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

α1-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. 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. H-7, 1-(5-isoquinoline sulphonyl)-2-methylpiperazine, a less specific inhibitor of protein kinase C than staurosporine, at a concentration of 100 μM inhibited both the transient NIE and the sustained PIE without affecting the transient PIE. 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. An amiloride analogue, 5-(N-methyl-N-isobutyl)amiloride (MIBA), inhibited only the sustained PIE with an IC50 of 0.3 μM which is approximately two orders of magnitude lower than amiloride. The receptor-linked stimulation of Na+/H+ exchange through protein kinase C activation may be a mechanism for α1-adrenoceptor-mediated sustained PIE.