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 μmol/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.

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Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Journal of Endocrinology ◽

10.1677/joe-07-0541 ◽

2008 ◽

Vol 197 (2) ◽

pp. 391-400 ◽

Cited By ~ 19

Author(s):

Y Takei ◽

H Hashimoto ◽

K Inoue ◽

T Osaki ◽

K Yoshizawa-Kumagaye ◽

...

Keyword(s):

Heart Rate ◽

Arterial Pressure ◽

Calcitonin Gene Related Peptide ◽

Calcitonin Receptor ◽

Genome Database ◽

Related Peptide ◽

Culture Cells ◽

Cardiovascular Actions ◽

Calcitonin Gene ◽

Receptor Activity Modifying Proteins

Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0.1–1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na+ concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0.1–1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15–20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activity-modifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10−10–10−9 M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTR+RAMP, to exert central and peripheral cardiovascular actions in mammals.

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Intrathecal administration of calcitonin gene-related peptide (CGRP) increases heart rate and decreases arterial pressure in the urethane anesthetized rat

Brain Research Bulletin ◽

10.1016/0361-9230(90)90175-y ◽

1990 ◽

Vol 25 (6) ◽

pp. 809-816 ◽

Cited By ~ 14

Author(s):

Joseph Rochford ◽

Kiran Yashpal ◽

James L. Henry

Keyword(s):

Heart Rate ◽

Arterial Pressure ◽

Intrathecal Administration ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

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Interaction of calcitonin and calcitonin gene-related-peptide at the calcitonin receptor in T 47 D cells

Acta Endocrinologica ◽

10.1530/acta.0.111s200 ◽

1986 ◽

Vol 113 (1_Suppl) ◽

pp. S200

Author(s):

A. ZINK ◽

H.G. SCHNEIDER ◽

F. RAUE

Keyword(s):

Calcitonin Gene Related Peptide ◽

Calcitonin Receptor ◽

Related Peptide ◽

Calcitonin Gene ◽

D Cells

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A New Calcitonin-Receptor-like Sequence in Rat Pulmonary Blood Vessels

Clinical Science ◽

10.1042/cs0850385 ◽

1993 ◽

Vol 85 (4) ◽

pp. 385-388 ◽

Cited By ~ 108

Author(s):

F. Njuki ◽

C. G. Nicholl ◽

A. Howard ◽

J. C. W. Mak ◽

P. J. Barnes ◽

...

Keyword(s):

Blood Vessels ◽

Vascular Tone ◽

Islet Amyloid Polypeptide ◽

Calcitonin Gene Related Peptide ◽

Binding Activity ◽

Calcitonin Receptor ◽

Islet Amyloid ◽

Related Peptide ◽

Calcitonin Gene

1. Two rat clones have been isolated which are similar to known calcitonin-receptor sequences. One of these does not have the distribution expected of a calcitonin receptor. It is widely distributed, with extremely high levels of expression in the lung, where it is associated with the blood vessels. 2. This rat sequence may represent the receptor for calcitonin-gene-related peptide or islet amyloid polypeptide. Both have binding activity in the lung and are potent vasodilators. The gene represented by this sequence may therefore play an important role in the maintenance of vascular tone.

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