Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor.

Kiowski, Wolfgang; Lüscher, Thomas F.; Linder, Lilly; Bühler, Fritz R.

doi:10.1161/01.cir.83.2.469

Cited by 208 publications

(93 citation statements)

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“…These data are consistent with the observation that endothelin-1 induces a very small (Kiowski et al, 1991) or no vasodilatation (Clarke et al, 1989) in the human forearm and does not dilate human dorsal hand veins (Haynes & Webb, 1993). The nitric oxide synthesis inhibitor L-NMMA significantly increased the pD2 value of endothelin-l in arteries without affecting the maximum response.…”

Section: Discussionsupporting

confidence: 90%

“…Macmillan Press Ltd, 1994 Endothelin-1 causes potent contractions of human isolated arteries, veins (Luscher et al, 1990;McNamara et al, 1992;MacLean et al, 1992) and small resistance vessels (Watt et al, 1989;Schiffrin et al, 1992), constricts dorsal hand veins in vivo (Haynes & Webb, 1993), reduces forearm blood flow when infused directly into the brachial artery (Kiowski et al, 1991) and increases arterial pressure when infused systemically (Vierhapper et al, 1990). A small vasodilator effect of endothelin has been reported in one study in which endothelin was infused in the forearm (Kiowski et al, 1991) and the cyclo-oxygenase inhibitor, aspirin, enhanced the constrictor effect of endothelin in human hand veins in vivo (Haynes & Webb, 1993). However, the receptor subtypes mediating the responses to endothelins in the human cardiovascular system are not yet known, and the precise role of prostaglandins and nitric oxide in modifying contractions remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Endothelin receptors mediating functional responses in human small arteries and veins

Riezebos

Watts

Vallance

1994

British J Pharmacology

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1 In the present study, responses of human omental small arteries and veins to endothelin-1 and endothelin-3 were characterized by use of the ETB receptor selective agonist, sarafotoxin S6c, the ETA receptor antagonist, BQ123, the ETB receptor antagonist, IRL1038, the NO-synthase inhibitor NGmonomethyl-L-arginine (L-NMMA, 300ELM) and indomethacin (10I1M).2 Small arteries (internal diameter 413 ± 22 Am) and parallel running veins (646 ± 35 Am) were mounted in a myograph under a normalized tension equivalent to 90% of a transmural pressure of 100 mmHg and 19 mmHg in vivo, respectively. 3 In small arteries and veins, endothelin-1 caused a concentration-dependent increase in wall tension (E.. = 3.90 ± 0.56 mN mm-' and 1.90 m ± 0.32 mN mm-' respectively, P < 0.05) and was equipotent (arteries: pD2 = 8.91 ± 0.11; veins: pD2 = 8.63 ± 0.08, NS). In endothelium intact arteries, L-NMMA significantly enhanced the sensitivity to endothelin-1 (pD2 control: 8.92 ± 0.16; pD2 L-NMMA: 9.37 ± 0.11; P<0.05). L-NMMA did not affect the sensitivity of veins to endothelin-1. Indomethacin was without effect in arteries and veins. In veins, endothelin-3 was about a hundred times less potent than endothelin-l and showed a biphasic response curve. Small arteries did not contract to endothelin-3. Neither small arteries nor veins contracted to sarafotoxin S6c. Furthermore, no relaxation to endothelin-1 or sarafotoxin S6c was seen in any precontracted vessels. 4 BQ123 (0.03-3 3LM) produced a concentration-dependent rightward parallel displacement of the endothelin-l concentration-response curve in small arteries and veins yielding pA2 values of 7.09 and 7.48 respectively. The slope of the Schild plot in arteries and veins was 1.26 ± 0.24 (NS from unity) and 0.61 ± 0.13 (P <0.05 compared to unity) respectively. IRL1038 (3 JLM) did not affect the potency of endothelin-1 in arteries and veins. In veins, the low sensitivity component (pD2 = 7.16 ± 0.08) of the biphasic response curve to endothelin-3 was completely blocked by BQ123 (31JM), whereas the high sensitivity component (pD2 = 8.66 ± 0.08) was resistant to BQ123 (3 JiM) and IRL1038 (3 JAM).5 These results indicate that contractions of human small vessels to endothelin-l are predominantly mediated by ETA receptors and that nitric oxide modulates the response to endothelin-l in small arteries but not in veins. The different antagonistic potency of BQ123 against endothelin-l and the differential endothelin-1/endothelin-3 potency ratios in arteries and veins provide evidence for the hypothesis that ETA receptors in human small arteries are different from ETA receptors in human small veins. There is no evidence of contractions mediated by 'classical' ETB receptors in these vessels, but small veins appear to contain a functional non ETA/non ETB receptor with a high affinity for endothelin-3.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Endothelin receptors mediating functional responses in human small arteries and veins

