Calcitonin gene-related peptide-evoked sustained tachycardia in calcitonin receptor-like receptor transgenic mice is mediated by sympathetic activity.
Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasodilators and exert positive chronotropic and inotropic effects on the heart. Receptors for CGRP and AM are calcitonin receptor-like receptor (CLR)/receptor-activity-modifying protein (RAMP) 1 and CLR/RAMP2 heterodimers, respectively. The present study was designed to delineate distinct cardiovascular effects of CGRP and AM. Thus a V5-tagged rat CLR was expressed in transgenic mice in the vascular musculature, a recognized target of CGRP. Interestingly, basal arterial pressure and heart rate were indistinguishable in transgenic mice and in control littermates. Moreover, intravenous injection of 2 nmol/kg CGRP, unlike 2 nmol/kg AM, decreased arterial pressure equally by 18 +/- 5 mmHg in transgenic and control animals. But the concomitant increase in heart rate evoked by CGRP was 3.7 times higher in transgenic mice than in control animals. The effects of CGRP in transgenic and control mice, different from a decrease in arterial pressure in response to 20 nmol/kg AM, were suppressed by 2 micromol/kg of the CGRP antagonist CGRP(8-37). Propranolol, in contrast to hexamethonium, blocked the CGRP-evoked increase in heart rate in both transgenic and control animals. This was consistent with the immunohistochemical localization of the V5-tagged CLR in the superior cervical ganglion of transgenic mice. In conclusion, hypotension evoked by CGRP in transgenic and control mice was comparable and CGRP was more potent than AM. Unexpectedly, the CLR/RAMP CGRP receptor overexpressed in postganglionic sympathetic neurons of transgenic mice enhanced the positive chronotropic action of systemic CGRP.
Research Laboratory, Orthopedic University Hospital Balgrist, University of Zürich, Zürich, Switzerland.
Thomas H
TH
Kunz
Michelle
M
Scott
Lars M
LM
Ittner
Jan A
JA
Fischer
Walter
W
Born
Johannes
J
Vogel
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D053607:Adrenomedullin / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism* / Q000494:pharmacology; D058286:Calcitonin Receptor-Like Protein; D019281:Dimerization; D006321:Heart / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D006339:Heart Rate; D018738:Hexamethonium / Q000494:pharmacology; D007022:Hypotension / Q000378:metabolism* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000378:metabolism; D017779:Sympathetic Fibers, Postganglionic / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013610:Tachycardia / Q000378:metabolism* / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; C545580:Calcrl protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; C545506:Ramp2 protein, mouse; C545509:Ramp2 protein, rat; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D011993:Recombinant Fusion Proteins; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D018738:Hexamethonium; D011433:Propranolol; D015740:Calcitonin Gene-Related Peptide