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


METHODS
Cell shortening and Ca(2+) transients were simultaneously recorded from isolated mouse ventricular myocytes loaded with the Ca(2+)-sensitive fluorescent dye indo-1.


RESULTS
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.


CONCLUSIONS
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.
Nishimaru
K
K
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.
Miura
Y
Y
Endoh
M
M
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009529:Nicardipine / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D005456:Fluorescent Dyes; D007211:Indoles; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D009529:Nicardipine; C048960:indo-1; D002118:Calcium