Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension.
Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.
D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D011651:Pulmonary Artery / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin