Endothelin-1-Induced Constriction Inhibits Nitric-Oxide-Mediated Dilation in Isolated Rat Resistance Arteries

Abstract

Vascular endothelial cells release dilatory compounds like nitric oxide and prostacyclin, as well as contractile factors like endothelin-1 (ET-1). We investigated the interaction of ET-1 with nitric-oxide-mediated dilation in cannulated pressurized (75 mm Hg) arterioles from rat cremaster muscle (180 ± 3 µm). Arterioles constricted spontaneously to 101 ± 3 µm, while ET-1 (0.4 nM)increased constriction to 78 ± 3 µm. Acetylcholine, an endothelium-dependent nitric-oxide-mediated vasodilator induced a dose-dependent dilation during spontaneous tone. After addition of ET-1, the response to acetylcholine was significantly impaired. Nitroprusside, an endothelium-independent nitric oxide donor, induced a dose-dependent dilation that was almost completely inhibited by ET-1. In contrast, 8-Br-cGMP-induced dilation was unaffected. Thus, ET-1 appears to inhibit nitric-oxide-mediated dilation at the level of cGMP formation or degradation. The effect of ET-1 appears to be specific for nitric oxide as responses to a prostacyclin analogue were impaired at low doses only. The inhibitory effect of ET-1 on nitric-oxide-mediated dilation could be mimicked with high potassium (65 ± 6 µm), but not with phenylephrine (74 ± 8 µm)-induced constriction. These data show a direct inhibitory effect of ET-1 on nitric-oxide-mediated dilation in isolated skeletal muscle arterioles.

Exogenous ghrelin improves blood flow distribution in pulmonary hypertension—assessed using synchrotron radiation microangiography

“…These results may suggest that ghrelin acts to maintain endothelium integritywhich could also help to prevent an over-expression of ET-1. The vasoactive effects of ET-1 and NO are reciprocally co-dependent such that, for example, the over-expression of ET-1 directly inhibits NO-mediated dilatation [3,17]. Although this study highlights the benefit of ghrelin in preventing the adverse changes in the pulmonary vasculature, recent evidence by the Cardillo research team has shown that ghrelin is able to reverse, or normalize, an impaired balance between NO and ET-1 in the systemic circulation of patients with metabolic syndrome.…”

Voluntary running exercise attenuates the progression of endothelial dysfunction and arterial calcification in ovariectomized rats

“…Moreover, eNOS protein was reduced and ET-1 levels were increased in the calcified aorta of OVX plus VDN rats, but these alterations were reversed by exercise training. Endothelin-1 downregulates eNOS protein in endothelial cells and isolated arteries (Bakker et al 1997, Potenza et al 2005, Ramzy et al 2006. Atkinson (1992) reported that calcification in the aorta of male rats with VDN treatment was detected on the extracellular surface area of elastic fibres.…”

“…Thus, NO and ET-1 play important roles in the regulation of vascular tone and homeostasis. Because ET-1 downregulates eNOS protein in endothelial cells and isolated arteries (Bakker et al 1997, Potenza et al 2005, Ramzy et al 2006, imbalance between NO and ET-1 may contribute to pathological endothelial dysfunction and calcification in aorta tissue. Because ET-1 downregulates eNOS protein in endothelial cells and isolated arteries (Bakker et al 1997, Potenza et al 2005, Ramzy et al 2006, imbalance between NO and ET-1 may contribute to pathological endothelial dysfunction and calcification in aorta tissue.…”

Brimonidine evokes heterogeneous vasomotor response of retinal arterioles: diminished nitric oxide-mediated vasodilation when size goes small

“…The prevailing inhibition of adrenergic ␣ 2 -mediated constriction in second-order arterioles under metabolic stress might help to alleviate the impact of brimonidine-induced constriction in small retinal arterioles and consequently facilitate flow distribution to the stressed tissues. On the other hand, because accumulating evidence suggests that endothelin-1 can either prevent ␣ 2 -AR-mediated NO release and vasodilation (4,32) or reduce smooth muscle sensitivity to NO (19), the enhanced endothelin-1 production during disease states, such as glaucoma (17,37,45), may compromise the vasodilatory effect of brimonidine. It is reasonable to speculate that the beneficial effect of brimonidine, in terms of vasodilation and flow enhancement, may be dependent on the local concentration of brimonidine, distribution and function of ␣ 2 -AR, endothelial NO synthase activity, endothelin-1 level, and the local metabolic environment.…”