

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Address reprint requests to: Paul M. Vanhoutte, M.D., Ph.D., Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota 55905.

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    Concentration-response curve of arginine vasopressin in canine basilar arteries with and without endothelium. The arterial rings were first contracted with the individual 50% effective dose (ED50) of uridine triphosphate (UTP). The relaxations are expressed as a percentage of the maximal response to papaverine. In the control groups, concentration-dependent relaxations were observed in rings with endothelium but not in those without. The relaxation was abolished in the subarachnoid hemorrhage (SAH) group (p < 0.0025) at vasopressin doses of 10−9, 10−8, and 10−7 M. The rings without endothelium from the SAH group reacted with a statistically significant increase in tension (p < 0.01) at vasopressin doses of 10−9 and 10−7 M. Values shown are mean ± standard error of the mean for 16 specimens, two rings from each of eight animals.

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    Relationship between the responses to arginine vasopressin and the angiographically determined vasospasm. Responses to arginine vasopressin in the rings with endothelium (abscissa) and the ratio of the cross-sectional area of the artery measured on Day 7 to that on Day 0 (ordinate) are plotted for each animal. A significant correlation (p < 0.05, Spearman's rank correlation test) was observed only in the eight dogs in the subarachnoid hemorrhage group (filled circles), but not in the eight dogs in the control group (open circles).

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    Responses of the canine basilar arteries (with and without endothelium) to thrombin. The rings were contracted with the 50% effective dose (ED50) of uridine triphosphate (UTP). Relaxation is expressed as a percentage of the maximal response to papaverine. In the control groups, thrombin caused transient but concentration-dependent relaxation in arterial rings with endothelium, but not in those without. In the subarachnoid hemorrhage (SAH) group, the endothelium-dependent relaxation was significantly less (p < 0.005) at thrombin doses of 0.01, 0.1, and 10 µ/ml. Values shown are the mean ± standard error of the mean for eight animals.

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    Concentration-response curve in rings of canine basilar artery without endothelium. Data shown are the mean ± standard error of the mean for eight animals. The rings were contracted with the 50% effective dose (ED50) of uridine triphosphate (UTP), and the relaxation is expressed as a percentage of the maximal response to papaverine (3 × 10−4 M). Left: Results for sodium nitroprusside. The relaxation was slightly but significantly reduced in the subarachnoid hemorrhage (SAH) group (p < 0.025) at doses of 10−8, 10−7, 10−6, and 10−5 M. Right: Results for papaverine. No significant difference was observed between the SAH and control groups.

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    Concentration-response curve of acetylcholine in quiescent rings of basilar arteries from the control (circles) and subarachnoid hemorrhage (SAH, squares) groups. Contractions are expressed as a percentage of the maximal response to uridine triphosphate (UTP). In both groups, acetylcholine caused concentration-dependent contractions only in rings with endothelium. Data shown are the mean ± standard error of the mean for eight animals.

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    Summary of the endothelium-dependent contractions elicited by adenosine diphosphate (ADP, 10−4 M), arachidonic acid (AA, 10−5 M), and the calcium ionophore A23187 (10−6 M). The maximal response for each agent is shown. Contractions are expressed as a percentage of the maximal response to uridine triphosphate (UTP). In the control group, the contractions were observed only in rings with endothelium. The endothelium-dependent contractions were maintained in the subarachnoid hemorrhage (SAH) group. In the control group, relaxation was elicited in rings without endothelium; conversely, the SAH group maintained arterial contraction (p < 0.05). Data shown are the mean ± standard error of the mean for eight animals.

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    Responses of the basilar arteries to hypoxia. In rings with endothelium (W), changing the gas mixture from 95% O2/5% CO2 to 95% N2/5% CO2 caused contractions, which were not observed in rings without endothelium (W/O). The contractions were maintained in the subarachnoid hemorrhage (SAH) group. Data shown are the mean ± standard error of the mean for eight animals.

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    Isometric tension recording in two rings of the same basilar artery of a dog in the subarachnoid hemorrhage group. In rings with endothelium (upper trace), rapid stretching to the optimal length of the ring caused subsequent spontaneous contraction, whereas in rings without endothelium (lower trace) the tension continually declined. The tension required to reach optimal length by the passive stretching (t1) and the peak tension of the contractile response (t2) were measured. The ratio t2/t1 was used to express the amplitude of the contractile responses (see Fig. 9). In rings without endothelium, where the contractile responses were not observed, t2 was measured as the tension at the same time point at which the peak contraction was obtained in the paired ring with endothelium.

