Urocortin inhibits mesenteric arterial remodeling in spontaneously hypertensive rats
Introduction
Urocortin (UCN), a 40-amino acid peptide, has 45% structural homology with the peptide corticotrophin-releasing factor (CRF) and belongs to a group of structurally related peptides which include, in addition to UCN and CRF, urotensin1 and sauvagine [5], isolated from fish neurosecretory cell and frog skin, respectively. Immunoreactivity study showed that UCN is widely distributed in central nervous, digestive, cardiovascular, reproductive, immune, and endocrine systems [24], [35]. These facts suggested that UCN may have important physiological roles in various tissues.
In addition to pituitary and central effects as neurotransmitters, peripheral effects of CRF-related peptides have been observed, particularly in the cardiovascular system in which UCN exerts cardioprotective effect. In cardiac system, in vitro studies have demonstrated that UCN can protect neonatal rat cardiac myocytes when administered before hypoxia or at the point of reoxygenation while in adult rat heart UCN reduced the infarct size of a perfused intact rat heart exposed to regional ischemia [3], which was confirmed by our recent in vivo study [17]. Furthermore, a number of studies have implied that the mitogen-activated protein kinase (MAPK) acts as a survival pathway in cardiac cells and other cell types [1], [6], which might be one of the underlying cardioprotective mechanisms of the effects induced by UCN [3], [9].
On the other hand, in normal mice and rats, intravenous administration of UCN caused decrease in blood pressure and improved the contractility of the heart [22] after long-term administration possibly by hindering the development of cardiac remodeling. In vasculature, UCN binds with high affinity to CRF 2 receptor (CRFR2), mediating a vasodilating action [8], [35]. CRFR2, localized at distinct central and peripheral sites has been shown to play an important role in vascular regulation [18], [30]. In rats, UCN was found to produce a potent, long lasting hypotension, which might be due to systemic vasodilation [5]. It has been shown that UCN could cause relaxation of rat basilar [26], tail [19], and coronary arteries [12], and result in a reduction in arterial pressure [25] and an increase in heart rate [23].
In a previous study, UCN was reported to induce both endothelium-dependent and endothelium-independent vascular relaxation [15], highly implying that UCN may affect vascular smooth muscle cells (VSMC) directly. Our in vitro study indicated that UCN could reduce the viability of adult rat VSMC [32]. These results suggest that UCN might play a role in vascular remodeling since VSMC are a key factor in the development of vascular remodeling [2]. So far however, there has been no in vivo investigation about the effects of UCN on vascular remodeling in spontaneously hypertensive rats (SHRs).
This present study deals with the inhibitory effect of UCN on the development of mesenteric arterial remodeling in SHRs. With the model of the rats, we firstly investigated the effects of long-term (56 days) intravenous UCN on the functional and structural changes of mesenteric arteries.
Section snippets
Materials and methods
Animal care and handling conformed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH), and the study was approved by the local institutional ethical committee.
Effects of UCN on blood pressure
To determine whether UCN could maintain a stable hypotensive action, the rats were treated for 56 days with UCN (1 μg/kg/d, 3.5 μg/kg/d and 7 μg/kg/d), enalapril (10 mg/kg/d), or saline. Before the treatment began, SBP in SHR groups had no significant difference, and was remarkably higher than that in WKY rats (n = 6, P < 0.01) (Table 1). A significant decrease of about 40 mmHg in SBP, which was approximately equivalent for both UCN (7 μg/kg/d) and enalapril, was observed 1 week after the beginning of
Discussion
Hypertension is a critical risk factor for cardiovascular events, and thus the research of the vascular function during hypertension has attracted extensive attention. It is well established that hypertension is always accompanied with increase in artery wall thickness, mainly caused by proliferation, hypertrophy, migration and apoptosis of vascular smooth muscle cells (VSMC) accompanying with elevated content of connective tissues [2]. In general, the resistance vessels of essential
Acknowledgements
This work was supported by grants from Natural Science Foundation of China (No. 30371646) and Key Subject of Ministry of Education of China (No. 03047).
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