Integrated control of pulmonary vascular tone by endothelin and angiotensin II in exercising swine depends on gender.

The lungs are now recognized as an active metabolic organ that is a major determinant of the plasma concentrations of the vasoconstrictors endothelin (ET) and ANG II. Several studies have suggested a complex interaction between ET and ANG II in the systemic and coronary vascular beds that is different at rest and during exercise. To date, the interaction between these vasoconstrictor peptides has barely been investigated in relation to the pulmonary vascular bed. Consequently, we investigated the integrated control of pulmonary vasomotor tone by ET and ANG II in 24 chronically instrumented swine (15 female and 9 male) at rest and during graded treadmill exercise. In the systemic circulation, ANG II type 1 (AT(1)) receptor blockade with irbesartan and mixed ET(A)/ET(B) blockade with tezosentan each produced vasodilation. The systemic vasodilator effect of ET(A)/ET(B) blockade was enhanced after AT(1) blockade in female swine, whereas a trend toward an increase was observed in male swine. In the pulmonary circulation, AT(1) receptor blockade had no effect on pulmonary vascular tone in male swine, whereas it resulted in an unexpected increase in pulmonary vasomotor tone in female swine. ET(A)/ET(B) receptor blockade did not result in a decrease in pulmonary vasomotor tone at rest but produced a decrease in vasomotor tone during exercise in both genders. This pulmonary vasodilation by ET(A)/ET(B) receptor blockade was enhanced after prior AT(1) blockade in female swine but not in male swine. In conclusion, in both the systemic and pulmonary circulation of female swine, ANG II inhibits the vasoconstrictor influence of ET. This interaction is gender specific. The observation that plasma ET levels were not altered by AT(1) blockade in either gender suggests that the interaction between these vasoconstrictors occurs locally in the vasculature.