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Mechanisms of endothelin-1-induced decrease in contractility in adult mouse ventricular myocytes.

ABSTRACT: The potent vasoconstrictor polypeptide endothelin-1 (ET-1) plays an important pathophysiological role in progression of cardiovascular diseases and elicits prominent effects on myocardial contractility. Although ET-1 produces a positive inotropy in cardiac muscle of most mammalian species, it induces a sustained negative inotropy in mice. This study was performed to gain an insight into the cellular mechanisms underlying the negative inotropy in adult mouse ventricular myocytes.Cell shortening and Ca(2+) transients were simultaneously recorded from isolated mouse ventricular myocytes loaded with the Ca(2+)-sensitive fluorescent dye indo-1.ET-1 decreased cell shortening in a concentration-dependent manner (pD(2) value of 10.1). The ET-1-induced decrease in cell shortening was associated with a decrease in Ca(2+) transients. In addition, the Ca(2+) transient/cell-shortening relationship was shifted to the right by ET-1, indicating decreased myofilament Ca(2+) sensitivity. The instantaneous relationship of the rising phase of the Ca(2+) transient and cell shortening was shifted to the right by ET-1. Decreased Ca(2+) transients and cell shortening induced by ET-1 were markedly attenuated by the specific Na(+)/Ca(2+) exchange inhibitor SEA0400.ET-1-induced negative inotropy in mouse ventricular myocytes was mediated by decreased Ca(2+) transients and myofilament Ca(2+) sensitivity. These data are entirely consistent with the involvement of increased Ca(2+) extrusion via the Na(+)/Ca(2+) exchanger in the ET-1-mediated decrease in Ca(2+) transients. Decreased Ca(2+) sensitivity may be due to retardation of cell shortening in response to a rise in Ca(2+) transients.

SUBMITTER: Nishimaru K

PROVIDER: S-EPMC2050817 | biostudies-other | 2007 Oct

REPOSITORIES: biostudies-other

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Project description:RATIONALE:Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. OBJECTIVE:To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. METHODS AND RESULTS:Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. CONCLUSIONS:Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

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Mechanisms of endothelin-1-induced decrease in contractility in adult mouse ventricular myocytes.

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