RYANODINE - ITS ALTERATIONS OF CAT PAPILLARY-MUSCLE CONTRACTILE STATE AND RESPONSIVENESS TO INOTROPIC INTERVENTIONS AND A SUGGESTED MECHANISM OF ACTION

Abstract

Cat right ventricular papillary muscles responded biphasically to cumulative additions of ryanodine, an insecticide. A progressive and pronounced negative inotropic effect was seen with low to intermediate ryanodine concentrations (5 nM-1 .mu.M); a rebound or reversal of these initial changes back toward pre-drug values was obtained as the ryanodine concentration was further increased to 100 .mu.M. Active force development (DF), the rate of force development (dF/dt) and the rate of relaxation all exhibited bidirectional changes. Time to peak force underwent only a progressive prolongation over the entire concentration range tested. This response pattern was seen with both normal and K+-depolarized (isoproterenol- or dibutyryl c[cyclic]AMP-restored) preparations. The response to a single addition of 100 .mu.M ryanodine, in the presence of 2.5 mM Ca2+ mimicked both the qualitative and quantitative aspects of the cumulative concentration response curve. In the presence of 5.0 mM Ca2+ the high concentration of ryanodine no longer caused depression but caused only a slowly developing, monophasic increase in DF. Ryanodine changed the response of ventricular muscle to other inotropic interventions. Ryanodine (1 .mu.M; 2.5 mM Ca2+) abolished the normal increase in dF/dt following paired electrical stimulation (PES) or 50 mOsM mannitol but not in response to a doubling of the stimulation rate (0.2-0.4 Hz). After ryanodine exposure, the potentiation of developed force by PES was shifted from the 1st (regular) to the 2nd (premature) contraction, producing a summation-like wave-form. Prior addition of the Ca channel antagonist D600 (.alpha.-isopropyl-.alpha.-[N-methyl-N-homoveratryl-.gamma.-aminopropyl]-3,4,5-trimethoxyphenylacetonitrile, 1 .mu.M) did not alter ryanodine-induced changes in PES. Caffeine (1 mM) alterred the responses to PES and hyperosmolarity similar to those seen with ryanodine. In the presence of high concentrations of both ryanodine (100 .mu.M) and Ca (5 mM) the transient and steady-state responses to a doubling of the stimulation rate (0.2-0.4 Hz) were markedly depressed; the decrease in DF or dF/dt normally accompanying a reduction in the rate of stimulation was attenuated. A functional inhibition of sarcoplasmic reticular Ca release by ryanodine is suggested.