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  • hUcn II influence on MAP is mediated by the

    2019-07-11

    hUcn II influence on MAP is mediated by the activation of CRF2 receptors. In vitro binding studies established that hUcn II is a selective ligand for CRF2 receptors with a slightly higher affinities for CRF2β compared with CRF2α and low or no affinity for CRF1 receptor [13], [19], [24]. Recent in vivo biological studies showed that Ucn II injected ip at doses ranging from 6 to 60 μg/kg did not exhibit CRF1-like action on colonic motor function while displaying a CRF2 receptor mediated inhibitory effect on gastric transit as monitored simultaneously in rodents [17], [19]. Therefore, unlike CRF and urocortin that bind to both CRF receptor subtypes [23], the decrease in blood pressure induced by iv hUcn II at the dose used should involve solely interaction with CRF2 receptors. This is further supported by the demonstration that the selective CRF2 antagonist, astressin2-B [26] injected iv completely blocked iv hUcn II-induced lowering of basal arterial blood pressure. Previous studies in mice demonstrate that genetic deletion of the CRF2 receptor abolished the reduction in MAP induced by the iv injection of urocortin, which is observed in awake or anesthetized wild type mice [2], [3]. RT-PCR and in situ hybridization techniques showed the expression of CRF2β mRNA, unlike CRF1, in rat rxr receptor and uterine vascular bed [8], [14]. A direct potent vasodilatory effect of CRF and urocortin occurring predominantly in mesenteric vascular bed has been ascribed to contribute in the drop in blood pressure [22], [27]. Likewise, we recently found that iv injection of hUcn II results in a robust stimulation of gastric mucosal blood flow and decrease in vascular resistance, which is prevented by astressin2-B in urethane-anesthetized rats [9]. Taken together these results indicate that iv injection of hUcn II induced hypotension is mediated by the activation of CRF2 receptors present within the vascular system. Convergent reports indicate that the activation of medullary TRH pathways plays a physiological role in autonomic mediated visceral responses to an acute cold stress [1], [18] that can be mimicked by the ic injection of TRH or analog [32]. The demonstration that iv hUcn II-induced hypotension while not influencing the net rise in MAP induced by ic RX-77368 indicates that the responsiveness to sympathetic stimulation is maintained under conditions of CRF2 receptors activation. Urocortin was reported to relax rat tail arteries precontracted with noradrenaline [15]. The observed attenuation of sympathetic mediated net rise in MAP at the highest dose of hUcn II may occur through vascular mechanisms downstream to the activation of alpha adrenergic receptors. In specific vascular beds, urocortin-induced vasorelaxant action has been ascribed to adenylate cyclase stimulation and activation of calcium dependent potassium channels [29], [30] and protein kinase mediated reduction in the sensitivity of contractile apparatus to calcium [15]. In summary, the present study provides the first pharmacological evidence that the activation of peripheral CRF2 receptor decreases arterial blood pressure as shown by the use of the selective CRF2 receptor agonist, hUcn II and CRF2 receptor antagonist, astressin2-B in rats. hUcn II-induced decrease in MAP was dose-related, rapid in onset and long acting and prevented by astressin2-B. In addition, we showed that iv injection of hUcn II did not influence the net rise in MAP induced by central sympathetic activation. These data indicate hUcn II exerts a potent CRF2 mediated hypotensive action that is responsive to central sympathetic activation.
    Acknowledgements
    Introduction Corticotropin-releasing factor (CRF) is a 41 amino acid peptide that plays a prominent role in the endocrine, autonomic, behavioral and immune responses to stress [12], [15], [36]. Evidence indicates that the actions of CRF are mediated through two G protein-coupled seven-transmembrane domain receptor subtypes designated CRF1[6], [8], [53] and CRF2[30], [38]. These receptors exhibit distinct pharmacological profiles and unique distribution patterns in brain and peripheral tissues. Studies in rats revealed an abundance of CRF1 receptors in pituitary, cerebellum, brain stem, amygdala, and cortex whereas CRF2 receptors are found predominantly in the lateral septum, ventromedial hypothalamus, choroid plexus, and olfactory bulb [5]. In the rhesus monkey brain, CRF2 receptors are also found throughout the neocortex, the amygdala, and the hippocampal formation indicating a broader distribution than in the rat brain [44].