Inotropic Effects of Staurosporine, NA 0345 and H-7, Protein Kinase C Inhibitors, on Rabbit Ventricular Myocardium: Selective Inhibition of the Positive Inotropic Effect Mediated by .ALPHA.1-Adrenoceptors.
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概要
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The influence of protein kinase C (PKC) inhibitors, staurosporine, NA 0345 and H-7, on the α<SUB>1</SUB>- and β-adrenoceptor-mediated positive inotropic effect (PIE) was studied in rabbit ventricular myocardium. Staurosporine (1-10 nM), NA 0345 (10-100 nM) and H-7 (1-10 μM) selectively attenuated the PIE mediated by α<SUB>1</SUB>-adrenoceptors at concentrations that did not affect the β-mediated PIE and basal force of contraction. Staurosporine at higher concentrations (> 10 nM) decreased the basal force, while NA 0345 and H-7 did not. In membrane fractions derived from rabbit ventricular muscle, neither staurosporine, NA 0345 nor H-7 modified the specific [<SUP>3</SUP>H]prazosin binding at the concentrations that elicited the functional modulation. Accumulation of [<SUP>3</SUP>H]inositol monophosphate (IP<SUB>1</SUB>) induced by α<SUB>1</SUB>-adrenoceptor stimulation was not affected by the PKC inhibitors. Phorbol 12, 13-dibutyrate (PDBu), a PKC activator, also selectively attenuated the α<SUB>1</SUB>-mediated PIE, but in association with the inhibition of the α<SUB>1</SUB>-mediated IP, accumulation. Staurosporine (1 nM), but not H-7, antagonized the PDBu-induced inhibitory action on the a1-mediated PIE. These findings indicate that staurosporine, NA 0345 and H-7 produce a selective inhibition of the α<SUB>1</SUB>-mediated PIE, probably through inhibition of the α<SUB>1</SUB>-adrenoceptor-mediated activation of PKC. On the contrary, externally administered phorbol ester may act by uncoupling of α<SUB>1</SUB>-adrenoceptors to activation of phospholipase C through a pathway different from endogenous diacylglycerol to lead to a selective inhibition of the α<SUB>1</SUB>-mediated PIE.
- 公益社団法人 日本薬理学会の論文
著者
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Norota Ikuo
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine
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Endoh Masao
Department Of Cardiovascular Pharmacology Yamagata University School Of Medicine
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ENDOH Masao
Department of Pharmacology, Yamagata University School of Medicine
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Takanashi Masahiro
Department of Pharmacology, Yamagata University School of Medicine
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Kasai Hideo
Department of Pharmacology, Yamagata University School of Medicine
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