Altered angiotensin-converting enzyme in lung and extrapulmonary tissues of hypoxia-adapted rats

Abstract

The effects of exposing rats to hypoxia (10% O2) at normal atmospheric pressure for periods of 14 or 28 days on angiotensin-converting enzyme (ACE) activity and stores of angiotensin I (ANG I) and angiotensin II (ANG II) in lung, kidney, brain, and testis were examined. ACE activity was measured by spectrophotometric assay, and active sites of ACE were estimated by measuring the binding of 125I-351A [N-(1-carbonyl-3-phenyl-propyl)-L-lysyl-L-proline], a highly specific active site-directed inhibitor of ACE, to tissue homogenates and perfused lungs. Hypoxia exposure produced progressive reductions in ACE activity in lung homogenates and in ACE inhibitor binding to perfused lungs. ANG II levels in lungs from hypoxia-adapted animals were significantly less than air controls, suggesting that the reduction in intrapulmonary ACE activity was associated with reduced local generation of ANG II. ACE activity was increased in kidney and unchanged in brain and testis of hypoxia-adapted rats compared with air controls. Thus the effects of chronic hypoxia on catalytically active ACE and ACE active sites in the intact animal were organ specific. Adaptation to chronic hypoxia did not significantly alter plasma renin activity or ANG I or ANG II levels or serum ACE content. The hypoxia-induced alterations in lung and kidney ACE were reversible after return to a normoxic environment.

Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.

“…Circulating ACE is thought to be derived from vascular endothelial sources, and elevated serum ACE is thought to be a marker of endothelial damage such as occurs with reduced lung ACE in oleic acid-induced acute lung injury (23,33,45). The subsequent return of serum ACE activity back to control values by days 8 and 14 of hypoxia in our study is consistent with other reports of unaltered serum ACE after 2 or 3 wk of hypoxia ( 16,19), though previous authors may have missed the initial fall. The return of serum ACE activity to control values by 8 and 14 d of hypoxia may be partly due to organ-or tissue-specific increases in ACE activity, such as the increase in renal ACE activity which we observed as early as 3 d of hypoxia.…”

“…Our main finding of increased ACE mRNA and antigen expression in small pulmonary arteries associated with alveolar ducts and alveolar walls during chronic hypoxic exposure provides a unifying explanation for the paradoxical results of previous studies in chronic hypoxia where ACE inhibitors were found to attenuate pulmonary hypertension (13)(14)(15), despite a reduction in total lung ACE activity (16)(17)(18)(19). Moreover, the ACE inhibitor, captopril, attenuated the hemodynamic and structural changes of pulmonary hypertension during chronic hypoxia, causing a marked reduction in the distal extension of smooth muscle into normally nonmuscular arteries at the level of alveolar ducts and walls, the sites of increased ACE expression.…”

“…The Estimation of lung, kidney, and serum ACE activity. Changes in ACE activity during hypoxic exposure are known to be organ specific (19). We followed the time course of lung, renal, and serum ACE activity during hypoxia at shorter intervals than previous workers to gain insight into potential mechanisms of altered lung ACE activity, since elevated serum ACE may reflect increased shedding from the pulmonary vascular endothelium (23).…”

“…In the systemic circulation, angiotensin II (All), formed by the action of ACE on angiotensin I, has been shown to be an important mediator of vascular smooth muscle cell growth (11,12) and thus potentially could modulate some of the structural changes associated with pulmonary hypertension. However, substantive evidence of a role for ACE in pulmonary hypertension is lacking, since, although inhibitors of ACE attenuate the medial thickening and right ventricular hypertrophy (13)(14)(15), most workers report a decrease in whole lung ACE activity during the development of pulmonary hypertension induced by chronic hypoxia (16)(17)(18)(19) or ingestion of monocrotaline (20). These disparate findings have led others to conclude that the beneficial effects of ACE inhibitors on pulmonary hypertension are either independent of inhibition of lung ACE or that downregulation of lung ACE may be a protective mechanism.…”

Importance of Angiotensin-Converting Enzyme in Pulmonary Hypertension

“…However, in situations associated with PH. the angiotensin-convert ing enzyme (ACE) lung tissue levels have been reported to be decreased in chronic hypoxic rats [4][5][6][7][8][9] (table 1). Ang II causes pulmonary vasoconstriction in man and in animals [10,11] and angiotensin by itself or in coopera tion with other growth factors [12,14] may also cause structural alterations of the pulmonary hypertensive ves sels.…”