Pharmacological properties of endothelin receptor subtypes mediating positive inotropic effects in rabbit heart

Kasai, Hisataka; Takanashi, Masahiro; Takasaki, Chikahisa; Endoh, Masao

doi:10.1152/ajpheart.1994.266.6.h2220

Cited by 30 publications

(29 citation statements)

References 12 publications

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“…The most pronounced positive inotropic effect is observed in rabbit ventricular myocardium among the species examined; and ET-1, ET-2, and ET-3 exert the effect with an identical efficacy and potency (70). While the positive inotropic effect of ET-3 (73), and ET-1 at lower concentrations (<10 −8 M) (72), is susceptible to ET A -receptor antagonists, the ET A -receptor antagonists are unable to shift the main portion of the concentration-response curve for ET-1 in rabbit papillary muscle (72,76,81). The potent ET A -receptor antagonist TAK-044 can inhibit the positive inotropic effect of ET-1 in the rabbit, but a concentration one hundred times higher than that which inhibits the ET-3-induced response is required (83).…”

Section: -4 Etmentioning

confidence: 90%

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Endoh

2006

J Pharmacol Sci

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Abstract. The experimental procedures to simultaneously detect contractile activity and Ca 2+transients by means of the Ca 2+ sensitive bioluminescent protein aequorin in multicellular preparations, and the fluorescent dye indo-1 in single myocytes, provide powerful tools to differentiate the regulatory mechanisms of intrinsic and external inotropic interventions in intact cardiac muscle. The regulatory process of cardiac excitation-contraction coupling is classified into three categories; upstream (Ca 2+ mobilization), central (Ca 2+ binding to troponin C), and / or downstream (thin filament regulation of troponin C property or crossbridge cycling and crossbridge cycling activity itself) mechanisms. While a marked increase in contractile activity by the Frank-Starling mechanism is associated with only a small alteration in Ca 2+ transients (downstream mechanism), the force-frequency relationship is primarily due to a frequencydependent increase of Ca 2+ transients (upstream mechanism) in mammalian ventricular myocardium. The characteristics of regulation induced by β-and α-adrenoceptor stimulation are very different between the two mechanisms: the former is associated with a pronounced facilitation of an upstream mechanism, whereas the latter is primarily due to modulation of central and / or downstream mechanisms. α-Adrenoceptor-mediated contractile regulation is mimicked by endothelin ET A -and angiotensin II AT 1 -receptor stimulation. Acidosis markedly suppresses the regulation induced by Ca 2+ mobilizers, but certain Ca 2+ sensitizers are able to induce the positive inotropic effect with central and / or downstream mechanisms even under pathophysiological conditions.

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Section: -4 Etmentioning

confidence: 90%

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Endoh

2006

J Pharmacol Sci

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“…29,30 Endothelin isopeptides elicit a PIE in association with a moderate increase in Ca 2+ transients and an increase in myofilament Ca 2+ sensitivity in most mammalian ventricular and atrial muscle, but not in dog ventricular myocardium. 19,29 In rabbit ventricular myocardium, the PIE of ET-1 is most pronounced among mammalian species examined, mediated mainly by atypical ETA receptors, 31 and is associated with stimulation of phosphoinositide hydrolysis. 32,33 Pharmacological analysis implies that the signaling pathways of the PIE and Ca 2+ sensitization induced by ET-1 involve activation of PKC and tyrosine kinase, 34 the NCX, 35 and Na + /H + exchanger.…”

Section: Endothelin Isopeptidesmentioning

confidence: 99%

Cardiac Ca2+ Signaling and Ca2+ Sensitizers

Endoh

2008

Circ J

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he heart is able to adjust its pump function to immediately meet the demand of vital organs in the body by increasing cardiac output several fold by means of increases in cardiac contractility and heart rate. Cardiac myocytes constitute a pseudo-syncytium, follow the all-ornone law, and all of them contribute to the maintenance of stroke volume. Therefore, under physiological conditions, alteration of the contractility of individual cardiac myocytes is directly reflected in cardiac pump function.Two of the most important intrinsic characteristics of the contractile regulation of cardiac myocytes are the FrankStarling mechanism and the positive force -frequency relationship. The Frank-Starling mechanism represents the basic cardiac contractility as a length -tension relationship ex vivo and left ventricular (LV) function curve in vivo, in which stretching of myocytes to an optimal length immediately increases the contractile force with little alteration of [Ca 2+ ]i, preceding to a stretch-induced slowly developing increase in contractile force associated with an increase in [Ca 2+ ]i mobilization. The positive force -frequency relationship induced by elevated heart rate increases ventricular contractility by a marked facilitation of [Ca 2+ ]i mobilization, resulting in an increase in stroke volume. 1 In addition to the intrinsic regulatory mechanisms characteristic of cardiac myocytes, numerous external regulatory mechanisms, including receptor activation induced by Circulation Journal Vol.72, December 2008neurotransmitters released by autonomic nerve stimulation, hormones, autacoids and cytokines, contribute to the adaptation of the cardiac pump. 2 In the operation of all of these multiple mechanisms, cardiac Ca 2+ signaling plays a key role in contractile regulation.In 1978, Allen and Blinks developed an experimental procedure for detecting [Ca 2+ ]i simultaneously with contractile activity by applying the Ca 2+ -sensitive bioluminescent protein aequorin to intact cardiac muscle. 3 Since then, it has been directly demonstrated by the use of aequorin and other fluorescent dyes such as fura-2, indo-1, and fluo-3 that Ca 2+ ions play a central role in the regulation of cardiac excitation -contraction (E-C) coupling in the intact myocardium or single cardiac myocytes.Although cardiac contractile regulation is essentially achieved by dynamic modulation of [Ca 2+ ]i mobilization (upstream mechanism), it has been proved that the process subsequent to elevation of [Ca 2+ ]i (central and downstream mechanism) is also an important target of cardiotonic agents and the contractile modulation induced by physiological and pathological interventions on the heart. In the early 1980s there was a strong movement toward the development of cardiotonic agents that act by novel mechanisms to replace the conventional cardiotonic agents, such as digitalis and catecholamines, that were used to treat the cardiac contractile dysfunction in congestive heart failure (CHF). 1,2 Those agents elicit a positive inotropic effect (PIE) by i...

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“…An increased ET A receptor could contribute increased right ventricular contractility. 33 Both pathways could have contributed to maintained right ventriculoarterial coupling, as was assessed by the Ees/Ea ratio.…”

Section: ј-Agtctggcttatatccaacacttcg-3јmentioning

confidence: 99%

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

et al. 2003

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Background-The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. Methods and Results-Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET B receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET A receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. Conclusions-Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan. (Circulation. 2003;107:1329-1335.)

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Pharmacological properties of endothelin receptor subtypes mediating positive inotropic effects in rabbit heart

Cited by 30 publications

References 12 publications

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Cardiac Ca2+ Signaling and Ca2+ Sensitizers

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

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