Endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction

1. The experimental model using periods of ventilation with a gas mixture containing 10% oxygen in the anesthetized pig was found to induce HPV that was reproducible and remained stable for up to two hours. 2. Intrapulmonary infusion of ET-1 during normoxia resulted in a dose-dependent increase in the SVR with a concomitant decrease in CO and rise in PVR. Infusion of ET-3 and S6c evoked similar responses, but of a considerably smaller magnitude. The dose-dependent systemic vasoconstriction evoked by ET-1 infusion was reduced after administration of the combined ETA and ETB receptor antagonist bosentan as well as the selective ETA receptor blockers BMS-182874 and TBC-11251 indicating that this effect is primarily mediated by ETA receptors. ETA receptors are present in porcine pulmonary arteries, since BMS-182874 caused a rightward shift of the concentration-response curve to ET-1 in vitro. 3. Administration of selective ETA- or combined ETA and ETB antagonists but not of a selective ETB antagonist reduced the SVR in normoxic pigs, indicating that ET acting through ETA receptors contributes to systemic vascular tone in the pig. In addition, ETA selective and non-selective ETA and ETB antagonists produced a reduction of PVR, although this effect was less consistent than the influence on SVR. This indicates that ETA receptors may contribute to basal pulmonary vascular tone. The plasma levels of ET-1 increased following the non-selective ET receptor antagonist bosentan but were unaffected by selective ETA receptor antagonism. 4. Intrapulmonary infusion of ET-1 produced in low doses a pulmonary vasodilatation during HPV in the pig. This pulmonary vasodilatory effect was also evident when ET-3 or S6c was infused. The pulmonary vasodilatory effect of ET-1 infusion was abolished following administration of the selective ETB receptor antagonist BQ-788, indicating that the pulmonary vasodilatory effect of ET in HPV in the pig is mediated by ETB receptors. Higher doses of ET-1 infusion during HPV resulted in systemic and pulmonary vasoconstriction. 5. Both combined ETA and ETB blockade using bosentan and selective ETA receptor inhibition using BMS-182874 or TBC-11251 reduced the development of HPV in the pig. In addition, bolus injection of TBC-11251 reversed already established HPV. Selective ETB receptor antagonism had no effect on HPV. These findings suggest that ETA receptor activation contributes to HPV in the pig. 6. The concentration-dependent contraction evoked by ET-1 in human vessels in vitro (LAD, IMA, PA, SV) was reduced after incubation with BQ-123 and bosentan. Inhibition of NO- and prostaglandin-synthesis enhanced the contractions in the LAD and IMA, but not in the PA and SV. These findings are in concord with a predominance of ETA receptors in the investigated vessels. Nitric oxide and prostacyclin seem to be important determinants of the functional response to ET in human LAD and IMA, but of less importance in the PA and SV. 7. In the human vessels investigated, the tissue content of ET-1 was higher than that of ET-3 and resembled the distribution of the perivascular C-fiber peptide CGRP. Tissue content of ET-1 was considerably lower than that of sympathetically stored NPY. In human plasma, the arterial and venous concentration of ET-1 was higher in patients with chronic hypoxemia and borderline hypertension than in the venous samples drawn from healthy subjects. The arterial and venous levels of ET-1 did not differ significantly either at rest or during ET-1 infusion, indicating that the pulmonary circulation does not extract ET-1 in these patients. 8. The study in patients with borderline pulmonary hypertension and chronic hypoxaemia showed no pulmonary vasodilatory effects of intrapulmonary ET-1 infusion but rather systemic vasoconstriction and decreased CO. The AVO2 difference increased markedly during ET-1 infusion. 9. (ABSTRACT TRUNCATED)