Several new concepts have emerged in relation to mechanisms that contribute to regulation of the cerebral circulation. This review focuses on some physiological mechanisms of cerebral vasodilatation and alteration of these mechanisms by disease states. One mechanism involves release of vasoactive factors by the endothelium that affect underlying vascular muscle. These factors include endothelium-derived relaxing factor (nitric oxide), prostacyclin, and endothelium-derived hyperpolarizing factor(s). The normal vasodilator influence of endothelium is impaired by some disease states. Under pathophysiological conditions, endothelium may produce potent contracting factors such as endothelin. Another major mechanism of regulation of cerebral vascular tone relates to potassium channels. Activation of potassium channels appears to mediate relaxation of cerebral vessels to diverse stimuli including receptor-mediated agonists, intracellular second messenger, and hypoxia. Endothelial- and potassium channel-based mechanisms are related because several endothelium-derived factors produce relaxation by activation of potassium channels. The influence of potassium channels may be altered by disease states including chronic hypertension, subarachnoid hemorrhage, and diabetes.

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Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.0 Ϯ 0.2 M when monkeys were fed normal diet to 10.6 Ϯ 2.6 M when they were fed modified diet (mean Ϯ SE; P ϭ 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 Ϯ 9% in monkeys fed modified diet, compared with 14 Ϯ 11% in monkeys fed normal diet ( P ϭ 0.008). Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 Ϯ 15% in hyperhomocyst(e)inemic monkeys ( P ϭ 0.03). We conclude that diet-induced moderate hyperhomocyst ( IntroductionModerate elevation of plasma homocyst(e)ine 1 concentration is associated with stroke, peripheral vascular disease, and myocardial infarction (1). Like hypercholesterolemia, hyperhomocyst(e)inemia is caused by both genetic and dietary factors and may possibly contribute to vascular disease in a large number of patients (2). Unlike hypercholesterolemia, hyperhomocyst(e)inemia has not been demonstrated to be a sufficient stimulus for development of atherosclerosis per se, but it appears to predispose to complications and perhaps progression of atherosclerosis. Plasma homocyst(e)ine concentration can be decreased by dietary supplementation with folic acid, which suggests that hyperhomocyst(e)inemia may be a treatable risk factor for vascular disease (1, 2).Mechanisms responsible for the association between hyperhomocyst(e)inemia and vascular disease are poorly understood. Results of studies with cultured endothelial cells suggest that homocysteine may impair vasomotor regulatory and antithrombotic properties of vascular endothelium. Exposure of cultured endothelial cells to homocysteine impairs nitric oxide-mediated inhibition of platelet aggregation (3) and inhibits thrombomodulin-dependent activation of protein C, a clinically important anticoagulant (4, 5). Homocysteine also induces cultured endothelial cells to express procoagulant molecules (6, 7) and alters binding of tissue plasminogen activator to endothelium (8). These effects of homocysteine in tissue culture suggest that endothelial dy...

Objectives The aim of this study was to determine whether oxidative stress is increased in calcified, stenotic aortic valves and to examine mechanisms that might contribute to increased oxidative stress. Background Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear. Methods Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide (H2O2) (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve. Results In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions. Conclusions This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.