Signal Transduction and Ca2+ Signaling in Intact Myocardium

Abstract

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.

Preload-induced changes in isometric tension and [Ca2+]i in rat myocardium

“…In contrast, no preload-dependent changes in Ca 2+ transient amplitude have been shown in ferret [22], rat [18,23] and human myocardium [24] while marked increase of peak isometric force was observed in all the cases. The relative invariance of Ca 2+ transient amplitude during the action of forcelength relation was interpreted as a "downstream" mechanism in regulation of force generation and calcium handling in myocardium [25].…”

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Diversity in the Excitation–Contraction Mechanisms of the Heart

“…The sympathetic nervous system is the major accelerator of myocardial function, which increases myocardial contractile force through β-adrenoceptor-mediated activation of adenylate cyclase in most animal species (19). The inotropic sensitivity to the sympathetic neurotransmitter noradrenaline is known to be affected by various factors.…”

“…α-Adrenoceptors are present in the myocardium and their stimulation results in no or weak positive inotropy through mechanisms different from those of β-adrenoceptor stimulation (19). Sustained positive inotropy is observed in the rabbit, guinea pig, and rat ventricle, but in the guinea pig and rat, a transient decrease in contractile force is observed before the increase.…”

“…In the ventricular myocardium, the parasympathetic neurotransmitter acetylcholine is generally considered to show no inotropy under basal conditions and negative inotropy after elevation of adenylate cyclase activity by adrenoceptor stimulation (19). In some cases, direct negative inotropy by muscarinic receptor stimulation has been reported in ventricles from the ferret, rat, dog, and hatched chick.…”

Role of Inositol-1,4,5-Trisphosphate Receptor in the Regulation of Calcium Transients in Neonatal Rat Ventricular Myocytes

“…In the physiological context, an internal Ca 2+ signal is derived either from the internal stores, from the extracellular space, or both. There are multiple different plasma-membrane channels that control Ca 2+ influx in response to various stimuli, while the release of Ca itself, or by multiple Ca 2+ effectors such as ryanodine receptors (RyRs) and IP 3 Rs (1,3,4,6). Ca 2+ transients are believed to be caused primarily by the cardiac action potential that induces brief pulses of Ca 2+ entry, and consequently activation of RyRs and mobilization of internal stored Ca 2+ (1,4).…”