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  • Author or Editor: Garnette R. Sutherland x
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Aaron S. Dumont, Fina Lovren, John H. McNeill, Garnette R. Sutherland, Christopher R. Triggle, Todd J. Anderson and Subodh Verma

Object. Cerebral revascularization with saphenous vein (SV) conduits is used in the management of hard-to-treat lesions that require deliberate arterial occlusion and in selected patients with occlusive vascular disease. Endothelial dysfunction is thought to contribute to acute perioperative vasospasm and chronic graft atherosclerosis. In the present study the authors examined the contribution of the potent vasoconstrictor endothelin-1 (ET-1) to endothelial dysfunction in human SVs.

Methods. The effects of an ETA/B receptor antagonist (bosentan), an ETA receptor antagonist (BQ-123), and an ETB receptor antagonist (BQ-788) on in vitro endothelium-dependent and -independent responses were studied in human SVs. Vascular segments were obtained in 34 patients who had undergone revascularization procedures, and isometric dose—response curves (DRCs) were constructed using the isolated tissue bath procedure as follows: 1) cumulative DRCs to norepinephrine; and 2) DRCs to acetylcholine (ACh) and sodium nitroprusside in the absence and presence of bosentan, BQ-123, or BQ-788. Maximal vasodilatory responses and sensitivity were compared between groups. In the presence of bosentan (Experiment 1) and BQ-123 or BQ-788 (Experiment 2), ACh responses were significantly augmented (percent maximum relaxation values: 7 ± 2 [control] compared with 17 ± 3 [bosentan], p < 0.002 [Experiment 1]; and 12 ± 2 [control] compared with 29 ± 2 [BQ-123] and 25 ± 2 [BQ-788], p < 0.003 and p < 0.002, respectively [Experiment 2]). The sensitivity of SVs to ACh was unaffected by treatment. These beneficial effects were specific for the endothelium.

Conclusions. Blockade of ET receptors significantly improves endothelial function in SVs. Furthermore, these effects appear to be independently and maximally mediated by antagonism of either ETA or ETB receptors. Interventions aimed at improving endothelial function may serve to counter perioperative vasospasm and impede atherosclerosis in SVs used for revascularization procedures.

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Aaron S. Dumont, M. Eric Hyndman, Randall J. Dumont, Paul M. Fedak, Neal F. Kassell, Garnette R. Sutherland and Subodh Verma

Object. Insulin resistance and hypertension are independent risk factors for stroke. Endothelial dysfunction in response to risk factors and carotid artery (CA) disease are important in the pathogenesis of stroke. Pravastatin may have cholesterol-independent pleiotropic effects. In the present study the authors examined the effects of short-course pravastatin treatment on endothelial function in CAs obtained in control and insulin-resistant rats with fructose-induced hypertension.

Methods. Thirty rats were divided into two experimental groups, in which 14 were fed a regular diet and 16 were fed a fructose-enriched diet for 3 weeks. The rats were then divided into four groups: control, pravastatin-treated control, fructose-fed, and pravastatin-treated fructose-fed. Pravastatin was administered (20 mg/kg/day) for 2 weeks. Excretion of the urinary nitric oxide (NO) metabolite nitrite (NO2 ) was also assayed. The CAs from all rats were subsequently removed and assessed for endothelium-dependent and -independent vascular reactivity in vitro. The rats in the fructose-fed group were insulin resistant, hyperinsulinemic, and hypertensive relative to the rats in the control and pravastatin-treated control groups and exhibited diminished endothelium-dependent vasomotion and urinary NO2 excretion (p < 0.05), with preserved endothelium-independent vasomotion. Strikingly, pravastatin treatment restored endothelium-dependent vasomotion and urinary NO2 excretion in rats in the fructose-fed pravastatin-treated relative to the fructose-fed group (p < 0.05).

Conclusions. The authors report, for the first time, that pravastatin restores endothelial function in CAs from insulin-resistant rats with fructose-induced hypertension. These beneficial effects were ascribed to direct, cholesterol-independent vascular effects of pravastatin and are likely the result of augmentation of NO production. These data provide impetus for further investigation of nonlipid-lowering indications for pravastatin therapy in the prevention and treatment of CA disease.