Riezebos

Watts

Vallance

1994

British J Pharmacology

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“…Infusion of endothelin leads to transient vasodilation followed by long-lasting and profound vasoconstriction. i 11 -12 - 14 The role of endogenous endothelin in humans is unknown, but animal studies suggest that it may contribute to blood pressure regulation. 15 Similarly, although the role of endothelin in arterial hypertension is controversial, 22 -2832 but not in humans.…”

Section: Endothelin Receptor Antagonists Inhibit Endothelin In Human mentioning

confidence: 99%

Endothelin receptor antagonists inhibit endothelin in human skin microcirculation.

1994

Self Cite

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Endothelin is a potent vasoconstrictor peptide produced by endothelial cells, but its role in physiology and disease is uncertain. We investigated the influence of the endothelin-A-selective receptor antagonist PD 147953 and the nonselective endothelin receptor antagonist PD 145065 on the effects of endothelin-1 and endothelin-3 in the skin microcirculation of healthy volunteers, using laser Doppler flowmetry. A double injection model was developed, allowing simultaneous injection of two substances, ie, agonist and antagonist or saline. The injection of saline led to a well-defined vasodilation at the injection site (maximum increase, from 19±2 to 97±15 perfusion units at 6 minutes; P<.001; n=10). Endothelin-1 (10~1 2 mol) decreased blood flow (difference from saline control, -79±14 perfusion units; P<.001; n = l l ) within the injection wheal (diameter, 4 to 5 mm), while endothelin-3 had no effect. In the surrounding area (at 8 mm from the injection site), both endothelin-1 (+116±32 perfusion units; P<.001; n = l l ) and endothelin-3 (+59±16 perfusion units; P<.001; n = l l ) markedly increased blood flow. Both endothelin receptor antagonists slightly increased blood flow (maximum differ-E ndothelium-derived factors such as nitric oxide, prostacyclin, 1 and endothelin-1 2 -3 participate in the regulation of vascular tone. The receptors activated by endothelins are of the endothelin-A (ETA) or endothelin-B (ETB) type. 410 In smooth muscle cells both receptors can mediate vasoconstriction, while ETB receptors on endothelial cells cause vasodilation through the release of nitric oxide and prostacyclin. 1112ETA receptors have a high affinity to endothelin-1 and a lesser affinity to endothelin-3, whereas ETB receptors bind endothelin-1 and endothelin-3 equally well. The role of endothelins in physiology and disease is unclear. Infusion of endothelin leads to transient vasodilation followed by long-lasting and profound vasoconstriction. i 11 -12

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“…5,6 Infusion of ET causes transient vasodilation followed by profound and long-lasting vasoconstriction. 7 Elevated ET-1 levels occur in human atherosclerosis, pulmonary hypertension, and congestive heart failure. 8 -10 After acute myocardial infarction, plasma ET levels predict 1-year mortality.…”

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confidence: 99%

Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

et al. 1998

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Background-Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. Methods and Results-In a double-blind, placebo-controlled randomized study, we investigated the effects of the ET A /ET B endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (PϽ0.05), whereas heart rate increased slightly (PϽ0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (PϽ0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (PϽ0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. Conclusions-Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ET A /ET B endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease. (Circulation. 1998;98:2235-2240.)

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Endothelin-1-induced vasoconstriction in humans. Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor.

Cited by 208 publications

References 50 publications

Endothelin receptors mediating functional responses in human small arteries and veins

Endothelin receptors mediating functional responses in human small arteries and veins

Endothelin receptor antagonists inhibit endothelin in human skin microcirculation.

Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

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