title: Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress.
abstract: Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1μM) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10μM) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress.
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Wei Mee
authors: WM
authors: Loh
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Wei Chih
authors: WC
authors: Ling
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Dharmani D
authors: DD
authors: Murugan
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Yeh Siang
authors: YS
authors: Lau
authors: Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, MI, USA.
authors: Francis I
authors: FI
authors: Achike
authors: State Key Laboratory for Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong.
authors: Paul M
authors: PM
authors: Vanhoutte
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address: rais@um.edu.my.
authors: Mohd Rais
authors: MR
authors: Mustafa
mesh_terms: D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: C529402:des-aspartate-angiotensin I; D000804:Angiotensin II; D000803:Angiotensin I
keywords: DAA-I; Endothelial function; Hypertension; Nitric oxide; Renin–angiotensin system