Receptor Activity-Modifying Protein 1 Increases Baroreflex Sensitivity and Attenuates Angiotensin-Induced Hypertension

Abstract

Abstract-Calcitonin gene-related peptide (CGRP) is a powerful vasodilator that interacts with the autonomic nervous system. A subunit of the CGRP receptor complex, receptor activity-modifying protein 1 (RAMP1), is required for trafficking of the receptor to the cell surface and high-affinity binding to CGRP. We hypothesized that upregulation of RAMP1 would favorably enhance autonomic regulation and attenuate hypertension. Blood pressure, heart rate, and locomotor activity were measured by radiotelemetry in transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1) and littermate controls. Compared with control mice, hRAMP1 mice exhibited similar mean arterial pressure, a lower mean heart rate, increased heart rate variability, reduced blood pressure variability, and increased baroreflex sensitivity (2.83Ϯ0.20 versus 1.49Ϯ0.10 ms/mm Hg in controls; PϽ0.05). In control mice, infusion of angiotensin II (Ang-II) increased mean arterial pressure from 118Ϯ2 mm Hg to 153Ϯ4 and 174Ϯ6 mm Hg after 7 and 14 days of infusion, respectively (PϽ0.05). In contrast, Ang-II hypertension was markedly attenuated in hRAMP1 mice with corresponding values of mean arterial pressure of 111Ϯ2, 119Ϯ2, and 132Ϯ3 mm Hg. Ang-II induced decreases in baroreflex sensitivity and heart rate variability, and increases in blood pressure variability observed in control mice were also abrogated or reversed in hRAMP1 mice (PϽ0.05). Moreover, during the Ang-II infusion, the pressor response to the CGRP receptor antagonist CGRP 8-37 was significantly greater (PϽ0.05) in hRAMP1 mice (ϩ30Ϯ2 mm Hg) than in control mice (ϩ19Ϯ2 mm Hg), confirming a significantly greater antihypertensive action of endogenous CGRP in hRAMP1 mice. We conclude that RAMP1 overexpression attenuates Ang-II-induced hypertension and induces a protective change in cardiovascular autonomic regulation. (Hypertension. 2010;55:627-635.)Key Words: calcitonin gene-related peptide Ⅲ parasympathetic nerve activity Ⅲ heart rate variability Ⅲ baroreflex sensitivity Ⅲ blood pressure Ⅲ transgenic mice C alcitonin gene-related peptide (CGRP) is expressed predominantly in the nervous system and contributes to a variety of physiological and pathological processes, including neurogenic inflammation, inhibition of cell proliferation and oxidative stress, and cardiovascular regulation. 1,2 CGRP is one of the most powerful vasodilators known, and sensory nerves containing CGRP provide extensive innervation of blood vessels. 1,2 Furthermore, CGRP and/or CGRP receptor expression are increased in several models of hypertension, including that induced by infusion of the vasoconstrictor peptide angiotensin II (Ang-II). [3][4][5][6] Although pharmacological blockade of CGRP receptors does not influence mean arterial pressure (MAP) of normotensive subjects, receptor blockade increases the severity of hypertension in several experimental models. 6 -8 These findings suggest that endogenous CGRP operates through a negative-feedback mechanism to oppose the development of hypertension.Although it is reason...

An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

“…The use of RAMP1 transgenic mice revealed that CGRP has an early protective effect at the level of the baroreceptors and cerebral vasculature in a similar AngII hypertension model. 16,27 Our present results indicate a much wider potential of CGRP and its receptors to protect against the onset and maintenance of AngII-induced hypertension.Analysis of MRVs after 28 days revealed similar vascular reactivity in all treatments with no loss of …”

“…13 Evidence indicates the importance of CGRP in aggressive models of rodent hypertension that are centered on the kidney. 14,15 By comparison, there is little evidence of detailed analysis involving the ongoing influence of endogenous CGRP on hypertensive mechanisms and vascular remodeling, especially with regard to NO and oxidative stress pathways.Sensory nerve-derived CGRP release is stimulated by mechanisms that include angiotensin II (AngII) and sympathetic nerve reflexes, 3,4 baroreflex sensitivity, 16 and sensory nerve activators. 17,18 We have investigated the AngII hypertension model in wild-type (WT) and αCGRP knockout (αCGRPKO) mice that have similar resting BP.…”

“…Sensory nerve-derived CGRP release is stimulated by mechanisms that include angiotensin II (AngII) and sympathetic nerve reflexes, 3,4 baroreflex sensitivity, 16 and sensory nerve activators. 17,18 We have investigated the AngII hypertension model in wild-type (WT) and αCGRP knockout (αCGRPKO) mice that have similar resting BP.…”

Regulation of Adrenomedullin and its Family Peptide by RAMP System – Lessons from Genetically Engineered Mice

“…ubiquitously, were reported to show markedly attenuated responses to angiotensin II-induced hypertension [57] . The pressor response to the CGRP receptor antagonist, CGRP8-37, was greater in RAMP1 Tg mice than in WT mice, confirming a greater antihypertensive action of endogenous CGRP in RAMP1 Tg mice.…”

Response to Letter by Tsuda

“…2 Using a model of hypertension produced by systemic administration of angiotensin II, we found that increased expression of RAMP1 greatly reduced the pressor response to angiotensin II. 3 Mechanisms that appeared to contribute to this effect included alterations in baroreflex sensitivity, sympathetic outflow, and sympathetic-mediated vasoconstriction. 3 Although many specifics regarding the pathways involved remain to be defined, these findings support the concept that CGRP and RAMP1 interact with the autonomic nervous system in a manner that protects against hypertension.…”