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Neuronal CGRP/RAMP1 receptors enhance baroreflex and abrogate phenylephrine-induced hypertension

      While calcitonin gene-related peptide (CGRP)-induced vasodilation is well known, the role of neuronal CGRP receptors in blood pressure (BP) regulation is unclear. We recently reported that transgenic expression of the CGRP receptor subunit ‘receptor activity-modifying protein 1’ (RAMP1) in the nervous system abrogates chronic angiotensin II (Ang II) hypertension [FASEB J 25:661.3, 2011]. It is not known if RAMP1 interacts with Ang II signaling specifically or if it also protects against other models of hypertension. In this study, we tested the hypothesis that nervous system-specific RAMP1 transgenic mice are protected against phenylephrine (PE)-induced hypertension. BP and heart rate (HR) were measured by telemetry in RAMP1 mice and littermate controls. Chronic infusion of PE (4000 ng/kg/min for 2 wks) increased mean BP from 105 ± 3 to 160 ± 1 mmHg in control mice (n = 4); and from 104 ± 2 to 126 ± 12 mmHg in RAMP1 mice (n = 4). PE-induced increases in sympathetic vasomotor tone (depressor response to ganglionic blockade) and decreases in spontaneous baroreflex sensitivity (sequence method) were also attenuated in RAMP1 mice (P < 0.05). Interestingly, acute pressor responses to intravenous injections of PE were also less in conscious RAMP1 mice (n = 5) vs. control mice (n = 4). After ganglionic blockade, pressor responses to PE were equivalent or greater in RAMP1 mice. We conclude: (1) nervous system-specific overexpression of CGRP/RAMP1 receptors abrogates both PE- and Ang II-induced hypertension; and (2) the mechanism involves enhanced baroreflex BP buffering and not blunted vascular responses to PE. (VA1BX001414, HL14388)
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