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Sulfur-Containing Angiotensin-Converting Enzyme Inhibitor 3-Thienylalanine-Ornithyl-Proline Activates Endothelial Function and Expression of Genes Involved in Renin–Angiotensin System

Chaudhary, Snehlata PhD*,†; Seth, Mahesh Kumar MSc*,§; Vats, Ishwar Dutt PhD*; Kumar, Krishan MPhil*; Biswas, Parbati PhD; Karar, Jayashree PhD; Hussain, M. Ejaz PhD§; Pasha, M.A.Q. PhD; Pasha, Santosh PhD*

Journal of Cardiovascular Pharmacology: April 2013 - Volume 61 - Issue 4 - p 311–317
doi: 10.1097/FJC.0b013e318280e16e
Original Article

Abstract: Experiments were performed to elucidate the mechanism of action of a 7-day oral administration of the sulfur-containing angiotensin-converting enzyme (ACE) inhibitor 3-thienylalanine-ornithyl-proline (TOP; 10 mg/kg/d) on endothelial dysfunction and oxidative stress compared with that of captopril (control; 40 mg/kg/d) in spontaneously hypertensive rats. The differential expression of messenger RNA by real-time reverse-transcriptase–polymerase chain reaction and protein by Western blot analysis was assessed for the markers nicotinamide adenine dinucleotide phosphate oxidase, p22phox, endothelial nitric oxide (NO) synthase, and AT1 receptor. Furthermore, TOP-induced vascular relaxation was also investigated using rat aortic rings in an organ bath. TOP significantly downregulated both messenger RNA and protein expressions of p22phox and AT1 receptor; the latter facilitates vasoconstriction through angiotensin II. In addition, TOP upregulated endothelial NO synthase, thus enhancing the production of NO. Vascular studies revealed that TOP caused endothelium-dependent vasorelaxation. In conclusion, unlike the free sulfur in captopril, the thiophene ring in TOP may act as a better scavenger of free radicals. Therefore, TOP exerted more significant antihypertensive effects than captopril, not only through angiotensin-converting enzyme inhibition but also through more effective antioxidation, because the inherent thiophene moiety resulted in the enhanced production of NO.

*Peptide Synthesis Laboratory, CSIR, Institute of Genomics and Integrative Biology, Delhi, India

Department of Chemistry, University of Delhi, Delhi, India

Functional Genomics Unit, Institute of Genomics and Integrative Biology, Delhi, India

§Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia, New Delhi, India.

Reprints: Dr Santosh Pasha, PhD, Peptide Synthesis Laboratory, CSIR, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India (e-mail:

S. Chaudhary and M.K. Seth have contributed equally.

Received February 24, 2012

Accepted November 30, 2012

© 2013 Lippincott Williams & Wilkins, Inc.