Antibronchoconstrictor activity of the intracellular calcium antagonist HA 1004 in guinea pigs

HA 1004 is a calcium antagonist vasodilator that inhibits contraction in vascular smooth muscle and lowers arterial blood pressure. The effects of HA 1004 on guinea pig airway smooth muscle contraction were compared to the effects of the calcium antagonists, verapamil and nifedipine and the bronchodilator, albuterol. In vitro, HA 1004, verapamil, nifedipine and albuterol inhibited Ca2+-induced contractions of the depolarized guinea pig trachea. HA 1004 and albuterol also relaxed the basal tracheal tone, whereas verapamil and nifedipine were inactive. The bronchorelaxant activity of HA 1004 was not blocked by propranolol. In vivo, intravenous administration of HA 1004, verapamil, nifedipine and albuterol effectively blocked bronchoconstriction induced by intravenous histamine and methacholine. HA 1004 also reversed a histamine-induced bronchospasm, as did albuterol, verapamil and nifedipine. Intratracheal administration of HA 1004 and albuterol inhibited histamine-induced bronchoconstriction without effecting blood pressure, whereas intratracheal administration of verapamil and nifedipine caused a significant reduction of blood pressure at their pulmonary active doses. These results show that HA 1004 has the ability to relax airway smooth muscle, inhibit contractile responses in the guinea pig airways, and there is separation of its cardiovascular and pulmonary effects when HA 1004 is administered directly to the lungs. The results are discussed in terms of the regulatory enzymes and sources of calcium that are involved in airway smooth muscle contraction.