Background
A 779 is a potent and selective angiotensin-(1-7)/ Mas receptor antagonist [1].
Angiotensin-(1-7) is a bioactive component of the renin angiotensin system (RAS) which plays an important role in cardiovascular homeostasis and hydroelectrolyte balance in physiological and pathologic conditions [1][2].
A 779 is an angiotensin antagonist selective for the heptapeptide angiotensin-(I-7) [Ang-(l-7)] [1].
In water-loaded rats, A 779 significantly inhibited the antidiuretic effect of Ang-(l-7). In the rostral ventrolateral medulla, A-779 completely blocked the pressor effect produced by Ang-(1-7) microinjection [1]. In conscious Wistar rats, infusion of vehicle or A-779 (80 ng/ min, i.v.) started 40 to 45 minutes after captopril administration produced a significant shift of the BK dose-response curve obtained after captopril. A-779 significantly attenuated the potentiation of the hypotensive effect of BK by the ACE inhibitor captopril in conscious rats [2]. In anaesthetized male Wistar rats, when AT1R and AT2R were blocked, A779 increased renal blood flow/wet kidney tissue weight (RBF/KW). Co-blockade of all AT1R, AT2R, and MasR might alter RBF/ KW in male more than in female rats, which supported a crosstalk between MasR and Ang II receptors in renal circulation [3].
参考文献:
Santos RA, Campagnole-Santos MJ, Baracho NC, et al.? Characterization of a new angiotensin antagonist selective for angiotensin-(1-7): evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors. Brain Res Bull. 1994;35(4):293-8.
Maia LG, Ramos MC, Fernandes L, et al.? Angiotensin-(1-7) antagonist A-779 attenuates the potentiation of bradykinin by captopril in rats. J Cardiovasc Pharmacol. 2004 May;43(5):685-91.
Mansoori A, Oryan S, Nematbakhsh M.? Role of Mas receptor antagonist (A779) in renal hemodynamics in condition of blocked angiotensin II receptors in rats. Acta Physiol Hung. 2016 Mar;103(1):13-20.
Protocol
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Animal experiment:
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A bilateral OVX operation is use to induce postmenopausal osteoporosis in female Wistar albino rats. The animals are generally anesthetized using single IP injection of ketamine?+?xylazine combination (80?mg/kg and 5?mg/kg; respectively). After ligation, the ovaries are excised from a longitudinal incision made on the dorsolateral body region. Sham rats have the same procedure without the ligation and excision. The risk of postoperative infection is eliminated by applying fusidic acid topical antibiotic cream twice weekly for 4 weeks. Following the sham and OVX operations, animals are divided into eight groups (n?=?8/group) including, Sham, Sham?+?Ang(1-7), Sham?+?A-779, Sham?+?Ang(1-7)+A-779, OVX, OVX?+?Ang(1-7), OVX?+?A-779 and OVX?+?Ang(1-7)+A-779. Eight weeks following sham and OVX operations, osmotic pumps are implanted subcutaneously to deliver Ang(1-7) (200?ng/kg/min), A-779 (400?ng/kg/min) or a mixture of Ang(1-7) and A-779 (200?ng/kg/min and 400?ng/kg/min; respectively) for 6 consecutive weeks. Body weights of all animals are monitored and recorded at the beginning and every week throughout the study. Animals' general health is maintained during periods of treatments. At the end of treatments periods, animals are placed fasting in metabolic cages for 16?hr and urine samples are collected and frozen at ?70°C. Then, the blood samples are collected by cardiac puncture under ketamine?+?xylazine anesthesia and serum samples are obtain by centrifugation at 4000 RPM to. Animals are then sacrificed by decapitation and the uterine tissues and femoral bones are removed and cleaned. Uterine tissues are cleaned from fats and the wet weights are determined directly and expressed as g/100?g body weight. In each rat, both femurs are removed and cleaned from soft tissues. The left femoral bone samples are frozen at ?70°C until analyzed, while the right femoral bones are kept in 10% formalin for mico-CT and minerals analysis.
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参考文献:
[1]. Abuohashish HM, et al. Angiotensin (1-7) ameliorates the structural and biochemical alterations of ovariectomy-induced osteoporosis in rats via activation of ACE-2/Mas receptor axis. Sci Rep. 2017 May 23;7(1):2293.
[2]. Abuohashish HM, et al. ACE-2/Ang1-7/Mas cascade mediates ACE inhibitor, captopril, protective effects in estrogen-deficient osteoporotic rats. Biomed Pharmacother. 2017 Aug;92:58-68.
[3]. Yan WF, et al. Effects and related mechanism of angiotensin-(1-7) on Toll-like receptor 4-mediated oxidative stress in human umbilical vein endothelial cells. Zhonghua Xin Xue Guan Bing Za Zhi. 2017 Mar 24;45(3):223-229.
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