Endothelial dysfunction: the common consequence in diabetes and hypertension.
ABSTRACT Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications in diabetes and hypertension. Diminished production and function of endothelium-derived nitric oxide and other vasoprotective factors and/or the exaggerated production of proinflammatory and vasoconstrictors such as angiotensin II, endothelin-1, reactive oxygen species, and cyclooxygenase-derived metabolites of arachidonic acid eventually lead to endothelial dysfunction, resulting in elevated vascular tone which contributes to hypertension, vascular, and cardiac remodeling, culminating in microvascular, macrovascular, and renal damages. Specific therapies targeting reactive oxygen species using antioxidants and inhibitors of the rennin-angiotensin system or increasing endothelial nitric oxide synthase activity might assist to reverse endothelial dysfunction and thus reduce the related cardiovascular morbidity and mortality in diabetes and hypertension.
- New England Journal of Medicine 07/2002; 346(25):1999-2001. · 51.66 Impact Factor
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ABSTRACT: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks' oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10(-7) mol/l) aortic rings as relaxation to acetylcholine (10(-10)-10(-4) mol/l) and sodium nitroprusside (10(-10)-10(-4) mol/l), respectively. Two weeks after clamping, SBP was significantly elevated (196 +/- 16 vs. 145 +/- 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 +/- 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 +/- 8 and 124 +/- 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 +/- 6 vs. 99 +/- 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 +/- 6%) and ramipril (94 +/- 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.Kidney and Blood Pressure Research 01/2006; 29(6):351-9. · 1.60 Impact Factor
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ABSTRACT: We studied the relationship among endothelial function, oxidative stress, and phenylephrine (PE; alpha(1)-adrenoceptor agonist)-induced contraction in mesenteric arteries from high-cholesterol (HC)-diet-fed mice. In HC mice (vs age-matched normal-diet-fed mice): (1) PE-induced contraction in endothelium-intact rings was enhanced (endothelial denudation increased contraction in "normal-diet" rings, but did not enhance it further in "HC" rings); (2) the enhanced PE-induced contraction was further enhanced in the presence of N(G)-nitro-L-arginine (L-NNA; nitric oxide synthase inhibitor) or L-NNA plus indomethacin (cyclooxygenase inhibitor) [to preserve endothelium-derived hyperpolarizing factor (EDHF)], but unchanged in the presence of charybdotoxin plus apamin (to block EDHF); (3) ACh-induced EDHF-type relaxation was reduced; and (4) oxidative stress [indicated by the plasma 8-isoprostane level (reliable systemic marker) and aortic superoxide production] was greater. In HC mice, PE-induced contraction was normalized by apocynin [NAD(P)H oxidase inhibitor] or tempol (superoxide dismutase mimetic), but enhanced by NADH [NAD(P)H oxidase substrate]. Oral dietary supplementation with apocynin (30 mg/kg/day for 4 weeks) corrected the above abnormalities. Hence: (1) PE-induced contraction is modulated by the endothelium, and the enhanced contractility in HC mice results from defective EDHF signaling and elevated oxidative stress, and (2) apocynin normalizes PE-induced contraction in HC mice by improving EDHF signaling.Free Radical Biology and Medicine 11/2006; 41(8):1289-303. · 5.27 Impact Factor