Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. Loss of NO(.) associated with these traditional risk factors may in part explain why they predispose to atherosclerosis. Among many enzymatic systems that are capable of producing ROS, xanthine oxidase, NADH/NADPH oxidase, and uncoupled endothelial nitric oxide synthase have been extensively studied in vascular cells. As the role of these various enzyme sources of ROS become clear, it will perhaps be possible to use more specific therapies to prevent their production and ultimately correct endothelial dysfunction.

Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV) To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L) HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (147 +/- 020 nM/mg tissue/min, n = 7 vs 052 +/- 005 nmol/mg tissue/min, n = 8, P < 0001) Endothelial removal increased O2- production in NV (073 +/- 008, n = 6, P < 005), while decreasing it in HV (076 +/- 015, n = 5, P < 005) There was no difference between denuded HV and denuded NV Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels Oxypurinol did not alter relaxations to nitroprusside Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process

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Hypercholesterolemia increases endothelial superoxide anion production.

Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.

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The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener

Nitric oxide (an endothelium-derived relaxing factor) induces smooth muscle relaxation and is an important mediator in the regulation of vascular tone. Advanced glycosylation end products, the glucose-derived moieties that form nonenzymatically and accumulate on long-lived tissue proteins, have been implicated in many of the complications of diabetes and normal aging. We demonstrate that advanced glycosylation products quench nitric oxide activity in vitro and in vivo. Acceleration of the advanced glycosylation process in vivo results in a time-dependent impairment in endothelium-dependent relaxation. Inhibition of advanced glycosylation with aminoguanidine prevents nitric oxide quenching, and ameliorates the vasodilatory impairment. These results implicate advanced glycosylation products as important modulators of nitric oxide activity and endothelium-dependent relaxation.

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Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

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Endothelial dysfunction in diabetes

Attenuation of endothelium-dependent relaxation in aorta from diabetic rats

Experiments were designed to characterize endothelium-dependent relaxation in thoracic aortic rings obtained from streptozotocin-induced diabetic rats. When the degree of the peak relaxation was compared, the endothelium-dependent relaxant responses to acetylcholine, histamine, or ADP in precontracted aortic rings showed that there was no significant difference between diabetic and control vessels. However, the time courses appeared quite different. The endothelium-dependent relaxant responses in diabetic vessels were more transient than those in control vessels. In addition, the rapid fade of the endothelium-dependent responses observed in diabetic vessels was significantly suppressed by pretreatment with superoxide dismutase. Pretreatment with catalase, deferoxamine, allopurinol, or indomethacin did not prevent the rapid fade of the endothelium-dependent relaxation. The endothelium-independent relaxation induced by nitric oxide also faded more quickly in diabetic vessels; this impairment was less pronounced in the presence of superoxide dismutase. These results suggest that the transient nature of the endothelium-dependent relaxation is more marked in diabetic rat aorta as a result of an enhanced accumulation of superoxide anion.

Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta.

harm to tissues, even on the arterial side of the circulation. Care must obviously be taken to extrude all macroscopic air from the syringe before injection to avoid frank air embolization. Contrast echo has been used to validate the location of endocardium 3 and to detect any intracardiac shunting. Kronik et al4 reported the use of Valsalva maneuver during contrast echo to detect right-to-left interatrial shunting in patients with ASD. It is probably not possible to differentiate between the true ASDs with small right-to-left shunts using Valsalva maneuver contrast echo. The amount of echo contrast material crossing from right to left is not closely correlated with the magnitude of the shunt flow. Valsalva maneuver may not provoke shunting in all patients with PFO. The effect of Valsalva maneuver on atrial pressures has been well described. 5 As the subject inhales, venous return increases increasing right atrial pressure. During the strain phase of the Valsalva maneuver, intrathoracic pressures increase causing right atrial filling and pressure to decrease. As the Valsalva maneuver is released, blood rushes into the right atrium, transiently causing right atrial pressure to exceed left atrial pressure. This explains why the echocardiographic contrast shunt ing we observed occurred during release of the strain phase of the Valsalva maneuver. The use of Valsalva maneuver contrast echo may have clinical value in the evaluation of patients suspected of having paradoxical embolism. Although most frequently occurring in patients with cyanotic congenital heart disease, paradoxical embolization was described in association with a PFO as early as 1877. 6 Although the ability and safety of Valsalva maneuver contrast echo to diagnose paradoxical embolization has not been established, it appears to be a reasonable method for establishing the presence or absence of a functional intracardiac communication.

Digoxin-diltiazem interaction

To determine how diabetes alters vasocontractile responses to endothelin-1 (ET-1) and the thromboxane A2-mimetic U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F2alpha) and to explore the possible mechanisms of the altered responses, contractions produced by these agonists were examined in aortic rings from rats with 8- to 12-weeks streptozotocin-induced diabetes in comparison with those from age-matched control rats. ET-1 (> or = 1 nM) and U46619 (> or = 100 nM) induced significantly greater contractions in diabetic aorta. The enhanced contractile responses of diabetic aorta to these agonists were abolished in the presence of 1 microM nifedipine, resulting in no significant difference in the maximum responses between control and diabetic aortas. Pretreatment with 1 microM calphostin C or 20 nM staurosporine caused marked reductions in contractions induced by ET-1 and U46619 in both control and diabetic aortas, and the difference in the maximum contractile responses to these agonists between control and diabetic aortas were eliminated by their treatment. These results suggest that chronic diabetes enhances aortic contractions induced by ET-1 and U46619 and the enhanced contractions are possibly due to an increased Ca2+ influx through transmembrane Ca2+ channels resulting from increased protein kinase C-activated process.

Hisao Kawasaki

Papers

Attenuation of endothelium-dependent relaxation in aorta from diabetic rats

Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta.

Digoxin-diltiazem interaction

Increased contractile responses to endothelin-1 and U46619 via a protein kinase C-mediated nifedipine-sensitive pathway in diabetic rat aorta.

Attenuated contractile response of diabetic rat aorta to caffeine but not to noradrenaline in Ca2+-free medium