Intracellular mechanism of the negative inotropic effect induced by α1-adrenoceptor stimulation in mouse myocardium

Shuta Hirano, Yoichiro Kusakari, Jin O-Uchi, Satoshi Morimoto, Makoto Kawai, Kenichi Hongo, Satoshi Kurihara

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Alpha1-adrenoceptor stimulation (α1ARS) shows a positive inotropic effect in most mammalian myocardium. In mouse myocardium, however, α1ARS showed the negative inotropic effect, of which intracellular mechanisms are not fully clarified. The purpose of this study is to investigate the intracellular mechanism of the negative inotropic effect by α1ARS in C57BL/6 mouse myocardium. We used isolated ventricular papillary muscles of C57BL/6 strain mouse which is widely used for genetic manipulation. We simultaneously measured isometric tension and intracellular Ca2+ concentration ([Ca2+]i) using the aequorin method. In twitch contraction, phenylephrine concentration-dependently (1-100 μM) decreased tension without significant changes in the Ca2+ transient, and these effects were completely blocked by prazosin (3 μM) or calphostin C (a PKC inhibitor, 1 μM). Phorbol 12-myristate 13-acetate (PMA) (a PKC activator, 1 μM) decreased tension as observed in phenylephrine. After PMA application, the negative inotropic effect of phenylephrine disappeared. To estimate the Ca2+ sensitivity, tetanic contraction was produced, and the relation between [Ca2+]i and tension at a steady state was measured. Phenylephrine (10 μM) decreased the Ca2+ sensitivity, and PMA showed a similar Ca2+ desensitizing effect. These results suggest that the negative inotropic effect of phenylephrine in mouse myocardium can be explained by the decrease in the Ca2+ sensitivity through the activation of PKC. The present result indicates that the effect of α1ARS differs among species and strains of experiment animals. Thus, we should be careful about using the results of mouse myocardium to understand the functions of the human heart.

Original languageEnglish (US)
Pages (from-to)297-304
Number of pages8
JournalJournal of Physiological Sciences
Volume56
Issue number4
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

Keywords

  • Ca sensitivity
  • Mouse myocardium (C57BL/6 strain)
  • PKC
  • α-adrenoceptor stimulation

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