Ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate Prevents Progression of Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

S. M. Malik; Satyanarayan Deep; Rahul Ranjan; A. K. Prasad; Dipti N Prasad; Shashi Bala Singh; Ekta Kohli

doi:10.14429/dlsj.3.12005

S. M. Malik Department of Chemistry, University of Delhi, Delhi -110 007, India
Satyanarayan Deep Department of Chemistry, University of Delhi, Delhi -110 007, India
Rahul Ranjan Defence Institute of Physiology and Allied Science
A. K. Prasad Department of Chemistry, University of Delhi, Delhi -110 007, India
Dipti N Prasad Defence Institute of Physiology and Allied Science
Shashi Bala Singh DRDO-Directorate of Life Sciences, New Delhi - 110 011, India
Ekta Kohli Defence Institute of Physiology and Allied Science

DOI: https://doi.org/10.14429/dlsj.3.12005

Keywords: Monocrotaline, Pulmonary arterial hypertension, Calcium channel blockers, right ventricle hypertrophy, medial wall thickness, apoptosis, Nitric oxide, H-DHPM.

Abstract

Therapies to prevent onset and progression of pulmonary arterial pressure are not very effective yet. This study was designed to investigate the effects of a novel dihydropyrimidinone, ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM) on pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). For the same purpose, rats were injected intraperitoneally (i.p.) a single dose (60 mg/kg) of MCT which led to development of PAH in 21 days. MCT insult caused high mortality, pulmonary vascular and parenchymal remodelling. Since the course of PAH pathogenesis is characterised by an early onset and progression phases, H-DHPM was administered i.p. at 30 mg/kg dosage in MCT pre-injected animals either from day 0 through day 21 or day 14 though day 21 of MCT injection in two separate treatment groups. H-DHPM significantly improved survival, prevented remodelling of pulmonary vasculature and parenchyma and subsequently ameliorated PAH pathogenesis. Moreover, we observed significant decrease in right ventricle hypertrophy, measured by wet weight of right ventricle (RV) divided by wet weight of left ventricle plus septum (LV+S), in H-DHPM treated groups as compared to MCT injected animals. These findings suggest H-DHPM not only prevented development of PAH but also treated the PAH pathogenesis in progressive phase. In conclusion, our data determines H-DHPM, might be a future drug for the prevention of PAH.

Author Biographies

S. M. Malik, Department of Chemistry, University of Delhi, Delhi -110 007, India

Mr Shajer M. Malik has received his MSc in Toxicology (Life Science) from Jamia Hamdard University. Currently, he is working as a Senior Research Fellow at Department of Physiology, Defence Institute of Physiology and Allied Science,Delhi. He is interested in the elucidating pathomechanisms of high altitude associated pulmonary hypertension and identifying the key therapeutic targets.

Satyanarayan Deep, Department of Chemistry, University of Delhi, Delhi -110 007, India

Dr Satyanarayan Deep has received his PhD in Life Sciences from Bharathair University. He has various publications on his name. His area of research was to understand molecular cause of neurodegeneration at high altitude.

Rahul Ranjan, Defence Institute of Physiology and Allied Science

Mr Rahul Ranjan has done MSc in Biomedical Science from University of Delhi. Currently he is working as a senior research fellow at department of Neurobiology, Defence Institute of Physiology and Allied Sciences, Delhi. He is interested in studying hypobaric hypoxia induced neurodegeneration.

A. K. Prasad, Department of Chemistry, University of Delhi, Delhi -110 007, India

Prof. A.K. Prasad obtained his PhD from University of Delhi. His major research interest lies in the areas : Biocatalysis and biotransformations, polymeric architecture & supra-molecular chemistry and synthesis of modified nucleosides and bioactive heterocycles.

Dipti N Prasad, Defence Institute of Physiology and Allied Science

Dr Dipti N. Prasad is Scientist ‘F’ and Head of Neurobiology Department, Defence Institute of Physiology and Allied Sciences, Delhi. She has supervised many graduated students and has publications in various national and international journals.

Shashi Bala Singh, DRDO-Directorate of Life Sciences, New Delhi - 110 011, India

Dr Shashi B. Singh, Director General, Life Sciences, DRDO. She has immensely contributed to the understanding of high altitude physiology and pioneered the development of nutraceuticals and prophylactics for several high altitude maladies that include hypophagia and cognitive impairment.

Ekta Kohli, Defence Institute of Physiology and Allied Science

Dr Ekta Kohli is Scientist ‘E’ at Defence Institute of Physiology and Allied Sciences, Delhi. Her major research area is Nanotechnology and Toxicology. She has publications in various national and International journals, chapters, and patent to her credit.