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    Responses to mechanical stretching in the control and in the subarachnoid hemorrhage (SAH) groups, in rings with (W) and without (W/O) endothelium. The contractile responses are expressed as the ratio of t1 and t2 (see Fig. 8). Data shown are the mean ± standard error of the mean for eight animals. No significant difference in the endothelium-dependent contractions was observed between the two groups.

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    Responses to serotonin (5-hydroxytryptamine) in arterial rings without endothelium obtained from the control (circles) and the subarachnoid hemorrhage (SAH, squares) groups. The response is expressed as a percentage of the maximal contraction to uridine triphosphate. In the control group, the contraction was followed by relaxation at higher concentrations; this was statistically significantly diminished in the SAH group (p < 0.025) at serotonin doses of 10−5 and 10−4 M). Data shown are the mean ± standard error of the mean for eight animals.

References

  • 1.

    Altiere JRKiritsy-Roy JACatravas JD: Acetylcholine-induced contractions in isolated rabbit pulmonary arteries: role of thromboxane A2. J Pharmacol Exp Ther 236:5355411986Altiere JR Kiritsy-Roy JA Catravas JD: Acetylcholine-induced contractions in isolated rabbit pulmonary arteries: role of thromboxane A2. J Pharmacol Exp Ther 236:535–541 1986

  • 2.

    Barry KJScott RM: Effect of intravenous ethanol on cerebral vasospasm produced by subarachnoid blood. Stroke 10:5355371979Barry KJ Scott RM: Effect of intravenous ethanol on cerebral vasospasm produced by subarachnoid blood. Stroke 10:535–537 1979

  • 3.

    Fein JMFlor WJCohan SLet al: Sequential changes of vascular ultrastructure in experimental cerebral vasospasm. Myonecrosis of subarachnoid arteries. J Neurosurg 41:49581974Fein JM Flor WJ Cohan SL et al: Sequential changes of vascular ultrastructure in experimental cerebral vasospasm. Myonecrosis of subarachnoid arteries. J Neurosurg 41:49–58 1974

  • 4.

    Furchgott RF: Role of endothelium in responses of vascular smooth muscle. Circ Res 53:5575731983Furchgott RF: Role of endothelium in responses of vascular smooth muscle. Circ Res 53:557–573 1983

  • 5.

    Furchgott RF: Studies on relaxation of rabbit aorta by sodium nitrite. The basis for the proposal that the acid-activable inhibitory factor from bovine retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide in Vanhoutte PM (ed): Vasodilatation. New York: Raven Press (In press1988)Furchgott RF: Studies on relaxation of rabbit aorta by sodium nitrite. The basis for the proposal that the acid-activable inhibitory factor from bovine retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide in Vanhoutte PM (ed): Vasodilatation. New York: Raven Press (In press 1988)

  • 6.

    Furchgott RFZawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:3733761980Furchgott RF Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376 1980

  • 7.

    Gibson QHRoughton FJW: The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol (Lond) 136:5075261957Gibson QH Roughton FJW: The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol (Lond) 136:507–526 1957

  • 8.

    Grady PABlaumanis ORNelson ER: Morphology and flow dynamics of focal arterial constriction in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins1980 pp 107112Grady PA Blaumanis OR Nelson ER: Morphology and flow dynamics of focal arterial constriction in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins 1980 pp 107–112

  • 9.

    Griffith TMEdwards DHLewis MJet al: The nature of endothelium-derived vascular relaxant factor. Nature 308:6456471984Griffith TM Edwards DH Lewis MJ et al: The nature of endothelium-derived vascular relaxant factor. Nature 308:645–647 1984

  • 10.

    Holzmann S: Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips. J Cyclic Nucleotide Res 8:4094191982Holzmann S: Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips. J Cyclic Nucleotide Res 8:409–419 1982

  • 11.

    Hughes JTSchianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:5155251978Hughes JT Schianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:515–525 1978

  • 12.

