Involvement of cyclic AMP in the direct inotropic action of amrinone. Biochemical and functional evidence.
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Biomedical subjects
Publications and source records attributed to M Reiter.
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1. The influence of (+)-propranolol, 10(-6) to 4 x 10(-5) mol/l, upon the positive inotropic effect of dihydro-ouabain was studied on guinea-pig papillary muscle. At 1 Hz, negative inotropically effective concentrations of (+)-propranolol decreased the inotropic effectiveness of the glycoside. 2. For equivalent diminution of the basal force of contraction, either by reduction of stimulation frequency or by increasing concentrations of (+)-propranolol, a similar decrease in the inotropic effectiveness of dihydro-ouabain was observed. In contract, reduction of [Ca2+]o had almost no effect on the effectiveness of the glycoside. 3. The inhibitory effect of (+)-propranolol on the inotropic effectiveness of dihydro-ouabain declined with reduction of stimulation frequency. At any stimulation frequency tested, the inhibitory effect of (+)-propranolol was proportional to the effect of a reduction of that particular frequency to the rested-state condition in the absence of (+)-propranolol. 4. The results are consistent with the hypothesis that the inhibition of the excitation-coupled sodium influx by (+)-propranolol is the cause of its inhibiting effect on the effectiveness of dihydro-ouabain.
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The action potential of guinea pig papillary muscle exposed to the ceveratrum alkaloid germitrine (2 mugM) is followed by a long-lasting after-depolarization (maximal amplitude, 8 mV; half-time of decay, 32 seconds; total duration, approximately 75 seconds). This after-depolarization interrupts the terminal phase of repolarization. During repetitive stimulation (0.1-1.0 Hz; 80 nM germitrine) the after-depolarizations that follow consecutive action potentials are summed, causing persistent depolarization of up to 10 mV. The after-depolarization is reversibly abolished by tetrodotoxin (TTX). Test contractions evoked at various times during or after the germitrine-induced after-depolarization reveal a phase during which the ability of the muscle to develop force is transiently increased. This positive inotropic influence reaches its maximum 1 minute after the conditioning stimulus and thereafter decays with a half-time 4.8 times longer than the half-time of decay of the after depolarization. It is reversibly abolished by TTX and augmented by dihydro-ouabain (DHO). We conclude: Germitrine induces an after-depolarization by prolonging dramatically the Na permeability component which is mediated by the fast Na channels and normally restricted to the first few milliseconds of the action potential. The germitrine-induced selective and persistent increase of sarcolemmal sodium permeability (PNA) causes a positive inotropic effect, probably because intracellularly accumulating Na ions exchange for extracellular Ca ions.
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