Effects of histamine H1 receptor antagonists on action potentials in guinea-pig isolated papillary muscles.

The effects of histamine H1 receptor antagonists (H1 antagonists) on action potentials in guinea-pig isolated papillary muscles were examined using a microelectrode technique. Terfenadine (0.03 microM) prolonged the action potential duration at 90% repolarization, without affecting the resting membrane potentials, the action potential amplitude or the maximal upstroke velocity, although its metabolite, terfenadine carboxylate, did not affect any action potential parameters. Astemizole, (+)-chlorpheniramine, and clemastine prolonged the action potential duration at 90% repolarization at 0.03, I and 10 microM, respectively. The action potential duration-prolonging effects of terfenadine and astemizole correspond to the reverse use-dependence phenomenon. However, ebastine and its metabolite, carebastine, did not affect the action potential parameters at 3 microM. Mequitazine, diphenhydramine, epinastine, ketotifen and oxatomide were also without effect at 10 microM. These H1 antagonists suppressed the histamine-induced contractions in guinea-pig isolated ileum longitudinal muscles. However, the potency order was inconsistent with that for prolonging the action potential duration. Terfenadine or astemizole prolonged the action potential duration at concentrations lower than each IC50 value for H1 receptor antagonism. Cimetidine, a H2 receptor antagonist, and thioperamide, a H3 receptor antagonist, had little effect on the action potentials. These results suggest that, in guinea-pig isolated papillary muscles, blockade of histamine receptors does not cause prolongation of the action potential duration, leading to prolongation of electrocardiographic QT intervals, and that H1 antagonists may be classified into three groups: (1) drugs causing prolongation of the action potential duration at concentrations producing H1 antagonism and (2) at concentrations higher than those producing H1 antagonism, and.