RECEPTOR ACTIVITY-MODIFYING PROTEIN-1 INCREASES BAROREFLEX SENSITIVITY AND ATTENUATES ANGIOTENSIN-INDUCED HYPERTENSION

摘要

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 (HR) and locomotor activity were measured by radiotelemetry in transgenic mice with ubiquitous expression of human RAMP1 and littermate controls. Compared with control mice, RAMP1 mice exhibited similar mean arterial pressure (MAP), a lower mean HR, increased HR variability, reduced blood pressure variability, and increased baroreflex sensitivity (2.83±0.20 vs. 1.49±0.10 ms/mmHg in controls) (P<0.05). In control mice, infusion of angiotensin II (Ang-II) increased MAP from 118±2 mmHg to 153±4 and 174±6 mmHg after 7 and 14 days of infusion, respectively (P<0.05). In contrast, Ang-II hypertension was markedly attenuated in RAMP1 mice with corresponding values of MAP of 111±2, 119±2 and 132±3 mmHg. Ang-II induced decreases in baroreflex sensitivity and HR variability, and increases in blood pressure variability observed in control mice were also abrogated or reversed in RAMP1 mice (P<0.05). Moreover, during the Ang-II infusion, the pressor response to the CGRP receptor antagonist CGRP8-37 was significantly greater (P<0.05) in RAMP1 mice (+30±2 mmHg) than in control mice (+19±2 mmHg), confirming a significantly greater antihypertensive action of endogenous CGRP in RAMP1 mice. We conclude that RAMP1 overexpression attenuates Ang-II induced hypertension and induces a protective change in cardiovascular autonomic regulation.