{beta}-adrenergic relaxation in pulmonary arteries: preservation of the endothelial nitric oxide-dependent {beta}2 component in pulmonary hypertension

Aims β-adrenoceptor (β-AR)-mediated relaxation was characterized in pulmonary arteries from normoxic and hypoxic (as model of pulmonary hypertension) mice. The endothelial NO synthase (eNOS) pathway was especially investigated because of its potential vasculoprotective effects. Methods Pulmonary arteries from control or hypoxic (0.5 atm for 21 days) wild-type or eNOS−/− mice were used for pharmacological characterization of β-AR-mediated relaxation in myograph, and for immunohistochemistry using anti-β-AR antibodies. Results In pulmonary arteries from normoxic mice, isoproterenol (β-AR agonist) and procaterol (selective β 2 -AR agonist) elicited relaxation, while cyanopindolol and CL316243 (β 3 -AR agonists) were ineffective. The effect of isoproterenol was antagonized by CGP20712A and ICI118551 (β 1 - or β 2 -AR antagonists, respectively) and also partially inhibited by N ω-nitro-L-arginine methylester (L-NAME, a NOS inhibitor), endothelium denudation, or eNOS gene deletion. Relaxation to procaterol was abolished by L-NAME or endothelium removal. In eNOS−/− mice, procaterol-induced relaxation was decreased but was insensitive to L-NAME, this residual effect involving other endothelium-dependent relaxant factors as compensatory mechanisms. Immunostaining for β 2 -AR was observed in the endothelial layer, but not the medial layer of pulmonary arteries. Pulmonary arteries from hypoxic mice exhibited decreased endothelial NO-dependent relaxation to acetylcholine. However, in these arteries, relaxation to procaterol was either unaffected (extralobar segments) or even increased (intralobar segments) and was still abolished by L-NAME or endothelium removal. Conclusion β 1 - and β 2 -AR, but not β 3 -AR, mediate relaxation of mice pulmonary arteries. The β 2 -AR component is dependent on eNOS activity and is preserved following chronic hypoxia. These data highlight the role of the β 2 -AR as a pharmacological target to induce/restore endothelial NO-dependent protective effects in pulmonary circulation.