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: email@example.com).
S. Chaudhary and M.K. Seth have contributed equally.
Received February 24, 2012
Accepted November 30, 2012