Negative inotropic effects of angiotensin II, endothelin-1 and phenylephrine in indo-1 loaded adult mouse ventricular myocytes

• Published in: Life sciences (1973) 2002-01, Vol.70 (10), p.1173-1184
• Main Authors: Sakurai, Kiyoharu, Norota, Ikuo, Tanaka, Hisao, Kubota, Isao, Tomoike, Hitonobu, Endoh, Masao
• Format: Article
• Language: English
• Subjects: Alkaloids; Angiotensin II; Angiotensin II - pharmacology; Animals; Benzophenanthridines; Ca 2+ transient; Calcium - metabolism; Chelerythrine; Depression, Chemical; Endothelin-1; Endothelin-1 - pharmacology; In Vitro Techniques; Indo-1; Indoles - metabolism; Male; Mice; Mice, Inbred C57BL; Mouse ventricular myocytes; Myocardial Contraction - drug effects; Myocardium - cytology; Myocardium - metabolism; Phenanthridines - pharmacology; Phenylephrine; Phenylephrine - pharmacology; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; α-adrenoceptor
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(01)01497-7

Angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine are receptor agonists that share the signal transduction acting through acceleration of phosphoinositide hydrolysis in the heart. Because the regulation of myocardial contractility induced by these receptor agonists shows a wide range of species-dependent variation among experimental animals, we carried out experiments to elucidate the mechanism of contractile regulation induced by these agents in mice which are employed currently more as transgenic models. Effects of Ang II, ET-1 and phenylephrine on cell shortening and Ca 2+ transients were investigated in single ventricular myocytes loaded with indo-1/AM. Ang II (10 −8, 10 −7 M), ET-1 (10 −10, 10 −9 M) and phenylephrine (10 −6, 10 −5 M in the presence of the β-adrenoceptor antagonist timolol) decreased the cell shortening [Ang II: 58.4 ± 9.03 (n = 8), 50.3 ± 11.90% (n = 6); ET-1: 48.4 ± 8.27, 31.2 ± 6.45% (n = 5); phenylephrine: 45.7 ± 11.60, 28.7 ± 5.89% (n = 5)]. By contrast, the amplitude of Ca 2+ transients was not significantly influenced by these agonists. The selective protein kinase C inhibitor chelerythrine at 10 −6 M significantly inhibited the decrease in cell shortening induced by these receptor agonists. These results indicate that Ang II, ET-1 and phenylephrine elicit a negative inotropic effect with insignificant alteration of Ca 2+ transients, which may be mainly mediated by activation of protein kinase C in mouse ventricular cardiomyocytes.