Role of angiotensin converting enzyme and angiotensin ii in the
development of hypoxic pulmonary hypertension.
Morrell, Nicholas W., Kenneth G. Morris, and Kurt R. Stenmark.
Developmental Lung Biology Laboratory, Department of Pediatrics,
and Cardiovascular Pulmonary Laboratory, Department of Medicine,
University of Colorado Health Sciences Center, Denver, Colorado
80262.
APStracts 2:0168H, 1995.
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 (AII) receptor antagonists to
investigate whether AII is involved directly in the hemodynamic and
structural changes of pulmonary hypertension, and 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 AII type 1 receptor antagonist, losartan,
4) the AII type 2 receptor antagonist, PD123319, or 5) saline. At 14
days, mean pulmonary arterial pressure (MPAP) was reduced (p<0.05) in
hypoxic rats treated with captopril (26.6 0.8mmHg) or losartan (24.4
1.0mmHg) compared to saline (32.0 1.4mmHg), but was unaffected by
PD123319 (29.5 1.7mmHg). Right ventricular hypertrophy was reduced in
hypoxic rats treated with captopril or losartan compared to saline
treated rats. Morphometry showed less medial thickening and
peripheral muscularization of small pulmonary arteries in hypoxic
animals treated with captopril or losartan. Co-administration of CP
-0597 did not reverse the protective effects of captopril on pulmonary
vascular remodeling. These results suggest a novel role for
endogenous AII, 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 AII production rather than potentiation of bradykinin.
Received 19 January 1995; accepted in final form 3 April 1995.
APS Manuscript Number H53-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 2 May 1995.