Noradrenaline, beta-adrenoceptor mediated vasorelaxation and nitric oxide in large and small pulmonary arteries of the rat.
1. Noradrenaline induces a meagre vasoconstriction in small muscular pulmonary arteries compared to large conduit pulmonary arteries. We have examined whether this may be partially related to differences in the beta-adrenoceptor-mediated vasorelaxation component and, in particular, beta-adrenoceptor-mediated NO release. 2. Noradrenaline induced a bell-shaped concentration-response in large (1202+/-27 microm) and small (334+/-12 microm) pulmonary arteries of the rat. In large arteries tension increased to 95.6+/-1.8% of 75 mM KCl (KPSS; n=8) at 2 microM, above which tension declined. The response in small arteries was meagre (12+/-1.5% KPSS, n=9), peaking at 0.2 microM. N(G)-monomethyl-L-arginine (L-NMMA; 100 microM) abolished the decline in tension induced by higher concentrations of noradrenaline in large arteries, and increased maximum tension (117+/-3.5% KPSS, n=5, P<0.05). In small arteries peak tension doubled (22.0+/-3.4% KPSS, n=6, P<0.01), but still declined above 0.2 microM. 3. Propranolol (1 microM) abolished the decline in tension at higher concentrations of noradrenaline in both groups, but increased tension substantially more in small (37.4+/-3.7% KPSS, n=5, P<0.001) than in large arteries (112.2+/-3.7% KPSS, n=9, P<0.05). In the presence of L-NMMA, propranolol had no additional effect on large arteries, whereas in small arteries there was greater potentiation than for either agent alone (67.8+/-5.9% KPSS, n=4). 4. Beta-adrenoceptor-mediated relaxation was examined in arteries constricted with prostaglandin F2alpha (50 microM). In the presence of propranolol isoprenaline caused an unexpected vasoconstriction, which was abolished by phentolamine (10 microM). In the presence of phentolamine, isoprenaline caused a maximum relaxation of 43.3+/-2.1% (n=6) in large, and 49.0+/-4.5% (n=6) in small arteries. L-NMMA substantially reduced relaxation in large arteries (7.4+/-1.5%, n=6, P<0.01), but was less effective in small arteries (26.8+/-5.8, n=5, P<0.05). 5. Atenolol (beta1-antagonist, 5 microM) reduced relaxation to isoprenaline (large: 34.8+/-4.5%, n=5; small: 35.0+/-1.9%, n=6), but in combination with L-NMMA had no additional effect over L-NMMA alone. ICI 118551 (beta2-antagonist, 0.1 microM) reduced isoprenaline-induced relaxation more than atenolol (large: 18.0+/-4.6%, n=6, P<0.05; small: 25.6+/-10.7%, n=6, P<0.05). ICI 118551 in combination with L-NMMA substantially reduced relaxation (large: 4.8+/-2.6%, n=9; small: 6.5+/-3.6%, n=5). 6. Salbutamol-induced relaxation was reduced substantially by L-NMMA in large arteries (control: 34.7+/-6.4%, n=6; +L-NMMA: 8.3+/-1.3%, n=5, P<0.01), but to a lesser extent in small arteries (control: 50.9+/-7.5%, n=6; +L-NMMA: 23.0+/-0.7%, n=5, P<0.05). Relaxation to forskolin was also partially antagonized by L-NMMA. 7. These results suggest that the meagre vasoconstriction to noradrenaline in small pulmonary arteries is partially due to a greater beta-adrenoceptor-mediated component than in large arteries. Beta-mediated vasorelaxation in large arteries was largely NO-dependent, whereas in small arteries a significant proportion was NO-independent. Noradrenaline stimulation was also associated with NO release that was independent of beta-adrenoceptors.
Priest
R M
RM
Department of Allergy and Respiratory Medicine, UMDS, St. Thomas' Campus, London.
Hucks
D
D
Ward
J P
JP
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D010120:Oxytocics / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D010120:Oxytocics; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C026777:ICI 118551; D001262:Atenolol; D011433:Propranolol; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D007545:Isoproterenol; D009638:Norepinephrine