The relation between the effects of veratridine on action potential and contraction in mammalian ventricular myocardium.

In the isolated papillary muscle of the guinea pig veratridine produces an increase of the force of contraction by increasing the rate of force development. Time to peak force is slightly reduced, whereas relaxation time is markedly prolonged. Threshold, half-maximally and maximally effective concentrations for the positive inotropic effect are 0.1, 0.4 and 1.6 muM, respectively. 2. The positive inotropic effect of the maximally effective concentration of veratridine amounts to 68% of the maximum positive inotropic effect of dihydro-ouabain tested on the same muscle (N = 12). 3. Veratridine prolongs the action potential (AP) by delaying repolarization. The effect is concentration-dependent (range: 0.4--3.2 muM); it requires 1--2 hrs of maintained exposure to reach a steady state and is only slowly reversible upon removal of the drug. A concentration causing a nearly maximal positive inotropic effect (0.8 muM) does not affect resting potential or rate of rise of the AP; the overshoot is slightly depressed. 4. Tetrodotoxin (5--16 muM) reversibly inhibits both AP prolongation and positive inotropic effect of veratridine by shifting the concentration-effect curves for these effects to higher concentrations of veratridine. It also prevents veratridine-induced spontaneous activity. 5. Dihydro-ouabain or reduction of [K]o below 5.9 mM augument the positive inotropic effect of veratridine, while the interaction between veratridine and noradrenaline is additive. 6. The positive inotropic effect of 1.6 muM veratridine declines progressively when the contraction frequency is reduced below 0.5 Hz; rested-state contractions (at 0.004 Hz) are not increased by 1.6 muM veratridine. 7. It is concluded that (a) veratridine delays repolarization by prolonging the Na permeability component which is mediated by the fast Na channels; (b) this specific sarcolemmal effect of veratridine is the sole cause for its positive inotropic action by effecting an increase of [Na]i which probably leads to a subsequent increase of Ca uptake.