Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia

1 The effect of basal tension (transmural tensions 235±29 mg wt (low tension: equivalent to ∼16 mmHg) and 305±34 mg wt (high tension: equivalent to ∼35 mmHg)) on rat pulmonary resistance artery responses to endothelin‐1 (ET‐1) and the selective ET B ‐receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N Ω ‐nitro‐ L ‐arginine methylester ( L ‐NAME, 100 μ M ) on ET receptor‐induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2 Control rat preparations showed greatest sensitivity for ET‐1 when put under low tension (pEC 50 : 8.1±0.1) compared with at the higher tension (pEC 50 : 7.7±0.1) and there were significant increases in maximum contractile responses to S6c (∼80%) and noradrenaline (∼60%) when put under high tension. 3 In control pulmonary resistance arteries, both ET‐1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET‐1 in vessels set at low tension (S6c pEC 50 : 9.2±0.1) and 200 fold more potent than ET‐1 when the vessels were set at high tension (S6c pEC 50 : 9.0±0.1). Chronic hypoxia did not change the potencies of ET‐1 and S6c but did significantly increase the maximum contractile response to ET‐1 by 60% (at low tension) and 130% (at high tension). 4 In control rat vessels, L ‐NAME itself caused small increases in vascular tone (5–8 mg wt tension) in 33–56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L ‐NAME‐induced tone was evident in 88% of vessels and had increased to 26.9±6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non‐preconstricted vessels, was small in control rat vessels (2–6 mg wt tension) but increased significantly to 22.5±8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5 L ‐NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET‐1 in any vessel studied. 6 Vasodilatation of pre‐contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC 50 : 7.12±0.19, maximum: 72.1±0.2.0%) compared to their age‐matched controls (pIC 50 : 5.77±0.15, maximum: 28.2±2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7 These results demonstrate that control rat preparations showed greatest sensitivity for ET‐1 when set at the lower tension, equivalent to the pressure expected in vivo (∼16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET‐1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET B2 receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.British Journal of Pharmacology (1998) 123 , 991–999; doi: 10.1038/sj.bjp.0701682