INFLUENCES OF THE ENDOTHELIUM AND HYPOXIA ON ALPHA(1)-ADRENOCEPTOR-MEDIATED AND ALPHA(2)-ADRENOCEPTOR-MEDIATED RESPONSE IN THE RABBIT ISOLATED PULMONARY-ARTERY

1 The effects of the inhibitor of nitric oxide synthase, N(omega)-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha1- and alpha2-adrenoceptor agonist), phenylephrine (alpha1-adrenoceptor agonist) and UK 14304 (alpha2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha2-adrenoceptors) and prazosin (10(-7) M, alpha1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2 Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3 Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4 Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5 In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide. Experimental hypoxia had differential effects on all three agonists and did not mimic the effect of nitric oxide synthase inhibition.