The calcium entry blocking, beta 1-adrenoceptor blocking and hypotensive effects of YM-16151-4 were studied in pithed rats and in conscious normotensive rats. In pithed rats, intravenous injection of YM-16151-4 inhibited a YC-170-induced pressor response and an isoproterenol-induced positive chronotropic response with DR10 values of 4.20 and 0.31 mg/kg, respectively. Similarly, a single oral dose of YM-16151-4 inhibited YC-170 and isoproterenol-induced responses with DR10 values of 109.94 and 9.14 mg/kg, respectively. On the other hand, both intravenous and single oral doses of YM-16151-4 produced a dose-dependent hypotensive effect with no increase in heart rate in conscious normotensive rats. The onset of this effect was slow but long-lasting. During repeated oral administration of YM-16151-4 (30 mg/kg) for 5 days, the hypotensive effect of the compound did not change, indicating that this effect did not increase and tolerance did not develop. The time course of the calcium entry blocking activity of YM-16151-4 was very similar to that of its beta 1-adrenoceptor blocking activity, suggesting that the activities of calcium antagonism and beta 1-adrenoceptor blockade of the compound were almost constant at any time after oral dosing. We conclude that YM-16151-4 combines calcium entry and beta 1-adrenoceptor blocking activities in vivo, and produces a hypotensive effect without an increase in heart rate.