Characterization of Ca(2+)-antagonistic effects of three metabolites of the new antihypertensive agent naftopidil, (naphthyl)hydroxy-naftopidil, (phenyl)hydroxy-naftopidil, and O-desmethyl-naftopidil.

The newly developed antihypertensive agent naftopidil blocks alpha 1-adrenoceptors and inhibits Ca2+ entry via potential-dependent channels in vascular and cardiac muscle. It is extensively metabolized in vivo. Since it is of interest whether its metabolites are still pharmacologically active, we have characterized the effects of (naphthyl)hydroxy-naftopidil (NHN), (phenyl)hydroxy-naftopidil (PHN), and O-desmethyl-naftopidil (DMN) in various isolated preparations of the guinea pig heart. In constant-flow Langendorff hearts, the compounds decreased force of contraction by 66-81% and slowed spontaneous heart rate by 28-48%. DMN reduced perfusion pressure by 33%. The fibrillation threshold, which was measured as the strength of alternating current required to induce ventricular fibrillation, increased more than 10-fold. In papillary muscles, 3 x 10(-5) M of all compounds reduced force of contraction (pD2 values approximately 5.5) and shortened the action potential duration in the plateau phase. The maximum depolarization velocity (dV/dtmax) was slightly reduced (10-21%) by NHN, PHN, and DMN. In voltage-clamped ventricular cardiomyocytes, the calcium current ICa was depressed by the three compounds (10(-6)-10(-4) M) in a concentration-dependent manner. In conclusion, the three naftopidil metabolites investigated have pharmacological activities similar to those of their parent compound and hence could contribute to the in vivo effects of naftopidil.