INTERACTIONS BETWEEN ENDOTHELIN-1-INDUCED CONTRACTIONS AND BRONCHODILATORS IN HUMAN ISOLATED BRONCHI

1. The aim of this study was to compare the ability of four different bronchodilators (atrial natriuretic peptide, salbutamol, sodium nitrop russide and isosorbide dinitrate) to reverse and also to protect again st contractions evoked by the spasmogens endothelin-l and methacholine in human isolated bronchial rings, 2, Contractions evoked by either e ndothelin-l or methacholine were reversed by atrial natriuretic peptid e (10(-9)-10(-6) mol/l), salbutamol (10(-9)-10(-5) mol/l), sodium nitr oprusside (10(-9)-10(-5) mol/l) and isosorbide dinitrate (10(-7)-10(-4 ) mol/l), 3, Sodium nitroprusside produced a significantly (P<0.05 for data points) greater mean maximal inhibition of endothelin-l-induced tone than methacholine-induced tone; however, the other dilators were equally effective at reversing either endothelin-1-or methacholine-ind uced contractions. Comparing sodium nitroprusside and salbutamol, sodi um nitroprusside was significantly (P<0.05 for data set) less effectiv e than salbutamol at reversing either endothelin-l-or methacholine-ind uced contractions. 4. To compare the ability of these bronchodilator s ubstances to protect against spasmogen challenge, cumulative concentra tion-response curves tell either endothelin-l (10(-10)-3 x 10(-7) mol/ l) or methacholine (10(-9)-3 x 10(-4) mol/l) were constructed In the p resence and absence of each bronchodilator, Atrial natriuretic peptide , at a concentration of 10(-6) mol/l, significantly attenuated contrac tions evoked by methacholine. In contrast, contractions evoked by endo thelin-l were enhanced by atrial natriuretic peptide at concentrations of 3 x 10(-7) and 10(-6) mol/l. Preincubation of salbutamol at a conc entration of 10(-6) mol/l significantly attenuated methacholine induce d contractions, but responses to endothelin-l were not altered by prei ncubation of salbutamol art concentrations of 3 x 10(-7) 10(-6) and 3 x 10(-6) mol/l, Sodium nitroprusside (10(-6) mol/l) and isosorbide din itrate (3 x 10(-5) mol/l) did not alter responses evoked by subsequent addition of either endothelin-1 or methacholine. At a concentration o f 10(-4) mol/l, however, isosorbide dinitrate significantly attenuated endothelin-1-evoked contractions, 5, These results show that drugs wh ich reverse agonist-induced tone in isolated bronchial rings may not n ecessarily protect against subsequent challenge with this agonist, Thi s suggests that the pharmacology of relaxation may be dissimilar to th at of protection.