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  • SNS-314 Mesylate synthesis CRF and urocortin produce marked

    2019-12-02

    CRF and urocortin 1 produce marked effects on the SNS-314 Mesylate synthesis when administered both i.v. or directly into the CNS (Parkes et al., 2001). Systemic i.v administration of CRF and urocortin 1 cause a marked and long-lasting reduction in mean arterial blood pressure in rats Briscoe et al., 2000, Lawrence et al., 2002, Spina et al., 1996, Vaughan et al., 1995. The hypotensive effects of systemic CRF treatment are blocked by pretreatment with the mixed CRF1/CRF2 receptor antagonist α-helical CRF9–41, but not by the selective CRF1 receptor antagonist antalarmin (Briscoe et al., 2000), suggesting that the reduction in mean arterial blood pressure is mediated by peripheral CRF2 receptors. Moreover, it has been shown that the hypotensive response produced following systemic urocortin 1 administration is prevented following pretreatment with the selective CRF2 receptor antagonist K41498, an analogue of antisauvagine-30 (Lawrence et al., 2002). The present results demonstrating potent effects of the selective CRF2 receptor agonist, urocortin 2, and their reversal by a selective CRF2 receptor antagonist, antisauvagine-30, have verified the pharmacological role of the CRF2 receptor in the cardiovascular system. Evidence for the involvement of the CRF2 receptor subtype in the modulation of cardiovascular function has come from mice where the CRF2 receptor gene has been deleted during development. Systemic administration of urocortin 1 has no effect on mean arterial blood pressure in CRF2-deficient mice, whereas wild-type mice showed a marked and sustained hypotensive response Bale et al., 2000, Coste et al., 2000; heart rate was not significantly affected (Coste et al., 2000). The observation that CRF2-deficient mice exhibit a modest increase in basal blood pressure compared with wild-type littermates Bale et al., 2000, Coste et al., 2000 could suggest that activation of the CRF2 receptor by an endogenous agonist is important for tonic cardiovascular regulation. However, the present results have demonstrated that acute administration of the antagonist antisauvagine-30 at doses in excess of those required for pharmacological blockade of vascular CRF2 receptors do not alter mean arterial blood pressure or heart rate. This would indicate that under the present experimental conditions, no endogenous CRF2 tone exists. Moreover, it could also be argued that the observed phenotype of the CRF2 knockout mice (modest hypertension) was the result of developmental compensation for the deletion of the CRF2 receptor. In conclusion, we have demonstrated that selective activation of presumed vascular CRF2 receptors can influence cardiovascular function in the conscious rat, but find no evidence for an endogenous CRF2-mediated tone. As a cautionary note, investigators who seek to probe the function of CRF receptors using peripheral administration of potent CRF2 receptor agonists should consider the impact that profound changes on the cardiovascular system can have on their physiological endpoints.
    Introduction Human urocortin II (hUcn II, also known as stresscopin-related peptide) and urocortin III (hUcn III also known as stresscopin) are novel members of the corticotropin-releasing factor (CRF) family that have been recently identified from the human genome data base and from homologous mouse gene [7], [13], [24]. The CRF family of ligands functions by activating two known G protein-coupled receptors, the CRF1 and CRF2 receptors [23]. In vitro studies established that CRF ligands differ in their binding affinity to CRF receptors. Both human and mouse Ucn II and Ucn III bind selectively to CRF2 receptor while urocortin has an equal affinity to CRF1 and CRF2 and CRF displayed a higher affinity for the CRF1 than CRF2 receptor [7], [13], [24]. Recent functional studies in rats and mice also indicate that peripheral administration of hUcn II and hUcn III exert biological actions linked with their selective interaction with CRF2 receptor [17], [19]. Intraperitoneal (ip) injection of urocortin, hUcn II and, less potently hUcn III, inhibited gastric emptying of a solid meal that was blocked by selective CRF2 receptor antagonists [7], [17], [19], [34]. By contrast, hUcn II or hUcn III did not influence colonic transit that is stimulated by peripheral injection of CRF and urocortin through CRF1 receptor [16], [17], [19].