The effects of papaverine and verapamil were studied in spontaneously beating right atria of guinea pigs, rabbits and rats and on segments of sinoatrial node tissue from rabbits. Papaverine (10(-4)M) produced a significant negative chronotropic effect in guinea pigs and rats, with a lesser effect in rabbits. Papaverine antagonized the positive chronotropic response to transmural nerve stimulation (TNS) of the sinoatrial node of rabbit atria in a concentration-dependent manner. The chronotropic response to 5 X 10(-7)M norepinephrine was enhanced in the presence of 10(-6)M papaverine, but was noncompetitively antagonized at concentrations above 10(-5)M. The negative chronotropic response to TNS was unaltered by papaverine except at concentrations at or above 5 X 10(-5)M; however, the negative chronotropic response to 5 X 10(-6)M methacholine was not altered by 10(-4)M papaverine. A local anesthetic (lidocaine) inhibited both the positive and negative chronotropic TNS response at a concentration that had no effect on the response to exogenous norepinephrine. Verapamil (10(-7) to 10(-6)M) had no significant effect on either the positive or negative chronotropic response to TNS. The effects of papaverine on TNS are attributed to the influence of at least three actions: 1) phosphodiesterase inhibition, 2) local anesthetic activity and 3) physiological antagonism of norepinephrine. The effects of 2 X 10(-4)M papaverine on action potentials of rabbit sinoatrial node cells were studied. Papaverine decreased the maximum diastolic potential, increased the action potential overshoot and transformed the normal ramp configuration of slow diastolic depolarization into a concave shape.