Vasorelaxing effects of propranolol in rat aorta and mesenteric artery: a role for nitric oxide and calcium entry blockade.
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 micromol/L) produced concentration-dependent relaxations in the aorta and mesenteric artery rings with intact endothelium. The isomers D- and L-propranolol produced relaxation responses that were equipotent to the racemic mixture. 4. Metoprolol (10-100 micromol/L) produced slight relaxations, whereas atenolol (10-100 micromol/L) had no relaxant activity. 5. The NO inhibitor N(G)-nitro-L-arginine methyl ester (100 micromol/L) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (1 micromol/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 Ca(2+)-free Krebs' solution, DL-propranolol (10-100 micromol/L) caused marked rightward shift in the concentration-response curves to CaCl(2), with a decrease of maximal responses in tissues with either intact or denuded endothelium. Nifedipine (1 micromol/L) in combination with DL-propranolol virtually abolished the CaCl(2)-induced contractile responses. 7. The relaxation responses induced by DL-propranolol were significantly reduced in aortic and mesenteric rings precontracted with phorbol-12,13-dibutyrate (1 micromol/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 beta-adrenoceptor blockade.
Priviero
Fernanda B M
FB
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
Teixeira
Cleber E
CE
Toque
Haroldo A F
HA
Claudino
Mário A
MA
Webb
R Clinton
RC
De Nucci
Gilberto
G
Zanesco
Angelina
A
Antunes
Edson
E
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
C494582:1H-(1,2,3)oxadiazolo(4,4-a)quinoxalin-1-one; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011433:Propranolol; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D009543:Nifedipine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester