Effect of calcitonin gene-related peptide on coronary microvessels and its role in acute myocardial ischemia.

Sekiguchi, Nobuyo; Kanatsuka, Hiroshi; Sato, Kouichi; Wang, Yan; Akai, Kenjiro; Komaru, Tatsuya; Takishima, Tamotsu

doi:10.1161/01.cir.89.1.366

Cited by 33 publications

(15 citation statements)

References 34 publications

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“…However, the receptor density and the efficiency of coupling between the receptor and the stimulus-response mechanisms in the human subcutaneous arteries will influence the maximal response to CGRP in any case. In the present study, we have shown that the maximal response and the sensitivity to CGRP is inversely related to the calibre of human subcutaneous arteries, which is in concert with the previous findings in the coronary arteries of rat (Sheykhzade & Nyborg, 1998), dog (Sekiguchi et al, 1994) and human (McEwan et al, 1986), and also in human cerebral arteries (Sams et al, 2000). Our present results therefore indicate that this observation can be explained either by an increase in CGRP 1 -receptor density or by increased efficiency of receptor-effector coupling downstream of the vasculature.…”

Section: Receptor Reserve and Calibre Dependency Of Cgrp-induced Relasupporting

confidence: 92%

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Sheykhzade

Lind

Edvinsson

2004

British J Pharmacology

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1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1- [(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E max . 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter B200 mm) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K A , for CGRP 1 receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP 1 -like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca 2 þ ] i ) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP 1 receptors in human subcutaneous arteries.

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Section: Receptor Reserve and Calibre Dependency Of Cgrp-induced Relasupporting

confidence: 92%

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Sheykhzade

Lind

Edvinsson

2004

British J Pharmacology

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“…The present findings with intravenous and intra-atrial CGRP extend these previous findings by demonstrating no effect of CGRP receptor antagonism on coronary flow during cardiac stress produced by rapid atrial pacing and coronary stenosis. One previous study in anesthetized dogs reported no effect of topically administered CGRP onto the left ventricular surface on coronary artery microvessel diameter before and at 10 min after LAD coronary artery occlusion (Sekiguchi et al, 1994). The present study extends the latter findings by demonstrating no effect on coronary flow with systemically administered CGRP (8-37) during both coronary constriction and atrial pacing, as well as demonstrating no effect on a functional measure of ischemia severity.…”

Section: Discussionsupporting

confidence: 81%

“…In vitro, CGRP potently relaxed human and dog epicardial coronary arteries (Gulbenkian et al, 1993;Quebbeman et al, 1993). In vivo, exogenous CGRP exerted systemic depressor (Franco-Cereceda et al, 1987;Shen et al, 2001) and coronary vasodilator effects with greater effect on coronary diameter observed in larger versus smaller vessels in both species (Ludman et al, 1991;Sekiguchi et al, 1994). These observations support dog as a relevant species for assessing CGRP antagonist cardiovascular effects in relation to similarity to human.…”

Section: Discussionmentioning

confidence: 88%

Calcitonin Gene-Related Peptide Receptor Antagonism Does Not Affect the Severity of Myocardial Ischemia during Atrial Pacing in Dogs with Coronary Artery Stenosis

Regan

Stump²,

Kane³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that also has potent vasodilator activity. There are conflicting preclinical reports regarding the effect of CGRP receptor antagonism in the setting of myocardial ischemia. The present study was conducted in a canine model in which regional myocardial ischemia was reproducibly evoked by serial periods of atrial pacing (80 beats per min above baseline rate) in the presence of a 40% stenosis of the left anterior descending (LAD) coronary artery. Ischemia severity was quantitated by changes in unipolar epicardial electrograms (EG) recorded in the area of ischemia. In validation studies, the calcium entry blocker diltiazem reduced ischemia severity (before versus after treatment: ⌬EG, 1.92 Ϯ 0.23 versus 0.54 Ϯ 0.24 mV; p Ͻ 0.05) and tended to increase LAD flow (7.7 Ϯ 0.7 versus 9.4 Ϯ 1.4 ml/min; p ϭ 0.10), whereas the coronary constrictor serotonin increased ischemia severity (before versus after treatment: ⌬EG, 2.11 Ϯ 0.44 versus 4.90 Ϯ 1.46 mV; p Ͻ 0.05) concomitant with a reduction in LAD flow (9.1 Ϯ 1.1 versus 5.4 Ϯ 1.5 ml/min; p Ͻ 0.05). A 30 g/kg/min i.v. infusion test dose of the CGRP receptor antagonist CGRP was validated by demonstrating complete block of the depressor effects of exogenous i.v. 0.03 to 0.3 g/kg CGRP. This dose of CGRP , administered either intravenously or intra-atrially, had no effect on ischemia severity or paced LAD flow, indicating no intrinsic effect of CGRP receptor antagonism on the severity of acute myocardial ischemia. Likewise, the administration of a hemodynamically active dosing regimen of CGRP (0.03 g/kg/min i.v.) had no effect on paced coronary flow or ischemia severity, suggesting no major role of CGRP in regulating ischemic blood flow.Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide widely distributed throughout the central and peripheral nervous systems (Brain and Grant, 2004). CGRP has been proposed to play a role in the pathophysiology of migraine based upon correlative changes in circulating CGRP concentrations during spontaneous and nitrate-induced migraine and during migraine treatment with triptans, as well as the provocation of headache with exogenous CGRP infusion in migraineurs (Edvinsson, 2007;Goadsby, 2008). Clinical studies demonstrating efficacy with two CGRP receptor antagonists, the parenteral agent olcegepant (BIBN4096BS) (Doods et al., 2000;Olesen et al., 2004) and the orally available MK-0974 (telcagepant) (Ho et al., 2008;Salvatore et al., 2008), have confirmed CGRP to be an important mediator of migraine.CGRP also possesses direct and potent vasorelaxant properties (Brain and Grant, 2004). In recognition of the vasodilatory properties of CGRP, as well as concerns regarding the cardiovascular liabilities of the currently available ergot and triptan migraine treatments (MaassenVanDenBrink et al., 1998;Wammes-van der Heijden et al., 2006), multiple groups have conducted preclinical studies of the cardiovascular effects of CGRP receptor antagonism. There has been parti...

