Angiotensin Converting Enzyme Inhibition Decreases Cell Turnover in the Neonatal Rat Heart

Abstract

The renin angiotensin system plays an important role in growth and development. Exposure of the neonate to an ACE inhibitor increases mortality and results in growth retardation and abnormal development. We have demonstrated that ACE inhibition in the developing kidney increases apoptosis and decreases cell proliferation, which may account for renal growth impairment. To evaluate the role of endogenous angiotensin in cardiac development, the relationship between ACE inhibition, cell proliferation, apoptosis, several modulators of apoptosis (bcl-2, bcl-xl, and clusterin) was examined in the developing rat heart. Thirty-five newborn rat pups were treated with enalapril (30 mg/kg/d) or a vehicle (control group) for 7 d, and hearts were removed for rt-PCR and Western blotting of bcl-2, bcl-xl, and clusterin. An additional 10 rat pups were treated with hydralazine (10 mg/kg/d) or a vehicle, to serve as a hypotensive control. Cell proliferation was determined by PCNA immunostaining, and apoptosis was detected using the total TUNEL technique. Enalapril treatment resulted in a 24% mortality, reduced body weight, and decreased heart weight (p Ͻ 0.05). Enalapril decreased proliferating myocytes by 23%, and reduced proliferating cardiac interstitial cells by 8.1% (p Ͻ 0.05). Enalapril also decreased myocytes apoptosis by 60%, but the proportion of myocytes undergoing apoptosis was 10-fold less than that of proliferating cells. Cardiac bcl-2 mRNA, clusterin mRNA, bcl-2 protein, and bcl-xl protein content were not changed, but clusterin protein expression was decreased by enalapril treatment. Hydralazine did not alter cardiac cell proliferation or apoptosis. We conclude that ACE inhibition decreases cell turnover in the developing rat heart, which may contribute to cardiac growth impairment. The loss of myocytes may lead to greater myocyte hypertrophy and myocardial damage during later life. The renin angiotensin system (RAS) plays a role in the maintenance of systemic arterial pressure in the newborn, and provides a homeostatic response to hypovolemia (1). Davidson (1) demonstrated parallel increases in plasma renin activity in arterial ANG-II concentration occurred in the immediate minutes after delivery. Furthermore, the release of catecholamines may be stimulated by the production of ANG II, and the activation of the sympathoadrenal system at birth has been implicated in several adaptive processes and structural integrity (2).In newborn animals and human infants, the activity of the RAS increases at birth, which is important in regulating cellular growth and organ differentiation (1, 3). ANG-II, which is a final product of the RAS, has been reported to exert atrophic effect on cardiac myocytes in cultures (4) and in vivo (5). ANG-II may stimulate a growth response in cardiac tissue indirectly, by increased blood pressure and total peripheral vascular resistance, which develops in response to ANG-II receptor coupling in the vasculature (5). Alternatively, ANG-II may have a direct effect by coupling to its cardiac membrane...

AT1 antagonist modulates activin-like kinase 5 and TGF-β receptor II in the developing kidney

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ACE inhibition modulates transforming growth factor-? receptors in the young rat

“…Based on recent animal and human experiments [1,2,3,4], the RAS is closely related to fetal growth and development. The fact that the total expression of the RAS increases greatly in the early fetal or neonatal stages of kidney development also implies that ANG II has important functions in developing kidneys [22].…”

“…Angiotensin II (ANG II) stimulates growth of many tissues, including the kidney [1,2]. ANG II can potentiate the mitogenic effect of other growth factors and acts synergistically with other factors to promote cell growth [3].…”

Angiotensin-Converting Enzyme Inhibition Modulates Mitogen-Activated Protein Kinase Family Expressions in the Neonatal Rat Kidney

“…The long-term ACE inhibition may have an effect on the renal hemodynamics, as a result of hypotension, microcirculation, or local ischemia in an in vivo model. In previous reports, there is no direct evidence that enalapril-induced hemodynamic changes affect cellular responses in the developing rat kidney (6,43). The effect of antihypertensive drugs (e.g.…”