Receptor activity-modifying protein 1 increases baroreflex sensitivity and attenuates Angiotensin-induced hypertension.
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 (2.83+/-0.20 versus 1.49+/-0.10 ms/mm Hg in controls; P<0.05). In control mice, infusion of angiotensin II (Ang-II) increased mean arterial pressure from 118+/-2 mm Hg to 153+/-4 and 174+/-6 mm Hg after 7 and 14 days of infusion, respectively (P<0.05). In contrast, Ang-II hypertension was markedly attenuated in hRAMP1 mice with corresponding values of mean arterial pressure of 111+/-2, 119+/-2, and 132+/-3 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 (P<0.05). Moreover, during the Ang-II infusion, the pressor response to the CGRP receptor antagonist CGRP(8-37) was significantly greater (P<0.05) in hRAMP1 mice (+30+/-2 mm Hg) than in control mice (+19+/-2 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.
Sabharwal
Rasna
R
Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242, USA.
Zhang
Zhongming
Z
Lu
Yongjun
Y
Abboud
Francois M
FM
Russo
Andrew F
AF
Chapleau
Mark W
MW
D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000503:physiopathology; D017704:Baroreflex / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010275:Parasympathetic Nervous System / Q000502:physiology; D010641:Phenotype; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C545502:RAMP1 protein, human; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D058261:Receptor Activity-Modifying Proteins; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015740:Calcitonin Gene-Related Peptide; D019808:Losartan