    Ignarro LJByrns REWood KS: Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical in Vanhoutte PM (ed): Vasodilatation. New York: Raven Press (In press1988)Ignarro LJ Byrns RE Wood KS: Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical in Vanhoutte PM (ed): Vasodilatation. New York: Raven Press (In press 1988)

  • 13.

    Katsuki SArnold WPMurad Fet al: Effects of sodium nitroprusside, nitroglycerin, and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues. J Cyclic Nucleotide Res 3:2392471977Katsuki S Arnold WP Murad F et al: Effects of sodium nitroprusside nitroglycerin and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues. J Cyclic Nucleotide Res 3:239–247 1977

  • 14.

    Katusic ZSShepherd JTVanhoutte PM: Calcium ionophore A23187, arachidonic acid and acetylcholine cause endothelium-dependent contractions in the canine basilar arteries. Fed Proc 46:8291987 (Abstract)Katusic ZS Shepherd JT Vanhoutte PM: Calcium ionophore A23187 arachidonic acid and acetylcholine cause endothelium-dependent contractions in the canine basilar arteries. Fed Proc 46:829 1987 (Abstract)

  • 15.

    Katusic ZSShepherd JTVanhoutte PM: Endothelium-dependent contraction to stretch in canine basilar arteries. Am J Physiol 252:H671H6731987Katusic ZS Shepherd JT Vanhoutte PM: Endothelium-dependent contraction to stretch in canine basilar arteries. Am J Physiol 252:H671–H673 1987

  • 16.

    Katusic ZSShepherd JTVanhoutte PM: Vasopressin causes endothelium-dependent relaxations of the canine basilar artery. Circ Res 55:5755791984Katusic ZS Shepherd JT Vanhoutte PM: Vasopressin causes endothelium-dependent relaxations of the canine basilar artery. Circ Res 55:575–579 1984

  • 17.

    Katusic ZSVanhoutte PM: Anoxic contractions in isolated canine cerebral arteries. Contribution of endothelium-derived factors, metabolites of arachidonic acid, and calcium entry. J Cardiovasc Pharm 8 (Suppl 8):S97S1011986Katusic ZS Vanhoutte PM: Anoxic contractions in isolated canine cerebral arteries. Contribution of endothelium-derived factors metabolites of arachidonic acid and calcium entry. J Cardiovasc Pharm 8 (Suppl 8):S97–S101 1986

  • 18.

    Liszczak TMVarsos VGBlack PMet al: Cerebral arterial constriction after experimental subarachnoid hemorrhage is associated with blood components within the arterial wall. J Neurosurg 58:18261983Liszczak TM Varsos VG Black PM et al: Cerebral arterial constriction after experimental subarachnoid hemorrhage is associated with blood components within the arterial wall. J Neurosurg 58:18–26 1983

  • 19.

    Martin WVillani GMJothianandan Det al: Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:7087161985Martin W Villani GM Jothianandan D et al: Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:708–716 1985

  • 20.

    Nakagomi TKassell NFSasaki Tet al: Impairment of endothelium-dependent vasodilatation induced by acetylcholine and adenosine triphosphate following experimental subarachnoid hemorrhage. Stroke 18:4824891987Nakagomi T Kassell NF Sasaki T et al: Impairment of endothelium-dependent vasodilatation induced by acetylcholine and adenosine triphosphate following experimental subarachnoid hemorrhage. Stroke 18:482–489 1987

  • 21.

    Ohta TKajikawa HFunatsu Net al: Cerebral vasospasm and its relaxation responses to vasodilators: pathological study of severe prolonged vasospasm in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins1980 pp 132138Ohta T Kajikawa H Funatsu N et al: Cerebral vasospasm and its relaxation responses to vasodilators: pathological study of severe prolonged vasospasm in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins 1980 pp 132–138

  • 22.

    Owen RMDewey JDBove AA: Evaluation of dimensions and steady-state hydraulic properties of coronary arteries. Biomed Sci Instrum 19:43521983Owen RM Dewey JD Bove AA: Evaluation of dimensions and steady-state hydraulic properties of coronary arteries. Biomed Sci Instrum 19:43–52 1983

  • 23.

    Palmer RMJFerrige AGMoncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:5245261987Palmer RMJ Ferrige AG Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526 1987

  • 24.

