Ryanodine: its alterations of cat papillary muscle contractile state and responsiveness to inotropic interventions and a suggested mechanism of action.

Cat right ventricular papillary muscles responded biphasically to cumulative additions of ryanodine. A progressive and pronounced negative inotropic effect was observed with low to intermediate ryanodine concentrations (5 nM-1 muM) while a rebound or reversal of these initial changes back toward pre-drug values was obtained as the ryanodine concentration was further increased to 100 muM. Active force development (DF), the rate of force development (dF/dt), as well as the rate of relaxation all exhibited these bidirectional changes. In contrast, time to peak force underwent only a progressive prolongation over the entire concentration range tested. This response pattern was observed with both normal and K+-depolarized (isoproterenol- or dibutyryl cAMP-restored) preparations. The response to a single addition of 100 muM ryanodine, in the presence of 2.5 mM Ca++ mimicked both the qualitative and quantitative aspects of the cumulative concentration response curve. In the presence of 5.0 mM Ca++ the high concentration of ryanodine no longer caused depression but instead caused only a slowly developing, monophasic increase in DF. Ryanodine also changed the response of ventricular muscle to other inotropic interventions. Ryanodine (1 muM; 2.5 mM Ca++) abolished the normal increase in dF/dt following either paired electrical stimulation (PES) or 50 mOsM mannitol, but not that 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 first (regular) to the second (premature) contraction, producing a summation-like waveform. Prior addition of the calcium channel antagonist D600 (1 muM) did not alter ryanodine-induced changes in PES. Caffeine (1 mM) produced alterations in the responses to PES and hyperosmolarity which were similar to those observed with ryanodine. In the presence of high concentrations of both ryanodine (100 muM) and calcium (5 mM) both the transient and steady-state responses to a doubling of the stimulation rate (0.2--0.4 Hz) were markedly depressed, whereas the decrease in DF or dF/dt normally accompanying a reduction in the rate of stimulation was attenuated. The data obtained in the present study are consistent with a functional inhibition of sarcoplasmic reticular calcium release by ryanodine.