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

Sammanfattning: Endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction Peter Holm A number of substances originating from the pulmonary endothelium have recently been found to be involved in the regulation of pulmonary vascular tone. Accumulating evidence suggests that endothelial dysfunction contributes to pulmonary hypertension, an important clinical problem often associated with hypoxemia. The plasma levels of the endothelium-derived peptide endothelin-1 (ET-1) are elevated in patients with pulmonary hypertension. In addition, although the most conspicuous effect of ET-1 is severe vasoconstriction ET-1 infusion has been found to produce pulmonary vasodilatation in experimental animals during hypoxic pulmonary vasoconstriction (HPV). The main purpose of the present study was to investigate the role for ET-1 in a large animal model of pulmonary hypertension, in humans with chronic hypoxia and pulmonary hypertension, and in human vasculature. 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. 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, TBC-11251 reversed already established HPV. Selective ETB receptor antagonism had no effect on HPV. Infusion of ET-1 and the ETB receptor agonists, endothelin-3 and sarafotoxin 6c produced pulmonary vasodilatation during HPV in the pig. The pulmonary vasodilatory effect of ET-1 infusion was abolished following administration of the selective ETB receptor antagonist BQ-788. During normoxia, ETA selective and non-selective ETA and ETB antagonists produced per se a reduction of systemic and pulmonary vascular resistance. The dose-dependent systemic vasoconstriction evoked by ET-1 infusion was reduced after administration of selective ETA receptor blockers during normoxia. The concentration-dependent contraction evoked by ET-1 in human vessels in vitro was reduced after incubation with bosentan and the selective ETA antagonist BQ-123 in concord with a predominance of ETA receptors. Inhibition of nitric oxide- and prostaglandin-synthesis enhanced the contractions in human systemic but not pulmonary arteries. In the human vessels investigated, the tissue content of ET-1 was higher than that of ET-3. In patients with borderline pulmonary hypertension and chronic hypoxemia the plasma concentration of ET-1 was higher than in healthy subjects. Intrapulmonary ET-1 infusion in the patient group did not induce pulmonary vasodilatation, but rather systemic vasoconstriction and decreased cardiac output. The arterial and venous levels of ET-1 did not differ either at rest or during ET-1 infusion, indicating that the pulmonary circulation does not extract ET-1 in these patients. In conclusion, the findings of the present study suggest an important function for ET-1 in hypoxic pulmonary hypertension: exogenously applied ET-1evokes vasodilatation in acute hypoxia in the pig but not in chronic hypoxia in humans. Endogenous ET-1 contributes to hypoxic pulmonary vasoconstriction and to basal systemic and pulmonary vascular tone during normoxia in the pig. The vasodilating effect is mediated by ETB receptors, whereas the vasoconstriction is caused by ETA receptor activation. Thus, ETA antagonism may represent a new principle in the treatment of pathological conditions associated with hypoxic pulmonary hypertension. Key words: bosentan, BMS-182874,, BQ-123, BQ-788, endothelin, endothelium, hypoxia, hypoxic pulmonary vasoconstriction, pulmonary hypertension, receptor antagonism, TBC 11251. ISSN 1401-7458

  Denna avhandling är EVENTUELLT nedladdningsbar som PDF. Kolla denna länk för att se om den går att ladda ner.