VASORELAXING EFFECTS OF PROPRANOLOL IN RAT AORTA AND MESENTERIC ARTERY: A ROLE FOR NITRIC OXIDE AND CALCIUM ENTRY BLOCKADE.

Priviero, Fernanda B. M.; Teixeira, Cleber E.; Toque, Haroldo A. F.; Claudino, Mário A.; Webb, R. Clinton; De Nucci, Gilberto; Zanesco, Angelina; Antunes, Edson

1. Propranolol has been prescribed successfully to patients with cardiovascular diseases, but the exact mechanisms by which it reduces peripheral vascular resistance have been poorly investigated. 2. The present study was designed to investigate the relaxing effects of propranolol in the rat isolated aorta and mesenteric artery, focusing on the contribution of the nitric oxide (NO)–cGMP pathway and calcium entry blockade. Relaxation responses to propranolol were obtained in precontracted rat aortic and mesenteric artery rings. 3. dl-Propranolol (10–100 mmol/L) produced concentration-dependent relaxations in the aorta and mesenteric artery rings with intact endothelium. The isomersd- andl-propranolol produced relaxation responses that were equipotent to the racemic mixture. 4. Metoprolol (10–100 mmol/L) produced slight relaxations, whereas atenolol (10–100 mmol/L) had no relaxant activity. 5. The NO inhibitor NG-nitro-l-arginine methyl ester (100 mmol/L) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (1 mmol/L), as well as removal of the endothelium, significantly reduced the relaxation responses induced by the lower concentrations of propranolol without affecting maximal responses. In addition,dl-propranolol markedly increased cGMP levels in endothelium-intact preparations. 6. In Ca2 -free Krebs’ solution,dl-propranolol (10–100 mmol/L) caused marked rightward shift in the concentration–response curves to CaCl2, with a decrease of maximal responses in tissues with either intact or denuded endothelium. Nifedipine (1 mmol/L) in combination withdl-propranolol virtually abolished the CaCl2-induced contractile responses. 7. The relaxation responses induced bydl-propranolol were significantly reduced in aortic and mesenteric rings precontracted with phorbol-12,13-dibutyrate (1 mmol/L). 8. In conclusion,dl-propranolol relaxes arterial smooth muscle by mechanisms involving activation of the NO–cGMP pathway and calcium influx blockade, independent of b-adrenoceptor blockade.

PROPANOLS; AORTA; MESENTERIC artery; NITRIC oxide; BLOOD vessels; ENDOTHELIUM; THERAPEUTICS

Clinical & Experimental Pharmacology & Physiology, 2006, Vol 33, Issue 5/6, p448

0305-1870

Academic Journal

10.1111/j.1440-1681.2006.04386.x