    Peerless SJKassell NFKomatsu Ket al: Cerebral vasospasm: acute proliferative vasculopathy? II. Morphology in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins1980 pp 8896Peerless SJ Kassell NF Komatsu K et al: Cerebral vasospasm: acute proliferative vasculopathy? II. Morphology in Wilkins RH (ed): Cerebral Arterial Spasm. Baltimore: Williams & Wilkins 1980 pp 88–96

  • 25.

    Peterson JWBun TZervas NT: Plasma-borne vasoactivity and modulation by the endothelium as determinants of cerebrovascular tone: possible role during cerebral vasospasm in Powers WJRaichle ME (eds): Cerebrovascular Diseases. Fifteenth Research (Princeton) Conference. New York: Raven Press1987 pp 187200Peterson JW Bun T Zervas NT: Plasma-borne vasoactivity and modulation by the endothelium as determinants of cerebrovascular tone: possible role during cerebral vasospasm in Powers WJ Raichle ME (eds): Cerebrovascular Diseases. Fifteenth Research (Princeton) Conference. New York: Raven Press 1987 pp 187–200

  • 26.

    Rapoport RMDraznin MBMurab F: Mechanisms of adenosine triphosphate-, thrombin-, and trypsin-induced relaxation of rat thoracic aorta. Circ Res 55:4684791984Rapoport RM Draznin MB Murab F: Mechanisms of adenosine triphosphate- thrombin- and trypsin-induced relaxation of rat thoracic aorta. Circ Res 55:468–479 1984

  • 27.

    Reidy MA: A reassessment of endothelial injury and arterial lesion formation. Lab Invest 53:5135201985Reidy MA: A reassessment of endothelial injury and arterial lesion formation. Lab Invest 53:513–520 1985

  • 28.

    Rubanyi GMLorenz RRVanhoutte PM: Bioassay of endothelium-derived factor(s): inactivation by catecholamines. Am J Physiol 249:H95H1011985Rubanyi GM Lorenz RR Vanhoutte PM: Bioassay of endothelium-derived factor(s): inactivation by catecholamines. Am J Physiol 249:H95–H101 1985

  • 29.

    Sasaki TKassell NFYamashita Met al: Barrier disruption in the major cerebral arteries following experimental subarachnoid hemorrhage. J Neurosurg 63:4334401985Sasaki T Kassell NF Yamashita M et al: Barrier disruption in the major cerebral arteries following experimental subarachnoid hemorrhage. J Neurosurg 63:433–440 1985

  • 30.

    Schwartz SMBenditt EP: Aortic endothelial cell replication. I. Effects of age and hypertension in the rat. Circ Res 41:2482551977Schwartz SM Benditt EP: Aortic endothelial cell replication. I. Effects of age and hypertension in the rat. Circ Res 41:248–255 1977

  • 31.

    Shimokawa HAarhus LLVanhoutte PM: Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res 61:2562701987Shimokawa H Aarhus LL Vanhoutte PM: Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res 61:256–270 1987

  • 32.

    Tanabe YSakata KYamada Het al: Cerebral vasospasm and ultrastructural changes in cerebral arterial wall. An experimental study. J Neurosurg 49:2292381978Tanabe Y Sakata K Yamada H et al: Cerebral vasospasm and ultrastructural changes in cerebral arterial wall. An experimental study. J Neurosurg 49:229–238 1978

  • 33.

    Vanhoutte PMRubanyi GMMiller VMet al: Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol 48:3073201986Vanhoutte PM Rubanyi GM Miller VM et al: Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol 48:307–320 1986

  • 34.

    Varsos VGLiszczak TMHan DHet al: Delayed cerebral vasospasm is not reversible by aminophylline, nife-dipine, or papaverine in a “two-hemorrhage” canine model. J Neurosurg 58:11171983Varsos VG Liszczak TM Han DH et al: Delayed cerebral vasospasm is not reversible by aminophylline nife-dipine or papaverine in a “two-hemorrhage” canine model. J Neurosurg 58:11–17 1983

  • 35.

    White RPShirasawa YRobertson JT: Comparison of responses elicited by alpha-thrombin in isolated canine basilar, coronary, mesenteric, and renal arteries. Blood Vessels 21:12221984White RP Shirasawa Y Robertson JT: Comparison of responses elicited by alpha-thrombin in isolated canine basilar coronary mesenteric and renal arteries. Blood Vessels 21:12–22 1984

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