Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

Abstract

IM, DiPette DJ. Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension. Am J Physiol Heart Circ Physiol 301: H683-H688, 2011. First published June 10, 2011 doi:10.1152/ajpheart.00598.2009.-In subtotal nephrectomy (SN)-and salt-induced hypertension, calcitonin generelated peptide (CGRP) plays a compensatory role to attenuate the blood pressure increase in the absence of an increase in the neuronal synthesis and release of this peptide. Therefore, the purpose of this study was to determine whether the mechanism of this antihypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide. Hypertension was induced in Sprague-Dawley rats by SN and 1% saline drinking water. Control rats were sham-operated and given tap water to drink. After 11 days, rats had intravenous (drug administration) and arterial (continuous mean arterial pressure recording) catheters surgically placed and were studied in a conscious unrestrained state. Baseline mean arterial pressure was higher in the SN-salt rats (157 Ϯ 5 mmHg) compared with controls (128 Ϯ 3 mmHg). Administration of CGRP (and adrenomedullin) produced a significantly greater dose-dependent decrease in mean arterial pressure in SN-salt rats compared with controls (ϳ2.0-fold for both the low and high doses). Interestingly, isolated superior mesenteric arterioles from SN-salt rats were significantly more responsive to the dilator effects of CGRP (but not adenomedullin) than the controls (pEC50, SN-salt, 14.0 Ϯ 0.1 vs. control, 12.0 Ϯ 0.1). Analysis of the CGRP receptor proteins showed that only the receptor component protein was increased significantly in arterioles from SN-salt rats. These data indicate that the compensatory antihypertensive effects of CGRP result from an increased sensitivity of the vasculature to dilator activity of this peptide. The mechanism may be via the upregulation of receptor component protein, thereby providing a more efficient coupling of the receptor to the signal transduction pathways.

Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis

“…RCP expression correlates with receptor activation in uterus and vasculature and its increase results in increased CGRP efficacy (Naghashpour et al, 1997; Supowit et al, 2011). The role of RCP expression as positive indicator of CGRP efficacy and the present evidences of CGRP protective effects in EAE led us to investigate whether a correlation with RCP expression could be present during EAE progression.…”

Role of CGRP-Receptor Component Protein (RCP) in CLR/RAMP Function

“…In these experiments, pial arteries from hypertensive rats dilated significantly greater than control in response to CGRP, suggesting that the efficacy of CGRP was increased, possibly as a mechanism to counter decreased circulating CGRP. An increase in CGRP efficacy has also been reported for a third animal model for hypertension, the subtotal nephrectomy-salt hypertensive rat (SN-salt) [42]. In this animal model, mean arterial pressure was elevated in the SN-salt animals, and isolated mesenteric arteries dilated significantly more in response to CGRP in SN-salt rats than in control rats, suggesting that the vasculature was hyper-responsive to CGRP.…”

“…Thus, RCP may have pleiotropic influences on cellular physiology, and may coordinate multiple cellular responses to activation of neuropeptide hormone receptors. The in vivo role for RCP in whole animal physiology is predicted to be complex, involving at least the CGRP and AM receptors, which has regulatory implications for a diverse array of physiologic systems, including regulation of vascular tone [42, 61-63], migraine [64-67], inflammation [68, 69] and obesity [70, 71]. The interaction between these physiologic systems is predicted to be complex, and a more complete analysis for the in vivo role of RCP will require production of knockout or conditional knockout mice for RCP.…”

Nicousamide normalizes renovascular hypertension in two-kidney one-clip hypertensive rats

“…In subtotal nephrectomy (SN) and salt-induced hypertension, CGRP plays a compensatory role to attenuate the BP increase in the absence of an increase in the neuronal synthesis and release of this peptide (12,13). Therefore, the purpose of this study was to determine whether or not the mechanism of this anti-hypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide.…”