TMB-8 as a pharmacologic tool in guinea pig myocardial tissues. I. Effects of TMB-8 on force of contraction and on action potential parameters in atrial and papillary muscles.

The compound 8-)N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) had been introduced as an intracellular Ca++ antagonist. We have studied the effects of TMB-8 on electrical and mechanical activity of isolated cardiac tissues in order to estimate its spectrum of action in heart muscle. In spontaneously beating right atria of the guinea pig, TMB-8 (1-100 microM) had a negative chronotropic effect. In left atria, TMB-8 (1-100 microM) induced a frequency-dependent biphasic inotropic effect: A transient increase in force of contraction was followed by a sustained decrease; the latter could be antagonized partially by an increase in Ca++]o. TMB-8 prolonged the time-to-peak force. At high concentrations of TMB-8 (greater than 10 microM), the electrical stimulation threshold was elevated. TMB-8 (20 microM) competitively inhibited the positive inotropic effect of Bay K 8644 and reduced the magnitude of the positive inotropic and/or chronotropic effects of veratridine, (-)-isoproterenol, forskolin, histamine and (-)-phenylephrine. TMB-8 (30 microM) prolonged the action potential duration (APD) in particular at 90% of repolarization (APD90)] and the refractory period, and decreased the AP amplitude and Vmax. In right ventricular papillary muscles, TMB-8 (30 microM) shortened the APD (APD20 = APD50 greater than APD90) and the refractory period but hardly affected the AP amplitude and Vmax. The resting membrane potential remained unchanged in both tissues. These findings suggest that in addition to interference with the Ca++ release from the sarcoplasmic reticulum, TMB-8 also affects the membrane conductances for cations.