Interactions between endothelin-I-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 nitroprusside and isosorbide dinitrate) to reverse and also to protect against contractions evoked by the spasmogens endothelin-1 and methacholine in human isolated bronchial rings. 2. Contractions evoked by either endothelin-1 or methacholine were reversed by atrial natriuretic peptide (10(-9)-10(-6) mol/l), salbutamol (10(-9)-10(-5) mol/l), sodium nitroprusside (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-1-induced tone than methacholine-induced tone; however, the other dilators were equally effective at reversing either endothelin-1- or methacholine-induced contractions. Comparing sodium nitroprusside and salbutamol, sodium nitroprusside was significantly (P < 0.05 for data set) less effective than salbutamol at reversing either endothelin-1- or methacholine-induced contractions. 4. To compare the ability of these bronchodilator substances to protect against spasmogen challenge, cumulative concentration-response curves to either endothelin-1 (10(-10)-3 x 10(-7) mol/l) or methacholine (10(-9)-3 x 10(-4) mol/l) were constructed in the presence and absence of each bronchodilator. Atrial natriuretic peptide, at a concentration of 10(-6) mol/l, significantly attenuated contractions evoked by methacholine. In contrast, contractions evoked by endothelin-1 were enhanced by atrial natriuretic peptide at concentrations of 3 x 10(-7) and 10(-6) mol/l. Preincubation of salbutamol at a concentration of 10(-6) mol/l significantly attenuated methacholine-induced contractions, but responses to endothelin-1 were not altered by preincubation of salbutamol at concentrations of 3 x 10(-7), 10(-6) and 3 x 10(-6) mol/l. Sodium nitroprusside (10(-6) mol/l) and isosorbide dinitrate (3 x 10(-5) mol/l) did not alter responses evoked by subsequent addition of either endothelin-1 or methacholine. At a concentration of 10(-4) mol/l, however, isosorbide dinitrate significantly attenuated endothelin-1-evoked contractions. 5. These results show that drugs which reverse agonist-induced tone in isolated bronchial rings may not necessarily protect against subsequent challenge with this agonist. This suggests that the pharmacology of relaxation may be dissimilar to that of protection.