Endothelin and Calcium Antagonists in the Skin Microcirculation of Patients With Coronary Artery Disease

Wenzel, René R.; Duthiers, Nadine; Noll, Georg; Bucher, Julia A.; Kaufmann, U; scher, T. F. L

doi:10.1161/01.cir.94.3.316

Cited by 53 publications

(39 citation statements)

References 57 publications

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“…146,147 This explains why ET-1-induced vasoconstriction is reversed by calcium channel blockers. [148][149][150][151] ET-1 rather acts in a paracrine than an endocrine mode of action, which is reflected by plasma levels of ET-1 in the picomolar range. 152,153 Infusion of an ET receptor antagonist into the brachial artery or systemically in healthy humans leads to vasodilation indicating a role of ET-1 in the maintenance of basal vascular tone.…”

Section: Endothelinmentioning

confidence: 99%

Working under pressure: the vascular endothelium in arterial hypertension

et al. 2000

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The vascular endothelium synthesizes and releases a spectrum of vasoactive substances like nitric oxide (NO) and endothelin (ET). In hypertension, the delicate balance of endothelium-derived factors is disturbed. ET acts as the natural counterpart to endothelium-derived NO, which exerts vasodilating, antithrombotic, and antiproliferative effects, and inhibits leukocyte-adhesion to the vascular wall. Besides its blood pressure rising effect also in man, ET induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, but also due to elevated blood pressure itself. Due to its position between blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both target and mediator of arterial hypertension. Oxi-

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Section: Endothelinmentioning

confidence: 99%

Working under pressure: the vascular endothelium in arterial hypertension

et al. 2000

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“…5,14 In the human forearm circulation, the drugs inhibit ET-induced vasoconstriction and have mild vasodilator effects. 15,16 In coronary artery disease, contractile ET B receptors on vascular smooth muscle cells are upregulated, [17][18][19] suggesting that combined ET A /ET B -receptor antagonists might be suited for this condition. Bosentan, an ET A /ET B antagonist, has been studied in animals and patients with congestive heart failure 20 ; it produced a marked vasodilation in both the peripheral and pulmonary circulation of these patients with very high plasma ET levels.…”

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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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“…With the DIT we could demonstrate for the first time in man under in-vivo conditions, that an ETA-selective endothelin antagonist induces vasodilatation; thus, there is a basal endothelin-induced vasoconstrictive tone in the skia microcirculation, which can be unmasked by an ETA-selective endothelin antagonist [16]. Under pathophysiological conditions, i. e. in patients with coronary artery disease, the endothelin receptor subtypes react differently when compared to an age-matched healthy control group (Figure 2) [15]. Indeed, a non-selective endothelin antagonist (ETA-/ETB-antagonist) induced higher vasodilatation when compared to an ETA-selective antagonist, indicating that under these pathophysiological conditions there is an important contribution of ETB-receptors to vasoconstriction induced by endogenous endothelin (Figure 2) [15].…”

Section: Studies Using the Ditmentioning

confidence: 91%

“…None of the above solutions induced changes in skin blood flow different to saline. However, absolute dilation to saline seems to decrease with age; this may be due to a decrease in the reactivity of the human skin to nociception and/or to atrophy of the skin with ageing [15].…”

Section: Studies Using the Ditmentioning

confidence: 99%

“…Under pathophysiological conditions, i. e. in patients with coronary artery disease, the endothelin receptor subtypes react differently when compared to an age-matched healthy control group (Figure 2) [15]. Indeed, a non-selective endothelin antagonist (ETA-/ETB-antagonist) induced higher vasodilatation when compared to an ETA-selective antagonist, indicating that under these pathophysiological conditions there is an important contribution of ETB-receptors to vasoconstriction induced by endogenous endothelin (Figure 2) [15]. Although the skin microcirculation may not represent the situation present in the coronary circulation, in-vitro experiments support our findings, as there is ah upregulation of ETB-receptors in coronary atherosclerotic plaques of patients with coronary artery disease [3].…”

Section: Studies Using the Ditmentioning

confidence: 99%

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Skin microcirculation in healthy subjects and patients with arteriosclerosis

Wenzel

Bruck

Baumgart

et al. 1999

Herz

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The concept to use the human skin microcirculation as a pharmacological in-vivo test system is old; however, methods developed in the 50s have been abandoned because of side effects and/or use of radioactive substances. We describe a newly developed minimally invasive method that allows in-vivo pharmacology in the human skin microcirculation injecting very low doses of a substance of drug without any systemic effects. The double injection technique (DIT) bears the potential to predict the effects of a drug and/or the vascular reactivity or dysfunction of other less accessible areas of the circulation (e.g. the myocardium). The DIT has been applied for studies in healthy volunteers and patients with atherosclerosis; the focus of interest was endothelial (dys-)function and the effect of exogenous vasoactive drugs. Using endothelin antagonists, we investigated the role of endogenous endothelin under physiological conditions and in atherosclerosis. The NO-synthase inhibitor L-NMMA has been applied to study the L-arginine-NO-pathway and the role of endothelial adrenoceptors. Ongoing studies with the DIT comparing coronary and skin microcirculation may help to develop minimally invasive methods to predict the effects of drugs and vascular function in the heart.

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Endothelin and Calcium Antagonists in the Skin Microcirculation of Patients With Coronary Artery Disease

Cited by 53 publications

References 57 publications

Working under pressure: the vascular endothelium in arterial hypertension

Working under pressure: the vascular endothelium in arterial hypertension

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

Skin microcirculation in healthy subjects and patients with arteriosclerosis

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