Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC101
Nervous system-targeted expression of CGRP/RAMP1 receptors enhances baroreflexes and opposes angiotensin-induced hypertension
R. Sabharwal1, F. M. Abboud1, A. F. Russo2, M. W. Chapleau1,3
1. Internal Medicine, University of Iowa, Iowa City, Iowa, United States. 2. Molecular Physiology & Biophysics, University of Iowa, Iowa City, Iowa, United States. 3. Veterans Affairs Medical Center, Iowa City, Iowa, United States.
While calcitonin gene-related peptide (CGRP)-induced vasodilation mediated by vascular CGRP receptors is widely recognized, the role of neuronal CGRP receptors in blood pressure (BP) regulation remains unclear. We recently reported that transgenic mice with ubiquitous expression of human receptor activity-modifying protein 1 (hRAMP1), an obligatory CGRP receptor subunit, exhibit increased baroreflex sensitivity for control of heart rate (BRS-HR) and resistance to angiotensin II (Ang-II) induced hypertension . The contributions of vascular vs. neuronal CGRP receptors to the favorable phenotype could not be definitively determined. The goal of this study was to determine if mice with hRAMP1 selectively targeted to the nervous system by the Nestin promoter  also show increased BRS-HR and resistance to hypertension. In addition to measuring BRS-HR (sequence technique), we assessed baroreflex BP buffering capacity - a measurement more relevant to BP control. Radiotelemeters, intravenous catheters and osmotic minipumps were implanted in male hRAMP1 (n=11) and littermate control (n=10) mice under ketamine-xylazine (91μg/g and 9.1μg/g, respectively, I.P.) anesthesia. Data were collected before and after 2 weeks of Ang-II infusion via osmotic minipump (1000 ng/kg/min) in conscious mice. Baroreflex BP buffering capacity was calculated as the fold increase in the pressor response to phenylephrine (IV) after vs. before ganglionic blockade (chlorisondamine, 12 μg/g). The depressor response to ganglionic blockade provided an estimate of sympathetic vasomotor tone. Mice were killed with an overdose of pentobarbital at the end of the experiment. Data (mean±SEM) were analyzed using t-tests and repeated measures ANOVA as applicable, with significance taken at P<0.05 (see Table). In control mice, Ang-II infusion increased mean 24-hr BP and sympathetic vasomotor tone, and decreased BRS-HR and baroreflex BP buffering. These deleterious effects were abrogated in hRAMP1 mice. Interestingly, baroreflex BP buffering capacity was markedly enhanced in hRAMP1 mice before as well as during Ang-II. Selective targeting of hRAMP1 to the nervous system was confirmed by RT-PCR and the absence of an enhanced vascular depressor response to CGRP (IV) in hRAMP1 (n=3) vs. control (n=3) mice (data not shown). In summary: 1) Under basal conditions, baroreflex BP buffering capacity is enhanced in hRAMP1 vs. control mice whereas BRS-HR, sympathetic vasomotor tone and mean BP are normal; and 2) the effects of Ang-II including hypertension, increased sympathetic tone, and impaired baroreflex are abrogated in hRAMP1 mice. The results identify protective autonomic and antihypertensive actions of neuronal CGRP/RAMP1 receptors and encourage targeting these receptors for therapeutic benefit.
Where applicable, experiments conform with Society ethical requirements