Analysis of the Inotropic Mechanism of Enoximone in Guinea Pig Ventricular Muscle

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Abstract
Force and action potentials were recorded in guinea pig papillary muscles. The peak force was 131.8 .+-. 3.3% of control at 2 .mu.M and 144.4 .+-. 2.0% at 4 .mu.M enoximone. Enoximone (2 .mu.M) increased the rate of rise of force (131.0 .+-. 4.9%) and time from peak to half-relaxation (106 .+-. 1.1%). The time to peak twitch force shortened (96.7 .+-. 0.6%). The action potential duration decreased at 2 .mu.M (96.4 .+-. 1.2%) and 4 .mu.M (92.8 .+-. 1.4%) enoximone. The action potential amplitude was 106.7 .+-. 0.8% in 2 .mu.M and 112.6 .+-. 0.6% in 4 .mu.M enoximone. The peak twitch force in response to a test stimulus given after varied intervals (i.e., mechanical restitution) was increased at all test intervals, whereas the time to full restitution was not affected any any concentration. The force in response to the preceding test interval (postextrasystolic potentiation) was also increased. Maximum potentiation was 11.9 .+-. 3.0 mN/mm2 in controls, 15.9 .+-. 3.3 mN/mm2 in 2 .mu.M enoximone, and 17.02 .+-. 3.2 mN/mm2 in 4 .mu.M enoximone. During the decay of postextrasystolic potentiation, there was a linear relationship between the peak force of the postpotentaited contraction and peak force of the potentiated contraction. The slope of the line increased from 0.34 to 0.43 (n = 12, p < 0.001) by enoximone (2 .mu.M). The results suggest that enoximone exerts its positive inotropic effect by (a) increasing calcium inflow during the action potential and/or (b) reducing calcium outflow, thereby increasing the recirculation of activator calcium.