BRONCHODILATOR MECHANISMS IN BULLFROG LUNG - DIFFERENCES IN RESPONSE TO ISOPROTERENOL, THEOPHYLLINE AND PAPAVERINE

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Abstract
The effects of bronchodilators and smooth muscle relaxants on mechanical responses and lung cyclic nucleotide levels in the isolated hemilung of R. catesbeiana demonstrate striking differences in intensity and time course of drug action in an unstimulated preparation of airway smooth muscle. Isoproterenol, nitroprusside and nitroglycerin elicit a fast onset relaxation (min) with ceiling effects at 20, 22 and 43%, respectively, of maximal relaxation. Theophylline, dibutyryl cAMP and papaverine produce maximal or near maximal relaxation, but require 8-32 h for peak effect. Papaverine-induced relaxation is accompanied by a slow increase in lung cAMP and cGMP and is markedly accelerated by isoproterenol, Theophylline (10-3 M) produces no change in cyclic nucleotide levels and its relaxant effect is not accelerated by isoproterenol. The hierarchy of relaxant responses suggests drug action at discrete loci in a highly compartmentalized effector chain, with cAMP-dependent mechanisms separable into at least 2 components. The 1st is activated by isoproterenol and elicits a rapid, limited response, presumably reflecting an increase in cAMP in a relatively restricted pool. The 2nd is activated by papaverine and elicits a very slow, but complete relaxation, presumably reflecting a more pervasive or diffuse accumulation of cAMP secondary to phosphodiesterase inhibition. The major portion of theophyline-induced relaxation in this preparation appears to be independent of changes in cyclic nucleotide metabolism.