Noradrenaline, β‐adrenoceptor mediated vasorelaxation and nitric oxide in large and small pulmonary arteries of the rat

Abstract

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 di erences in the b-adrenoceptor-mediated vasorelaxation component and, in particular, b-adrenoceptor-mediated NO release. 2 Noradrenaline induced a bell-shaped concentration-response in large (1202+27 mm) and small (334+12 mm) pulmonary arteries of the rat. In large arteries tension increased to 95.6+1.8% of 75 mM KCl (KPSS; n=8) at 2 mM, above which tension declined. The response in small arteries was meagre (12+1.5% KPSS, n=9), peaking at 0.2 mM. N G -monomethyl-L-arginine (L-NMMA; 100 mM) abolished the decline in tension induced by higher concentrations of noradrenaline in large arteries, and increased maximum tension (117+3.5% KPSS, n=5, P50.05). In small arteries peak tension doubled (22.0+3.4% KPSS, n=6, P50.01), but still declined above 0.2 mM. 3 Propranolol (1 mM) 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, P50.001) than in large arteries (112.2+3.7% KPSS, n=9, P50.05). In the presence of L-NMMA, propranolol had no additional e ect on large arteries, whereas in small arteries there was greater potentiation than for either agent alone (67.8+5.9% KPSS, n=4). 4 b-Adrenoceptor-mediated relaxation was examined in arteries constricted with prostaglandin F 2a (50 mM). In the presence of propranolol isoprenaline caused an unexpected vasoconstriction, which was abolished by phentolamine (10 mM). 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, P50.01), but was less e ective in small arteries (26.8+5.8, n=5, P50.05). 5 Atenolol (b 1 -antagonist, 5 mM) 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 e ect over L-NMMA alone. ICI 118551 (b 2 -antagonist, 0.1 mM) reduced isoprenaline-induced relaxation more than atenolol (large: 18.0+4.6%, n=6, P50.05; small: 25.6+10.7%, n=6, P50.05). 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, P50.01), but to a lesser extent in small arteries (control: 50.9+7.5%, n=6; +L-NMMA: 23.0+0.7%, n=5, P50.05). 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 b-adrenoceptor-mediated component than in large arteries. b-Mediated vasorelaxation in large arteries was largely NO-dependent, whereas in small arteries a signi®cant proportion was NO-independent. Noradrenaline stimulation was also asso...

Potentiation of cyclic AMP‐mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat

“…We have previously demonstrated that isoprenaline concentrations above 100 nM cause a small but signi®cant aadrenoceptor-mediated vasoconstriction in pulmonary arteries of the rat (Priest et al, 1997). With the exception of experiments using PE or ME as the vasoconstrictor, all other studies involving isoprenaline were therefore performed in the presence of 10 mM phentolamine; we have previously shown that phentolamine has no e ect on salbutamol-induced relaxation (Priest et al, 1997). Tension was allowed to stabilize following every addition, and is expressed in terms of the initial induced tension.…”

“…The presence of a functioning endothelium was determined by application of acetylcholine (ACh; 10 mM) following agonist induced contraction. After 60 min equilibration the arteries were subjected to a standard run up procedure of three 4 min exposures to PSS containing high K + (KPSS, 75 mM [K + ], equimolar substitution for NaCl) (Leach et al, 1992;Priest et al, 1997). Arteries producing less than 1 mN mm 71 were discarded.…”

“…The heart and lungs and a section of large intestine were excised and placed in a physiological salt solution (PSS) containing (in mM): NaCl 118, NaHCO 3 24, MgSO 4 1, NaH 2 PO 4 0.435, glucose 5.56, Na-pyruvate 5, CaCl 2 1.8 and KCl 4. Pulmonary (1141+22 mm i.d., n=142) and mesenteric arteries (344+69 mm, n=20) were dissected free of connective tissue and mounted in a small vessel myograph as previously described (Leach et al, 1992;Priest et al, 1997), and equilibrated with 5% CO 2 in O 2 , (pH 7.35 ± 7.40, 378C). In some experiments the endothelium was disrupted in situ by gently rubbing the luminal surface of the artery with a 40 mm wire or human hair.…”

“…Plane & Garland, 1996), and it has been suggested that stimulation of a 1 -adrenoceptors may potentiate relaxation to b-adrenoceptor agonists in pulmonary arteries (Peng et al, 1996;Priest et al, 1997). This could have functional signi®cance, as sympathetic stimulation causes changes in pulmonary vascular resistance that are mediated via noradrenaline and a-and b-adrenoceptors (Hyman et al, 1990).…”

“…This could have functional signi®cance, as sympathetic stimulation causes changes in pulmonary vascular resistance that are mediated via noradrenaline and a-and b-adrenoceptors (Hyman et al, 1990). We have previously shown that relaxation of PGF 2a constricted rat pulmonary arteries by b-adrenoceptor agonists is largely endothelium dependent and mediated via nitric oxide (NO) (Priest et al, 1997), and there is evidence that noradrenaline-induced vasoconstriction of pulmonary arteries may be depressed due to stimulation of NO synthesis via both a-and b-adrenoceptors (MacLean et al, 1993;Tulloh et al, 1994;Priest et al, 1997). Constriction of porcine pulmonary arteries with the a 1 -adrenoceptor agonist phenylephrine (PE) has also been associated with an endothelium-dependent rise in cyclic GMP (Pepke-Zaba et al, 1993).…”