Inotropic response of rabbit ventricular myocytes to endothelin-1: difference from isolated papillary muscles

Talukder, Milton; Norota, Ikuo; Sakurai, Kiyoharu; Endoh, Masao

doi:10.1152/ajpheart.2001.281.2.h596

Cited by 28 publications

(26 citation statements)

References 31 publications

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“…ET-1, but not ET-3, shows much higher potency for induction of the positive inotropic effect in rabbit single ventricular myocytes than papillary muscles, the reason for which is currently unknown (81). The positive inotropic effect of ET-1 is associated with a moderate increase in L-type Ca 2+ current (78) and an increase in myofilament Ca 2+ sensitivity (77,81), the latter being susceptible to the inhibitors of the Na + / H + exchanger (80), PKC and tyrosine kinase (82).…”

Section: -4 Etmentioning

confidence: 91%

“…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: 99%

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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: 91%

Section: -4 Etmentioning

confidence: 99%

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Endoh

2006

J Pharmacol Sci

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“…In contrast, the concentrationdependence of the response to endothelin-1 (ET-1) shows a prominent difference according to the preparation: indo-1-loaded single myocytes are much more sensitive than aequorin-loaded ventricular myocardium, which indicates that the procedure for preparing single myocytes could increase the receptor affinity to ET-1. 8 These observations indicate that for analyses of inotropic effects of drugs in single myocytes, it is important to take the characteristics of the cardiotonic agent and the preparation into consideration.…”

Section: Methodsmentioning

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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“…These observations imply that the activations of both PKA induced by cAMP generated by weak β-adrenoceptor stimulation and PKC activated by diacylglycerol (DAG) produced by ET A -receptor stimulation are required for induction of the PIE (4). By contrast, in the rabbit ventricular myocardium, the PIE elicited by ET-1 alone is not susceptible to β-adrenoceptor-blocking agent, while likewise inhibitable with PKC inhibitor (1,8). The present results indicate that the mechanism of myofilament Ca 2+ sensitization induced by ET-1 is identical in that activation of MLCK may be involved in both species, which is susceptible to wortmannin at a concentration of 1 μM.…”

Section: Discussionmentioning

confidence: 47%

Wortmannin Inhibits the Increase in Myofilament Ca2+ Sensitivity Induced by Cross-Talk of Endothelin-1 With Norepinephrine in Canine Ventricular Myocardium

et al. 2009

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Abstract. Endothelin-1 (ET-1) modulates cardiac contractility by cross-talk with norepinephrine (NE) in canine ventricular myocardium. The present experiments were performed to investigate the influence of wortmannin that has inhibitory action on phosphatidylinositol 3-kinase (PI3-K) (IC 50 = 3 nM) and myosin light chain kinase (MLCK) (IC 50 = 200 nM) on Ca 2+ signaling and the inotropic effects of ET-1 induced by cross-talk with NE. Experiments were carried out in isolated canine ventricular trabeculae and indo-1 / AM-loaded single ventricular cardiomyocytes. ET-1 alone elicited a transient small negative inotropic effect (NIE). In the presence of NE at low (1 -10 nM) and high (100 nM) concentrations, ET-1 induced a long-lasting positive inotropic effect (PIE) or a marked sustained NIE, respectively. Wortmannin up to 300 nM did not affect the contractility; and at 1 μM and higher, it decreased the basal contraction without suppressing Ca 2+ transients. Wortmannin (1 μM) inhibited the long-lasting PIE of ET-1 without affecting the ET-1-induced increase in Ca 2+ transients. Wortmannin at the same concentration did not affect the ET-1-induced transient and sustained NIE and the PIE mediated by β-adrenoceptor stimulation. These results imply that wortmannin exerts selective inhibitory action on the increase in myofilament Ca 2+ sensitivity induced by cross-talk of ET-1 with NE probably through an inhibition of MLCK in canine ventricular myocardium.

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Inotropic response of rabbit ventricular myocytes to endothelin-1: difference from isolated papillary muscles

Cited by 28 publications

References 31 publications

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Signal Transduction and Ca2+ Signaling in Intact Myocardium

Cardiac Ca2+ Signaling and Ca2+ Sensitizers

Wortmannin Inhibits the Increase in Myofilament Ca2+ Sensitivity Induced by Cross-Talk of Endothelin-1 With Norepinephrine in Canine Ventricular Myocardium

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