The role of calcium antagonists in bronchial reactivity

Abstract

Calcium (Ca) ions play an important pathophysiologic role in allergic reactions. Thus, mediator release from mast cells, synthesis of some newly formed chemical mediators, airway smooth muscle contraction, and nerve-impulse conduction are all dependent on the availability and flux of Ca ions. It is likely, therefore, that Ca antagonists would modify allergic bronchoconstriction. In vitro, Ca antagonists have been demonstrated to inhibit mediator release (histamine, slow-reacting substance of anaphylaxis, and platelet-activating factor) from mast cells, passively sensitized human lung fragments, and leukocytes. Ca antagonists have also been found to inhibit synthesis of leukotrienes in rat lungs and cyclooxygenase products in sheep, possibly by inactivating phospholipase A 2 and/or 5-lipoxygenase. In addition, nifedipine, verapamil, and gallopamil have demonstrated inhibition of airway smooth muscle contractions to histamine, carbachol, and antigen in various species. In vivo effects of Ca antagonists are variable, depending on the species, experimental design, the stimulus or the agonist, and the Ca antagonist used. Animal studies have demonstrated the inhibition of histamine, methacholine, citric acid, and prostaglandin F 2α-induced bronchoconstriction in guinea pigs and dogs by intravenous nifedipine. In contrast, verapamil inhibited antigen-induced bronchoconstriction in allergic sheep without any effect on histamine- and carbachol-induced responses. Ca antagonists (nifedipine and verapamil) have been of limited value in human subjects and generally have no significant bronchodilating activity. Both nifedipine and verapamil prevent the exercise-induced asthma and partly attenuate the histamine and methacholine-induced bronchoconstriction. Oral nifedipine is generally more effective than oral verapamil against acute antigen-induced bronchoconstriction; however, this efficacy may be limited by systemic side effects. Inhaled Ca antagonists may be more effective and free of systemic side effects, as demonstrated by greater efficacy of inhaled verapamil. A new Ca antagonist, gallopamil (a methoxy derivative of verapamil), is being investigated as an aerosol, and preliminary studies in animals and humans have found it fourfold to seventeenfold more potent than verapamil. In sheep, gallopamil has been found to attenuate histamine, carbachol, and platelet-activating factor-induced bronchoconstriction, as well as to inhibit early and late-phase allergic airway responses. Studies in human subjects have also demonstrated the inhibition of antigen-induced bronchoconstriction by inhaled gallopamil, with efficacy comparable or better than cromolyn sodium. Although the currently available Ca antagonists are of limited value in the treatment of asthma, it is hoped that newer potent agents (e.g., gallopamil), when these are administered via inhaled route, may be of potential use.