Effect of phentolamine, alprenolol and prenylamine on maximum rate of rise of action potential in guinea-pig papillary muscles

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Abstract
Effects of phentolamine (13.3, 26.5 and 53.0 μM), alprenolol (3.5, 7.0 and 17.5 μM) and prenylamine (2.4, 4.8 and 11.9 μM) on the transmembrane potential were studied in isolated guinea-pig papillary muscles, superfused with Tyrode's solution. Phentolamine, alprenolol and prenylamine reduced the maximum rate of rise of action potential (V max) dose-dependently. Higher concentrations of phentolamine and prenylamine caused a loss of plateau in a majority of the preparations. Resting potential was not altered by any of the drugs. Readmittance of drug-free Tyrode's solution reversed these changes induced by 13.3 μM of phentolamine and all conconcentrations of alprenolol almost completely but those induced by higher concentrations of phentolamine and all concentrations of prenylamine only slightly. V max at steady state was increased with decreasing driving frequencies (0.5 and 0.25 Hz) and was decreased with increasing ones (2–5 Hz) in comparison with that at 1 Hz. Such changes were all exaggerated by the above drugs, particularly by prenylamine. Prenylamine and, to a lesser degree, phentolamine and alprenolol delayed dose-dependently the recovery process of V max in premature responses. V max in the first response after interruption of stimulation recovered toward the predrug value in the presence of the above three drugs. The time constants of recovery process ranged between 10.5 and 15.0 s for phentolamine, between 4.5 and 15.5 s for alprenolol. The time constant of the main component was estimated to be approximately 2 s for the recovery process with prenylamine. On the basis of the model recently proposed by Hondeghem and Katzung (1977), it is suggested that the drug molecules associate with the open sodium channels and dissociate slowly from the closed channels and that the inactivation parameter in the drug-associated channels is shifted in the hyperpolarizing direction.

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