INVESTIGATION OF THE MECHANISM OF BETA(2)-AGONIST-INDUCED ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM

1. We have previously described activation of the renin-angiotensin sy stem in asthma, and also by high-dose nebulized beta(2)-agonists. In t his study we sought to determine the mechanism responsible. 2. The inf luence of the angiotensin-converting enzyme inhibitor, lisinopril, on the response of the renin-angiotensin system and serum potassium to ne bulized salbutamol was investigated in a randomized, double-blind, cro ssover study in eight healthy volunteers using a factorial block desig n. On study days, subjects received lisinopril 20 mg orally or identic al placebo tablets followed 3 h later by nebulized salbutamol or place bo inhalation; plasma renin, angiotensin II, serum angiotensin-convert ing enzyme and potassium were measured at intervals for 120 min after inhalation. 3. Following salbutamol, plasma renin and angiotensin II c oncentrations were increased significantly compared with placebo [mean (SEM) plasma renin of 61.7 (15.6) mu-units/ml and angiotensin II of 1 7.7 (5.4) pg/mol 15 min after salbutamol, P<0.05 versus placebo]. Base line plasma renin concentrations were increased [160.1 (20.6) mu-units /ml] and baseline plasma angiotensin II concentrations were reduced [1 .4 (0.1) pg/ml] by lisinopril, P<0.05 versus placebo in each case. Inh ibition of angiotensin-converting enzyme completely inhibited this sal butamol-induced rise in plasma angiotensin II [mean (SEM) plasma angio tensin II of 1.5 (0.4) pg/ml 15 min after salbutamol, P<0.05 versus pl acebo] but had no effect on the changes in plasma renin concentrations after the beta(2)-agonist [mean (SEM) plasma renin of 198.4 (18.9) mu -units/ml 15 min after salbutamol]. 4. Serum angiotensin-converting en zyme concentrations tended to increase throughout the study period fol lowing salbutamol compared with placebo, although this difference was not statistically significant. Lisinopril caused complete suppression of serum angiotensin-converting enzyme. 5. Salbutamol significantly re duced serum potassium concentrations [mean (SEM) baseline serum potass ium of 4.26 (0.16) mmol/l decreasing to 3.08 (0.2) mmol/l at 45 min, P <0.05 versus placebo]. Although lisinopril had no significant effect o n serum potassium, the hypokalaemic response to salbutamol was signifi cantly reduced in the presence of the angiotensin-convering enzyme inh ibitor [mean (SEM) decrease in serum potassium of -1.2 (0.2) mmol/l co mpared with -0.8 (0.2) mmol/l, P<0.05 versus placebo]. 6. Mean blood p ressure was unaffected by active therapy. One subject experienced dizz iness and headache after lisinopril. 7. The results of this study conf irm that nebulized salbutamol causes activation of plasma renin and an giotensin II. Pretreatment with an angiotensin-converting enzyme inhib itor prevented the salbutamol-induced increase in plasma angiotensin I I but not renin concentration. 8. We conclude that elevation of plasma angiotensin II induced by high-dose nebulized beta(2)-agonists involv es the classical components of the renin-angiotensin system including angiotensin-converting enzyme.