 Lucia B. Fuentes (Correspondence)  + This article is published under the terms of the Creative Commons Attribution License 4.0 Author(s) retain the copyright of this article. Publication rights with Alkhaer Publications. Published at: http://www.ijsciences.com/pub/issue/2019-02/ DOI: 10.18483/ijSci.302; Online ISSN: 2305-3925; Print ISSN: 2410-4477 Maternal Exposure to Enalapril Impairs Alveolarization in Neonatal Developing Rat Lung Diego N. Capelari 1,2 , Susana I. Sánchez 2 , Hugo H. Ortega 3 , Lucia B. Fuentes 2  1 Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-SL) – Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET). San Luis, Argentina 2 Facultad de Química, Bioquímica y Farmacia. Universidad Nacional de San Luis (UNSL). Ejército de los Andes 950. D5700HHW - San Luis, Argentina 3 Departamento de Ciencias Morfológicas, Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral (UNL). R.P. Kreder 2805. S3080HOF - Esperanza, Santa Fe, Argentina Abstract: The renin-angiotensin system (RAS) during fetal or neonatal stages has been involved in lung growth and differentiation process. We studied the effects of maternal exposure to enalapril during late gestation (G13-G21) on lungs from their offsprings. Pregnant rats were administered with enalapril (2,85 mg/kg/day) and lungs analyzed at postnatal ages, significant difference between P0 and P30. Enalapril-treatment did not modify ACE activity in mothers, but decreased significantly in P0 treated-pups suggesting direct placental drug transference. sACE expression increased with age in both groups. AT1 receptors expression was high and localized in alveolar, bronchiole and endothelium cells. We detected larger but fewer alveoli with decreased septation at earlier postnatal stage in enalapril-treated pups. Quantification of immunopositive nuclei demonstrated that in treated pups the proliferation impairs in newborn lungs and thus progressively increased during two postnatal weeks, at difference with controls animals, where the highest proliferation levels were at P0 and then decreased significantly. In coincidence, high α-smooth muscle actin staining at the tips of developing secondary septal structures was observed at P15, evidencing an active elastogenesis. In summary, decreased ACE activity produced histomorphological changes and an impaired cellular proliferation at the saccular stage; however an active proliferation and elastogenesis, at later stages, suggest that the developing lung has the capacity to recover once treatment was stopped. Alterations in RAS function could contribute to the abnormalities in lung development tissue indicating that the system is one intrinsic factor necessary to differentiation and alveolarization process. However, other local factors could be involved in this mechanism. Keywords: Renin-Angiotensin-System, Angiotensin-Converting Enzyme, Cellular Proliferation, Enalapril, Lung Development 1. Introduction Distribution of the renin–angiotensin system (RAS) is developmentally regulated in a tissue-specific manner. Angiotensin II (Ang II), the active peptide of the RAS, can act as a modulator of growth and differentiation in a variety of cells and tissues [1-4]. The actions of Ang II are mediated by two receptor subtypes designated as AT 1 and AT 2 [5]. Angiotensin-converting enzyme (ACE, E.C. 3.4.15.1), critical component of the RAS, is a Zn 2+ metallopeptidase, responsible for proteolytic cleavage of angiotensin I into Ang II [6]. The ACE gene codifies for two splice variants, the somatic isoform (sACE) expressed primarily in endothelial and epithelial cells, and the testicular isoform [7]. In the lung, ACE activity begins from gestational day 18 and increases fourfold prior to birth (21 days gestation) [8,9]. The discovery of ACE inhibitors represents a major advance in treatment of hypertension, being captopril and enalapril, the first inhibitors approved, widely used in hypertension treatment and other cardiovascular pathologies [10]. ACE inhibitor´s administration is contraindicated during pregnancy because of mayor fetal malformations [11,12] and increased risks of fetopathy [13-15] due to their ability to pass the fetoplacental barrier [16]. In previous reports oligohydramnios was described, often accompanied by hypoplastic lungs, respiratory failure and death in the neonatal period [10, 14,15].