Abstract
The calcium channel blockers (CCB) have been clinically effective in exercise-induced asthma. The completeness of protection with the CCB might be related specifically to inhibition of Ca 2+ influx or release. To examine this hypothesis, the rank order of potency of inhibition of the CCB, nicardipine, diltiazem and verapamil on the steady-state and kinetic parameters of the phasic and tonic responses to the muscarinic receptor agonist carbachol (10 μM) and KCl (40 mM) in the intact isolated guinea-pig trachea was determined. The Ca 2+ channel agonist Bay K 8644 was also examined for its effects on intracellular Ca 2+. Nicardipine abolished the KCl response at both 0.1 μM and 1 μM concentrations. The amplitude of the KCl response was inhibited equally by 1 μM diltiazem (61% inhibition) and 1 μM verapamil (68% inhibition). The rate constant of onset of the KCl response was similarly inhibited 60 % by diltiazem and 66% by verapamil. Nicardipine abolished the carbachol phasic response at the 1 μM concentration. The amplitude of the phasic response was inhibited equally by 0.1 μM nicardipine (61.3% inhibition), 1 μM diltiazem (64.5% inhibition) and 1 μM verapamil (71% inhibition). The rate constant of decay of the phasic response was inhibited equally by 0.1 μM nicardipine (43% inhibition) and 1 μM diltiazem (29% inhibition). The rate constant of onset of the phasic response was unaffected by nicardipine, diltiazem and verapamil. Only 1 μM nicardipine inhibited the amplitude and rate constant of onset of the tonic response. The only effect of Bay K 8644 (1 μM) was to increase the phasic response amplitude. The CCB demonstrate a similar order of potency for inhibition of the phasic responses and clinical efficacy of the CCB in exercise-induced asthma (nicardipine > verapamil > diltiazem). The fact that the order of potency is the same for the in vitro and clinical evaluations supports our hypothesis that the clinical effectiveness of the CCB is specifically directed at the receptor-mediated phasic response. The CCB also demonstrate some response selectivity. Nicardipine demonstrated an order of potency which was KCl > phasic > tonic. The weak effect of the CCB in allergic asthma may be related to their poor potency on the tonic response. It is possible that CCB might be developed with a greater potency for tonic responses.
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