Effects of inhibitors of protein kinase C and Na+/H+ exchange on alpha 1-adrenoceptor-mediated inotropic responses in the rat left ventricular papillary muscle.
1. Alpha 1-adrenoceptor stimulation of rat left ventricular papillary muscle produced a triphasic inotropic response: an initial transient positive inotropic effect (PIE) followed by a transient negative inotropic effect (NIE) and a sustained PIE. 2. The protein kinase C inhibitor, staurosporine, at concentrations ranging from 30 nM to 100 nM inhibited the sustained PIE, but had no significant effect on the transient PIE and NIE. 3. H-7, 1-(5-isoquinoline sulphonyl)-2-methylpiperazine, a less specific inhibitor of protein kinase C than staurosporine, at a concentration of 100 microM inhibited both the transient NIE and the sustained PIE without affecting the transient PIE. 4. Amiloride, an inhibitor of Na+/H+ exchange, at concentrations ranging from 0.1 mM to 1 mM inhibited the sustained PIE and, at higher concentrations, also inhibited the transient NIE. 5. An amiloride analogue, 5-(N-methyl-N-isobutyl)amiloride (MIBA), inhibited only the sustained PIE with an IC50 of 0.3 microM which is approximately two orders of magnitude lower than amiloride. 6. The receptor-linked stimulation of Na+/H+ exchange through protein kinase C activation may be a mechanism for alpha 1-adrenoceptor-mediated sustained PIE.
Otani
H
H
Department of Pharmacology, Kansai Medical University, Osaka, Japan.
Otani
H
H
Uriu
T
T
Hara
M
M
Inoue
M
M
Omori
K
K
Cragoe
E J
EJ
Inagaki
C
C
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006352:Heart Ventricles / Q000187:drug effects; D006859:Hydrogen / Q000378:metabolism*; D066298:In Vitro Techniques; D007474:Ion Exchange; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D019311:Staurosporine
D000470:Alkaloids; D007546:Isoquinolines; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D000584:Amiloride; D006859:Hydrogen; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C056369:5-(N-methyl-N-isobutyl)amiloride; D012964:Sodium; D011493:Protein Kinase C; D019311:Staurosporine; D011224:Prazosin