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

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.

Download Full-text

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.

Download Full-text

Anti nociception Induced by Intrathecal administration of antiserum against calcitonin gene-related peptide (CGRP): comparison between mechanical and thermal algesic tests In rats.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)56092-9 ◽

1989 ◽

Vol 49 ◽

pp. 83

Author(s):

Minoru Kawamura ◽

Yasushi Kuraishi ◽

Masabumi Minami ◽

Takoshi Hotani ◽

Hiroyuki Yoshimura ◽

...

Keyword(s):

Intrathecal Administration ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

Download Full-text

Calcitonin gene-related peptide in viscerosensitive response to colorectal distension in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.1.g191 ◽

1997 ◽

Vol 273 (1) ◽

pp. G191-G196 ◽

Cited By ~ 15

Author(s):

V. Plourde ◽

S. St-Pierre ◽

R. Quirion

Keyword(s):

Acetic Acid ◽

Visceral Pain ◽

Intrathecal Administration ◽

Calcitonin Gene Related Peptide ◽

Visceral Hyperalgesia ◽

Afferent Pathways ◽

Colorectal Distension ◽

Related Peptide ◽

Balloon Distension ◽

Calcitonin Gene

The role of calcitonin gene-related peptide (CGRP) on colorectal distension-induced visceral pain was investigated in conscious rats. Intracolonic administration of acetic acid (0.6%) resulted in a significantly increased number of abdominal contractions in response to colorectal balloon distension from 5.8 +/- 1.2 in controls to 16.6 +/- 1.0 in acetic acid-treated animals (P < 0.05), evidencing sensitization of visceral afferent pathways and subsequently visceral hyperalgesia. This sensitization phenomenon was not observed in animals previously treated with systemic capsaicin. Likewise, in animals not treated with capsaicin, use of an intravenous antagonist for CGRP [human CGRP-(8-37)], completely reversed the sensitizing effects of acetic acid. Furthermore, intravenous administration of CGRP dose dependently increased the number of abdominal contractions in response to colorectal distension from 3.0 +/- 1.1 (CGRP 250 ng) to 17.0 +/- 1.2 (CGRP 500 ng, P < 0.05), as previously observed in acetic acid-treated animals. Finally, intrathecal administration of hCGRP-(8–37) (mid-lumbar) also resulted in a total dose-dependent reversal of CGRP (500 ng) or acetic acid-induced visceral hypersensitivity. These results demonstrate that CGRP plays a major role in this model of visceral afferent nerve sensitization from gastrointestinal origin.

Download Full-text

Calcitonin gene-related peptide (CGRP) augments baroreflex control of heart rate and renal sympathetic nerve activity (RSNA) in rabbits

Anesthesiology ◽

10.1097/00000542-199209001-00721 ◽

1992 ◽

Vol 77 (Supplement) ◽

pp. A721

Author(s):

H. Okamoto ◽

S. Hoka ◽

T. Kawasaki ◽

M. Sato

Keyword(s):

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Calcitonin Gene Related Peptide ◽

Nerve Activity ◽

Baroreflex Control ◽

Renal Sympathetic Nerve Activity ◽

Related Peptide ◽

Calcitonin Gene ◽

Renal Sympathetic

Download Full-text

Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00598.2009 ◽

2011 ◽

Vol 301 (3) ◽

pp. H683-H688 ◽

Cited By ~ 13

Author(s):

Scott C. Supowit ◽

Khurshed A. Katki ◽

Travis W. Hein ◽

Prakash Gupta ◽

Lih Kuo ◽

...

Keyword(s):

Mean Arterial Pressure ◽

Arterial Pressure ◽

Tap Water ◽

Calcitonin Gene Related Peptide ◽

Subtotal Nephrectomy ◽

Related Peptide ◽

Receptor Component ◽

Calcitonin Gene ◽

Induced Hypertension ◽

Component Protein

In subtotal nephrectomy (SN)- and salt-induced hypertension, calcitonin gene-related peptide (CGRP) plays a compensatory role to attenuate the blood pressure increase in the absence of an increase in the neuronal synthesis and release of this peptide. Therefore, the purpose of this study was to determine whether the mechanism of this antihypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide. Hypertension was induced in Sprague-Dawley rats by SN and 1% saline drinking water. Control rats were sham-operated and given tap water to drink. After 11 days, rats had intravenous (drug administration) and arterial (continuous mean arterial pressure recording) catheters surgically placed and were studied in a conscious unrestrained state. Baseline mean arterial pressure was higher in the SN-salt rats (157 ± 5 mmHg) compared with controls (128 ± 3 mmHg). Administration of CGRP (and adrenomedullin) produced a significantly greater dose-dependent decrease in mean arterial pressure in SN-salt rats compared with controls (∼2.0-fold for both the low and high doses). Interestingly, isolated superior mesenteric arterioles from SN-salt rats were significantly more responsive to the dilator effects of CGRP (but not adenomedullin) than the controls (pEC50, SN-salt, 14.0 ± 0.1 vs. control, 12.0 ± 0.1). Analysis of the CGRP receptor proteins showed that only the receptor component protein was increased significantly in arterioles from SN-salt rats. These data indicate that the compensatory antihypertensive effects of CGRP result from an increased sensitivity of the vasculature to dilator activity of this peptide. The mechanism may be via the upregulation of receptor component protein, thereby providing a more efficient coupling of the receptor to the signal transduction pathways.

