Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

Donckier, Julian; Stoleru, L.; Hayashida, Wataru; Mechelen, Henri Van; Selvais, Philippe; Galanti, Laurence; Clozel, Jean‐Paul; Ketelslegers, Jean‐Marie; Pouleur, H.

doi:10.1161/01.cir.92.1.106

Cited by 45 publications

(24 citation statements)

References 36 publications

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“…Our results are in keeping with those of a previous study in experimental models of hypertension 19 demonstrating that nonselective antagonism of ET A and ET B receptors markedly lowers blood pressure in hypertensive animals but has only minor effect in healthy controls, thereby suggesting that the pressor activity of endothelin is upregulated in hypertension. In contrast, under physiological conditions, the peptide does not seem to modulate vasoconstriction.…”

Section: Discussionsupporting

confidence: 92%

Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension

et al. 1999

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Section: Discussionsupporting

confidence: 92%

Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension

et al. 1999

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“…The present study supports a role for endogenous ET-1 in the maintenance of vascular tone under basal physiological conditions as demonstrated by the lower SVR in normal conscious dogs after 2 days of oral ET A receptor antagonism. This study confirms and extends previous short-term investigations 6,18,19,20 by illustrating that chronic ET A receptor antagonism attenuates the progressive increase in SVR in this model of experimental CHF, thereby supporting the conclusion that endogenous ET-1, via the ET A receptor, contributes to the increase in SVR during CHF. An additional mechanism for the decrease in SVR with selective ET A blockade could involve enhanced release of endogenous vasodilatory substances released from the endothelium as a result of increases in plasma ET-1 and subsequent ET B activation.…”

Section: Discussionsupporting

confidence: 89%

Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

et al. 1998

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Abstract-Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET A and ET B , resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ET A antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (nϭ6) and a group that received an orally active ET A receptor antagonist (A-127722, Abbott Pharmaceuticals, 5mg/kg PO bid, nϭ6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET A receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET A receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET A receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET A receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET A receptor antagonism in CHF. (Hypertension. 1998;31:766-770.)

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“…Taken together with the rapid rate of increase in plasma IR endothelin, the effects are unlikely to be due to de novo synthesis, although the processing of stored precursors cannot be excluded. These data support other endothelin peptide measurements obtained following endothelin receptor antagonism in animals (Loffler et al, 1993;Donckier et al, 1995;Teerlink et al, 1995) and patients with chronic heart failure (Kiowski et al, 1995).…”

Section: Tak-044 Competed Biphasically For the Binding Of ['25i]-et-1supporting

confidence: 88%

“…dothelin receptor antagonism . However, plasma concentrations of IR endothelin are increased following non-selective endothelin receptor antagonism (Loffler et al, 1993;Donckier et al, 1995;Kiowski et al, 1995;Teerlink et al, 1995). Our aim was to determine whether the systemic infusion of the cyclic hexapeptide endothelin receptor antagonist Kikuchi et al, 1994) altered the concentrations of IR endothelin in human plasma.…”

Section: Introductionmentioning

confidence: 99%

The increase in human plasma immunoreactive endothelin but not big endothelin‐1 or its C‐terminal fragment induced by systemic administration of the endothelin antagonist TAK‐044

Plumpton

Ferro

Haynes

et al. 1996

British J Pharmacology

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1 We examined the effects of systemic infusion, in healthy human volunteers, of the endothelin antagonist TAK-044 on the plasma concentrations of mature endothelin, big endothelin-1 and the Cterminal fragment of big endothelin-1, by selective solid-phase extraction and specific radio- block > 95% of ETA but <5% ETB receptors) had no effect on the immunoreactive plasma concentrations of the three peptides. 4 At the higher dose of 750 mg TAK-044 (giving a serum concentration of 80 nM, calculated to block >99% of ETA and >75% ETB receptors), the immunoreactive plasma endothelin concentrations were increased 3.3 fold over basal levels (P<0.01). The concentrations of big endothelin-l or C-terminal fragment of big endothelin-1 were unchanged. 5 At both doses of TAK-044, there were significant decreases in diastolic blood pressure, and peripheral vascular resistance, with corresponding increases in cardiac index and stroke index. There were no changes in systolic or mean arterial blood pressures or heart rate. 6 Since only the concentrations of the mature peptide were increased, we conclude that the most likely sources of endothelin contributing to the observed rise were displacement of receptor-bound peptide and reduction in plasma clearance rather than peptide synthesis.

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Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

Cited by 45 publications

References 36 publications

Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension

Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension

Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

The increase in human plasma immunoreactive endothelin but not big endothelin‐1 or its C‐terminal fragment induced by systemic administration of the endothelin antagonist TAK‐044

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