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“…These neuropeptides produce coronary vasodilation and negative inotropic and chronotropic effects, which would be expected to limit the deleterious consequences of ischemia on the myocardium (35). Our previous study (45) has shown that I/R injury caused more profound impairment in terms of LVEDP, LVDP, and CF in TRPV1 Ϫ/Ϫ than in WT hearts, indicating that TRPV1 protects against I/R injury.…”

Section: Discussionmentioning

confidence: 95%

TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice

Zhong¹,

Wang²

2007

American Journal of Physiology-Heart and Circulatory Physiology

100

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Zhong B, Wang DH. TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol 293: H1791-H1798, 2007. First published June 22, 2007; doi:10.1152/ajpheart.00169.2007.-Although the transient receptor potential vanilloid type 1 (TRPV1)-containing afferent nerve fibers are widely distributed in the heart, the relationship between TRPV1 function and cardiac ischemic preconditioning (PC) has not been well defined. Using TRPV1 knockout mice (TRPV1 Ϫ/Ϫ ), we studied the role of TRPV1 in PC-induced myocardial protection. Hearts of gene-targeted TRPV1-null mutant (TRPV1 Ϫ/Ϫ ) or wild-type (WT) mice were Langendorffly perfused in the presence or absence of CGRP 8-37, a selective calcitonin generelated peptide (CGRP) receptor antagonist; or RP-67580, a selective neurokinin-1 receptor antagonist when hearts were subjected to three 5-min periods of ischemia PC followed by 30 min of global ischemia and 40 min of reperfusion (I/R). PC before I/R decreased left ventricular (LV) end-diastolic pressure and increased LV developed pressure, coronary flow (CF), peak-positive maximum rate of rise of LV pressure in WT mice (PC-WT) compared with PC-TRPV1 Ϫ/Ϫ , TRPV1 Ϫ/Ϫ , or WT hearts (P Ͻ 0.05), and PC also decreased LV end-diastolic pressure in PC-TRPV1 Ϫ/Ϫ compared with TRPV1 Ϫ/Ϫ . CGRP or RP-67580 abolished PC-induced protection in WT but not TRPV1Ϫ/Ϫ hearts (P Ͻ 0.05). Moreover, PC decreased lactate dehydrogenase release and infarct size in PC-WT compared with PC-TRPV1 Ϫ/Ϫ , TRPV1 Ϫ/Ϫ , or WT hearts, and it also lowered these parameters in PC-TRPV1 Ϫ/Ϫ compared with TRPV1 Ϫ/Ϫ hearts (P Ͻ 0.05). Radioimmunoassay showed that the release of substance P and CGRP after PC was higher in WT hearts than in TRPV1 Ϫ/Ϫ hearts (P Ͻ 0.05), which was attenuated by capsazepine in WT but not TRPV1 Ϫ/Ϫ hearts. Thus PC-induced protection of the heart was impaired in TRPV1 Ϫ/Ϫ hearts, indicating that TRPV1 contributes to the beneficial effects of preconditioning against I/R injury through release substance P and CGRP. transient receptor potential vanilloid type 1; ischemia-reperfusion; substance P; calcitonin gene-related peptide ISCHEMIC PRECONDITIONING (PC) confers a remarkable cardioprotection in a variety of species as well as in humans, which is triggered by repeated, no-lethal, brief episodes of myocardial ischemia and reperfusion, resulting in potent and immediate protection against subsequent injurious ischemia-reperfusion (I/R) (29, 32). The protective effect of ischemic PC has been shown to be attenuated in the diabetic (19) and aging hearts (40), whereas sensory nerve function is known to be impaired during these pathological processes. However, the relationship between sensory nerve function and ischemic PC has not been well defined.Capsaicin-sensitive sensory nerves are widely distributed in the cardiovascular system and can be activated by a variety of physical and chemical stimuli. The myocardium and the coronary vascular system possess dense cap...

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Effect of calcitonin gene-related peptide on coronary microvessels and its role in acute myocardial ischemia.

Abstract: CGRP preferentially dilates the coronary arterial microvessels > 100 microns in diameter but has only a small effect on those < 100 microns. Endogenous CGRP does not modulate the tone of coronary arterial microvessels during acute myocardial ischemia in beating canine hearts.

Cited by 33 publications

References 34 publications

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Calcitonin Gene-Related Peptide Receptor Antagonism Does Not Affect the Severity of Myocardial Ischemia during Atrial Pacing in Dogs with Coronary Artery Stenosis

TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice

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