enalapril and Hypoxia

Both the renin-angiotensin-aldosterone system (RAAS) and hypoxia are vital physiological factors involved in the control of nephrogenesis and vascularization. We investigated the relationship between RAAS and hypoxia in the developing kidney. The expression of VEGF and heme oxygenase (HO)-1 related with the oxygen was analyzed in the enalapril- or spironolactone-treated neonatal rat kidneys. Enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) was administered to newborn rat pups for 7 d. The newborn rats were injected i.p. with pimonidazole (200 mg/kg), a marker of severe tissue hypoxia, 1 h before killing. VEGF and HO-1 protein expression was significantly increased by immunoblots and immunohistochemistry in both the enalapril- and spironolactone-treated kidneys, compared with the controls (p < 0.05). HO-1 mRNA expression was increased in the spironolactone-treated group (p < 0.05). The immunoactivity of pimonidazole was not different from that of the controls in the enalapril-treated group, whereas it was increased in the spironolactone-treated group. The results of this study indicate that aldosterone blockade or angiotensin II inhibition in the developing rat kidney up-regulated renal VEGF and HO-1 expression regardless of the hypoxic conditions and may differentially modulate VEGF and HO-1 production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Blotting, Western; Enalapril; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Hypoxia; Immunohistochemistry; Kidney; Mineralocorticoid Receptor Antagonists; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spironolactone; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A

Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart.. First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor(-/-) mouse heart under normoxia (21% O(2)) and hypoxia (1% O(2)) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF(164); n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis.. The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Enalapril; Fibroblast Growth Factors; Heart; Hypoxia; In Vitro Techniques; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nitric Oxide; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Vascular Endothelial Growth Factor A

Chronic hypoxia induces pulmonary hypertension and right ventricular hypertrophy. These changes are completely reversible, except for persistent myocardial fibrosis. The aim of the present study was to determine whether treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril can reduce the ventricular collagen content in animals recovering from chronic hypoxia. Adult male Wistar rats were exposed to intermittent high-altitude hypoxia simulated in a barochamber (7000 m, 8 hr/day, 5 days a week, 24 exposures), then transferred to normoxia and divided into two groups: (a) treated with enalapril (0.1 g/kg/day for 60 days) and (b) without treatment. The corresponding control groups were kept under normoxic conditions. Enalapril significantly decreased the heart rate, systemic arterial pressure, and absolute left and right ventricular weights in both hypoxic and control rats; on the other hand, the pulmonary blood pressure was unchanged. The content and concentration of collagen was reduced in both ventricles of enalapril-treated hypoxic and control animals by 10-26% compared with the corresponding untreated groups. These data suggest that the partial regression of cardiac fibrosis due to enalapril may be independent of the pressure load.

Topics: Altitude Sickness; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Enalapril; Hemodynamics; Hydroxyproline; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Myocardium; Organ Size; Pulmonary Fibrosis; Rats; Rats, Wistar

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.

Topics: Adaptation, Physiological; Angiotensin I; Angiotensin II; Animals; Dipeptides; Enalapril; Hypoxia; Lisinopril; Lung; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains