title: Sulfur-containing angiotensin-converting enzyme inhibitor 3-thienylalanine-ornithyl-proline activates endothelial function and expression of genes involved in Renin-Angiotensin system.
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.
authors.affiliation: Peptide Synthesis Laboratory, CSIR, Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Chaudhary
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Seth
authors.forename: Ishwar Dutt
authors.initials: ID
authors.lastname: Vats
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.forename: Parbati
authors.initials: P
authors.lastname: Biswas
authors.forename: Jayashree
authors.initials: J
authors.lastname: Karar
authors.forename: M Ejaz
authors.initials: ME
authors.lastname: Hussain
authors.forename: M A Q
authors.initials: MA
authors.lastname: Pasha
authors.forename: Santosh
authors.initials: S
authors.lastname: Pasha
mesh_terms: D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C540584:3-thienylalanyl-ornithyl-proline; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D016166:Free Radical Scavengers; D009842:Oligopeptides; D012333:RNA, Messenger; D013876:Thiophenes; D009569:Nitric Oxide; D002216:Captopril