Download Full-text

Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.4.1707 ◽

1991 ◽

Vol 70 (4) ◽

pp. 1707-1712 ◽

Cited By ~ 20

Author(s):

S. Adnot ◽

I. Cigarini ◽

R. Herigault ◽

A. Harf

Keyword(s):

Substance P ◽

Arterial Pressure ◽

Pressor Response ◽

Dynamic Compliance ◽

Calcitonin Gene Related Peptide ◽

Lung Mechanics ◽

Lung Lobe ◽

Related Peptide ◽

Calcitonin Gene

To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Hemodynamic effects of calcitonin gene-related peptide in spontaneously hypertensive rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.258.2.r425 ◽

1990 ◽

Vol 258 (2) ◽

pp. R425-R429 ◽

Cited By ~ 8

Author(s):

K. Ando ◽

B. L. Pegram ◽

E. D. Frohlich

Keyword(s):

Arterial Pressure ◽

Total Peripheral Resistance ◽

Spontaneously Hypertensive Rats ◽

Peripheral Resistance ◽

Calcitonin Gene Related Peptide ◽

Hemodynamic Effects ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Related Peptide ◽

Calcitonin Gene

Systemic and regional hemodynamic effects of intravenously injected calcitonin gene-related peptide (CGRP), 220 and 650 pmol, were compared in nine Wistar-Kyoto (WKY) and nine spontaneously hypertensive rats (SHR). CGRP (higher dose) reduced mean arterial pressure (from 135 +/- 2 to 83 +/- 2 and from 179 +/- 4 to 116 +/- 3 mmHg; P less than 0.01, each, in WKY and SHR, respectively) through a fall (-38 +/- 4 and -40 +/- 3%; P less than 0.01) in total peripheral resistance associated with an unchanged cardiac output and an increased heart rate. The decreases in arterial pressure and total peripheral resistance were not different between these two strains. Of particular significance were the highly selective reductions in organ vascular resistances, being greatest in the cutaneous (-78 +/- 3 and -67 +/- 4%) and gastric (-80 +/- 3 and -84 +/- 2%) circulations in WKY and SHR, respectively (P less than 0.01). Reduction in coronary, cerebral, and hepatic vascular resistances, although significant (P less than 0.05, at least), were only moderately reduced compared with the two former circulations. These effects were similar in WKY and SHR and demonstrate that CGRP is a highly selective and potent natural vasodilating peptide that has the most striking effects in skin and stomach, suggesting possible modulator functions in regulating certain regional hemodynamics.

Download Full-text

Effects of neuropeptides on heart rate in dogs: comparison of VIP, PHI, NPY, CGRP, and NT

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.2.h311 ◽

1988 ◽

Vol 255 (2) ◽

pp. H311-H317 ◽

Cited By ~ 6

Author(s):

D. F. Rigel

Keyword(s):

Heart Rate ◽

Neuropeptide Y ◽

Vasoactive Intestinal Polypeptide ◽

Sinus Node ◽

Calcitonin Gene Related Peptide ◽

Adrenergic Blockade ◽

Related Peptide ◽

Sinus Node Artery ◽

Calcitonin Gene ◽

Intestinal Polypeptide

This study was designed to evaluate the potential chronotropic actions of several cardiac neuropeptides in pentobarbital-anesthetized dogs. After bilateral vagotomy and stellectomy and muscarinic receptor blockade, I injected vasoactive intestinal polypeptide, peptide histidine isoleucine, neuropeptide Y, neurotensin, and calcitonin gene-related peptide into the intact sinus node artery. Neurotensin, calcitonin gene-related peptide, and neuropeptide Y exhibited no physiologically significant changes in heart rate. However, the structural homologues vasoactive intestinal polypeptide and peptide histidine isoleucine each augmented heart rate with maximal increases (approximately 120 beats/min) similar to those of norepinephrine. Vasoactive intestinal polypeptide and peptide histidine isoleucine were twice and 1/18, respectively, as potent as norepinephrine. The cardioacceleratory responses to vasoactive intestinal polypeptide and peptide histidine isoleucine were more slowly developing and longer lasting than those of norepinephrine. The responses to these two peptides were unchanged after beta-adrenergic blockade with propranolol in a dose sufficient to eliminate or greatly attenuate the norepinephrine tachycardia. These results indicate a potential role of endogenous vasoactive intestinal polypeptide and peptide histidine isoleucine in nonadrenergic, noncholinergic heart rate control in the dog.

Download Full-text