Positive chronotropic effect of Bay K 8644: participation of endogenous norepinephrine

The chronotropic effect of Bay K 8644, a dihydropyridine known to increase the slow inward current, was studied in spontaneously beating rat atria. Increases in atrial rate were concentration-dependent and the maximal increase (106 +/- 10 beats/min) was obtained at 3 x 10(-6) mol/l. Reserpine pretreatment, or propranolol 3 x 10(-7) mol/l, or propranolol plus prazosin 10(-6) mol/l decreased the maximum chronotropic effect of Bay K 8644 by about 60%. Blockade of the removal mechanisms of catecholamines (hydrocortisone 3 x 10(-5) mol/l plus cocaine 10(-5) mol/l) did not prevent the chronotropic effect of the compound. Exposure to Bay K 8644 increased the spontaneous outflow of tritium from atria preloaded with [3H]-norepinephrine by 30%. The results indicate that Bay K 8644 produces positive chronotropic effects through two mechanisms: a direct one and an indirect mechanism that involves the participation of norepinephrine released from sympathetic nerve endings.