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 similar to 16 mmHg) and 305+/-34 mg wt (high t ension: equivalent to similar to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ETB-recepto r agonist sarafotoxin S6c (S6c) were studied. The effects of nitric ox ide synthase inhibition with N-omega-nitro-L-arginine methylester (L-N AME, 100 mu M) on ET receptor-induced responses, as well as vasodilato r responses to acetylcholine (ACh) and S6c, were also investigated. Ch anges with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2 Control rat preparations showe d 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 (similar to 80%) and noradrenaline (similar to 60%) when put under high tension. 3 In control pulmonary resistance arteries, both ET-1 a nd 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 hig h tension (S6e 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 increa ses 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 t one was evident in 88% of vessels and had increased to 26.9+/-6.6 mg w t tension. Vasodilatation to sodium nitroprusside, in non-preconstrict ed vessels, was small in control rat vessels (2-6 mg wt tension) but i ncreased significantly to 22.5+/-8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate a n 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 (hi gh tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6 Vasodi latation 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 con trols (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 res ults demonstrate that control rat preparations showed greatest sensiti vity for ET-1 when set at the lower tension, equivalent to the pressur e expected in vivo (similar to 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary r esistance arteries from control animals exhibited little endogenous to ne, 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 ETB2 receptor sti mulation. Relaxation to ACh was increased in pulmonary resistance arte ries from chronic hypoxic rats.