Angiotensin-(1-7) induced vascular relaxation in spontaneously hypertensive rats
Introduction
Micro- and macrovascular complications contribute to mortality and morbidity in patients with hypertension [1]. Numerous studies have shown that endothelial dysfunction of small arteries occurs in patients with essential [2,3] or secondary hypertension [4,5], and in the early stage of various hypertensive models [6]. Normally, endothelial cells release nitric oxide (NO) [7,8], and NO then induces the vascular smooth muscle cells (VSMC) relaxation, through the intracellular cGMP-protein kinase G (PKG) signal pathway [9]. Decreased NO generation induced by endothelial dysfunction of small arteries, and impaired NO-dependent vascular relaxation are implicated in the development and progression of hypertension [7,10] and contribute to further progression of organ damage [11].
Enhanced vasoconstriction and attenuated vasodilatation especially in the mesenteric artery (MA) resulted in increased total peripheral resistance, and sustained high blood pressure in hypertension [12]. Coronary artery (CA) disease is one usual cause of mortality, due to attenuated vasodilatation and sustained coronary arterial contraction in hypertensive patients [13,14]. Endothelial dysfunction induces impaired coronary arterial relaxation, reduces the blood supply to the heart and subsequently causes myocardial ischemia and angina [15]. Although pulmonary arterial endothelial dysfunction in hypertensive patients is not common, there are still occurrences of pulmonary hypertension in hypertensive patients [16,17], and in hypertensive models [18,19]. Attenuated pulmonary arterial relaxation increases pulmonary vascular resistance and the risk of pulmonary hypertension [20].
Angiotensin (Ang)-(1-7) is accepted as one important biologically active peptide in the renin-angiotensin system (RAS) family to adjust cardiovascular activity [21,22]. Ang-(1-7) is generated from the hydrolysis of Ang II or Ang I catalyzed by angiotensin converting enzyme 2 (ACE2) [23]. Most of its effects are mediated by the Mas receptor [24]. The Mas receptor expresses abundantly in the vessel endothelial cell and is selectively blocked by its specific antagonist d-Alanine-Ang-(1-7) (A-779) [[25], [26], [27]]. Our recent studies found that microinjection of Ang-(1-7) into either paraventricular nucleus (PVN), or rostral ventrolateral medulla (RVLM) increases arterial blood pressure and sympathetic activity in renovascular hypertensive rats or chronic heart failure rats [[28], [29], [30]]. While some studies show the opposite effect of Ang-(1-7) in peripheral tissues on modulating arterial blood pressure. It has been reported that intravenous injection of Ang-(1-7) decreases blood pressure [31] and induces the mesenteric arterial relaxation in normal rats [32]. Ang-(1-7) prevented Ang I- and Ang II-mediated changes in vascular resistance more potently in SHR-stroke prone than in WKY [33]. Ang-(1-7) improves endothelial function and delays the development of cardiac remodeling and heart failure in rats with myocardial infarction [34]. These findings suggest the probable beneficial effect of Ang-(1-7) on endothelial function and vascular tension. However, whether Ang-(1-7) induces MA, CA, and pulmonary artery (PA) relaxation, and decreases blood pressure in hypertension, is still unclear. Whether NO and the downstream cGMP-PKG signal pathway mediate the Ang-(1-7) effects on arteries is also unclear.
The present study was designed to determine whether Ang-(1-7), by means of the NO-cGMP-PKG signal pathway, decrease blood pressure, and induce MA, CA, and PA relaxation in spontaneously hypertensive rats (SHR).
Section snippets
Materials and methods
The experiments were carried out in male adult Wistar-Kyoto rats (WKY) and SHR at an age of 13 weeks old (Vital River Laboratory Animal Technology Co. Ltd, Beijing, China). The procedures were approved by Nanjing Medical University Experimental Animal Care and complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication, 8th edition, 2011). The rats were kept in a temperature-controlled at 22 °C room on a 12 h–12 h
General data in WKY and SHR
The systolic blood pressure measured in conscious state and the mean arterial pressure measured under anesthesia were significantly increased in SHR, while body weight or heart rate between WKY and SHR had no significant difference (Table 1). Compared with WKY, the high K+ solution induced vasoconstriction in MA, CA and PA was enhanced significantly in SHR (Table 2). ACh-induced dose-dependent relaxations in MA, CA and PA in SHR were attenuated significantly compared with WKY (Fig. 1).
Effects of Ang-(1-7) on baseline renal sympathetic nerve activity, mean arterial pressure and heart rate
Discussion
Numerous studies have shown that endothelial dysfunction is a hallmark of hypertension. Enhanced vasoconstriction and attenuated vasodilatation due to the endothelial dysfunction of MA, results in increased total peripheral resistance and sustained high blood pressure in hypertension [38]. Endothelial dysfunction induced impaired coronary arterial relaxation reduces the blood supply to the heart and subsequently causes myocardial ischemia and angina in hypertension [11,39,40]. Attenuated
Conflicts of interest
The authors declare no conflict of interest.
Author contributions
All authors contributed to the work in this paper. Y.H. conceived and designed the experiments. F.Z., X.S.R., Y.X., Y.R.L and S.S performed the experiments. F.Z., P.L. and A.D.C analyzed the data. Y.H. and H.T wrote or contributed to the writing of the manuscript. H.T provided intellectual suggestions and critically reviewed the manuscript.
Author disclosure statement
No competing financial interests exist.
Sources of funding
This work was supported by the National Natural Science Foundation of China [81470538 & 31571168], Jiangsu Qing Lan Project and the Natural Science Basis Research Plan in Shanxi Province of China (2018JC-012).
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These authors contributed equally to this work.