Recent reports about the clinical efficacy of the organic nitrates, nitroglycerin and isosorbide dinitrate, in the treatment of asthma are conflicting. Although the effects of organic nitrates on vascular smooth muscle have been studied extensively, relatively little is known about the actions of these drugs in the lung. In previous studies comparing the effects of vasodilators on bovine tracheal and lung parenchymal strips in vitro, we found that nitroglycerin and nitroprusside, another NO-containing vasodilator, effectively relaxed potassium-induced tone in the trachealis muscle, but not in the parenchymal strips. This finding suggests that marked heterogeneity may exist in the responsiveness to organic nitrates and related vasodilators of airway smooth muscle from different levels within the respiratory tree. Such differences, together with undetermined effects on mediator release, may be responsible for the reportedly inconsistent efficacy of the nitrates in asthma, as variations in the site(s) of airway constriction may greatly alter the responses of these drugs. The proposed project will systematically examine and compare the effects of nitrates with those of more traditional agents used in asthma (eg. Beta-agonists, methylxanthines, cromoglycate) and the newer Ca-channel blockers. Studies will be conducted to compare the capacity of the drugs to relax airway smooth muscle obtained from various levels of bovine and procine lung and trachea when partially contracted by several endogenous bronchoconstrictors (eg. acetylcholine, histamine, cyclooxygenase and lipoxygenase metabolites of arachidonic acid). Concurrent studies will also determine and compare the effects of the various drugs on the release of mediators from lung which are thought to be involved in the pathogenesis of asthma. Results from this research will document and compare the effects of nitroglycerin and other drugs on airway smooth muscle from different sites within the lung as well as their effects on mediator release. Such knowledge will provide some of the basic information needed to help develop a more rational use of the various drugs in the treatment of reversible airway obstructive diseases.
