Pharmacological characteristics of the positive inotropic effect of angiotensin II in the rabbit ventricular myocardium.
1. In order to elucidate the mechanism underlying the positive inotropic effect (PIE) of angiotensin II (AII), we measured changes in phosphoinositide hydrolysis and contractile force induced by AII in the rabbit ventricular myocardium. 2. AII (1.0 nM-3 microM) produced a PIE in a concentration-dependent manner in the presence of bupranolol (0.3 microM) and prazosin (0.1 microM), the maximal response being about 40% of that to isoprenaline and the EC50 30 nM. 3. The PIE of AII was associated with a concentration-dependent increase in the total duration of contraction; the time to peak force and the relaxation time were prolonged. 4. AII (10 nM-30 microM) elicited an accumulation of [3H]-inositol monophosphate in a concentration-dependent manner in rabbit ventricular slices prelabelled with myo-[3H]-inositol. 5. The PIE and the accumulation of [3H]-inositol monophosphate induced by AII were inhibited by a non-selective AII receptor antagonist, saralasin (10 nM-1 microM) and by a selective AT1 receptor antagonist, losartan (10 nM-1 microM), but not a selective AT2 receptor antagonist, PD 123319 (1 microM). 6. A tumour-promoting phorbol ester, phorbol 12,13-dibutyrate (PDBu, 10-100 nM), inhibited the AII-induced PIE and [3H]-inositol monophosphate accumulation in a concentration-dependent manner. 7. These results suggest that AII exerts a PIE through activation of AT1 receptors and subsequent acceleration of phosphoinositide hydrolysis. Activation of protein kinase C by PDBu may inhibit the AII-induced stimulation of phosphoinositide hydrolysis and thereby the PIE of AII in the rabbit ventricular myocardium.
Ishihata
A
A
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Endoh
M
M
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002046:Bupranolol / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D012504:Saralasin / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D010716:Phosphatidylinositols; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D015240:Phorbol 12,13-Dibutyrate; D002046:Bupranolol; D012504:Saralasin; D019808:Losartan; D011224:Prazosin