ENDOTHELIUM-DEPENDENT RELAXATIONS IN SHEEP PULMONARY-ARTERIES AND VEINS - RESISTANCE TO BLOCK BY N-G-NITRO-L-ARGININE IN PULMONARY-HYPERTENSION

1 The effect of the nitric oxide synthase inhibitor, N-G-nitro-L-argin ine (L-NOARG), on endothelium-dependent relaxation to a receptor-indep endent agent, ionomycin, was examined in isolated pulmonary arteries a nd veins from control, short-term and chronic pulmonary hypertensive s heep. Al vessel segments were contracted to optimal levels of active f orce with endothelin-l to record endothelium-dependent relaxation. 2 P ulmonary hypertension was induced by continuous pulmonary artery air e mbolization for 1 day (short-term) and 14 days (chronic) and was assoc iated with a 2 and 3 fold increase in pulmonary vascular resistance re spectively. 3 L-NOARG (0.1 mM) reduced the maximum relaxation (R(max)) to ionomycin in large and medium-sized pulmonary arteries from contro l sheep by approximately 70%. By contrast, L-NOARG (0.1 mM) did not in hibit the R(max) to ionomycin in matched vessels from short-term and c hronic pulmonary hypertensive sheep. 4 Resistance of ionomycin-induced relaxations to inhibition by L-NOARG, was confined to the arterial va sculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium-sized chronic pulmonary hypertensive ve ins were, like those in control veins, abolished by L-NOARG. Both larg e and medium-sized pulmonary veins from short-term pulmonary hypertens ive sheep, however, were resistant to block by L-NOARG. 5 Neither sens itivity ((p)EC(50)) nor R(max) to ionomycin in large, short-term pulmo nary hypertensive arteries was affected when the extracellular concent ration of K+ was increased isotonically to 30 mM. Nifedipine (0.3 mu M ) was present throughout to prevent high K+-induced smooth muscle cont raction. In the presence of this high extracellular K+, however, L-NOA RG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L-NOARG only weakly inhi bited ionomycin relaxations. 6 In conclusion, the onset of pulmonary h ypertension in sheep following air embolization, is associated with th e development of resistance of endothelium-dependent relaxations to bl ock by L-NOARG. The mechanism of L-NOARG resistance appears to be due to the up-regulation of a K+ channel-mediated backup vasodilator mecha nism which can compensate for the loss of nitric oxide (NO)-mediated r elaxation. Although this mechanism remains functionally 'silent' in th e presence of NO it is able to maintain adequate endothelium-dependent vasodilatation during pulmonary hypertension if NO synthesis is compr omised.