Investigation of the Mechanism of β2-Agonist-Induced Activation of the Renin—Angiotensin System
Authors: Millar Evelyn A. , McInnes Gordon T. , Thomson Neil C. 
Published: August 2015

1. We have previously described activation of the renin—angiotensin system in asthma, and also by high-dose nebulized β2-agonists. In this study we sought to determine the mechanism responsible.
2. The influence of the angiotensin-converting enzyme inhibitor, lisinopril, on the response of the renin—angiotensin system and serum potassium to nebulized salbutamol was investigated in a randomized, double-blind, crossover study in eight healthy volunteers using a factorial block design. On study days, subjects received lisinopril 20 mg orally or identical placebo tablets followed 3 h later by nebulized salbutamol or placebo inhalation; plasma renin, angiotensin II, serum angiotensin-converting enzyme and potassium were measured at intervals for 120 min after inhalation.
3. Following salbutamol, plasma renin and angiotensin II concentrations were increased significantly compared with placebo [mean (SEM) plasma renin of 61.7 (15.6) μ-units/ml and angiotensin II of 17.7 (5.4) pg/mol 15 min after salbutamol, P &lt; 0.05 versus placebo]. Baseline plasma renin concentrations were increased [160.1 (20.6) μ-units/ml] and baseline plasma angiotensin II concentrations were reduced [1.4 (0.1) pg/ml] by lisinopril, P &lt; 0.05 versus placebo in each case. Inhibition of angiotensin-converting enzyme completely inhibited this salbutamol-induced rise in plasma angiotensin II [mean (SEM) plasma angiotensin II of 1.5 (0.4) pg/ml 15 min after salbutamol, P &lt; 0.05 versus placebo] but had no effect on the changes in plasma renin concentrations after the β2-agonist [mean (SEM) plasma renin of 198.4 (18.9) μ-units/ml 15 min after salbutamol].
4. Serum angiotensin-converting enzyme concentrations tended to increase throughout the study period following salbutamol compared with placebo, although this difference was not statistically significant. Lisinopril caused complete suppression of serum angiotensin-converting enzyme.
5. Salbutamol significantly reduced serum potassium concentrations [mean (SEM) baseline serum potassium of 4.26 (0.16) mmol/l decreasing to 3.08 (0.2) mmol/l at 45 min, P &lt; 0.05 versus placebo]. Although lisinopril had no significant effect on serum potassium, the hypokalaemic response to salbutamol was significantly reduced in the presence of the angiotensin-convering enzyme inhibitor [mean (SEM) decrease in serum potassium of −1.2 (0.2) mmol/l compared with −0.8 (0.2) mmol/l, P &lt; 0.05 versus placebo].
6. Mean blood pressure was unaffected by active therapy. One subject experienced dizziness and headache after lisinopril.
7. The results of this study confirm that nebulized salbutamol causes activation of plasma renin and angiotensin II. Pretreatment with an angiotensin-converting enzyme inhibitor prevented the salbutamol-induced increase in plasma angiotensin II but not renin concentration.
8. We conclude that elevation of plasma angiotensin II induced by high-dose nebulized β2-agonists involves the classical components of the renin—angiotensin system including angiotensin-converting enzyme.