The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts

Chai, Wenxia; Mehrotra, Swati; Danser, A.H. Jan; Schoemaker, Regien G.

doi:10.1016/j.ejphar.2005.12.039

Cited by 92 publications

(66 citation statements)

References 36 publications

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“…The results presented herein are consistent with several in vivo and in vitro studies in rats (9,10,14,22,35,39,40), mice (28,29,37), guinea pigs (15), dogs (2), pigs (18 -20), and humans (21,24,34,36), demonstrating that cardiac sensory nerves possess protective activities in I/R injury and that these effects are mediated by CGRP and/or substance P. Major endpoints assessed in these studies include determination of cardiac hemodynamics and function, infarct size, CK release, and levels of CGRP and/or substance P in the systemic and coronary circulations. Although most of these reports suggest that CGRP is the primary candidate, it must be noted that many of these studies make extensive use of capsaicin (the main pungent ingredient in chili peppers) treatment.…”

Section: Discussionsupporting

confidence: 81%

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Huang R, Karve A, Shah I, Bowers MC, DiPette DJ, Supowit SC, Abela GS. Deletion of the mouse ␣-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 294: H1291-H1297, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00749.2007.-Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and A␦-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the ␣-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from ␣-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the ␣-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the ␣-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of ␣-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress. genetically modified mice; cardiac; isolated perfused heart preparations; sensory nervous system CALCITONIN GENE-RELATED PEPTIDE (CGRP), a 37-amino acid neuropeptide, is derived from the tissue-specific splicing of the primary transcript of the calcitonin/␣-CGRP gene (6,8,13,38). Whereas calcitonin is produced mainly in the C cells of the thyroid, CGRP synthesis is limited almost exclusively to specific regions of the central and peripheral nervous systems. There is a second CGRP gene (␤-CGRP) that does not produce calcitonin, which is also synthesized primarily in neuronal tissues. The two CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by one and three amino acids, respectively, and the biological activities of the two peptides are quite similar in most vascular beds. However, ␣-CGRP is by far the predominant product in dorsal root ganglia sensory neurons and appears to be the CGRP gene product that has markedly greater activity in the regulation of cardiovascular function (5, 11, 31).Immunoreactive CGRP and its receptor are...

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Section: Discussionsupporting

confidence: 81%

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The present findings indicating no effect of CGRP receptor antagonism on the severity of regional myocardial ischemia are generally consistent with in vivo studies of CGRP and BIBN4096BS in rat and pig reporting no effect on coronary ischemia/reperfusion infarct size (Kä llner et al, 1998;Wu et al, 2001). Likewise, in vitro studies in isolated mouse and rat hearts have reported no effect of CGRP and BIBN4096BS on postischemia/reperfusion cardiac function, creatine kinase release or infarct size (Lu et al, 1999;Wang and Wang, 2005;Chai et al, 2006;Zhong and Wang, 2007). It is noteworthy that some in vitro studies in isolated mouse and rat hearts, although demonstrating no intrinsic effect of CGRP receptor antagonism on ischemic injury or function, have reported an attenuation of ischemic preconditioning cardioprotection elicited by a set program of ischemia-reperfusion cycles preceding longer periods of myocardial ischemia (Lu et al, 1999;Chai et al, 2006;Zhong and Wang, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, in vitro studies in isolated mouse and rat hearts have reported no effect of CGRP and BIBN4096BS on postischemia/reperfusion cardiac function, creatine kinase release or infarct size (Lu et al, 1999;Wang and Wang, 2005;Chai et al, 2006;Zhong and Wang, 2007). It is noteworthy that some in vitro studies in isolated mouse and rat hearts, although demonstrating no intrinsic effect of CGRP receptor antagonism on ischemic injury or function, have reported an attenuation of ischemic preconditioning cardioprotection elicited by a set program of ischemia-reperfusion cycles preceding longer periods of myocardial ischemia (Lu et al, 1999;Chai et al, 2006;Zhong and Wang, 2007). To date, the effect of CGRP receptor antagonism on ischemic preconditioning has been demonstrated only in isolated rodent hearts, and the pathophysiologic significance of this observation is uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…CGRP receptor antagonism in the setting of myocardial ischemic injury (Kä llner et al, 1998, Wu et al, 2001Lu et al, 1999;Wang and Wang, 2005;Chai et al, 2006;Zhong and Wang, 2007), some in vitro studies have suggested a potential detrimental effect (Lu et al, 1999;Chai et al, 2006;Zhong and Wang, 2007) depending on experimental protocol used. To date, no study has assessed the effects of CGRP receptor antagonism in an experimental myocardial ischemia paradigm permitting within-animal, pre-versus posttreatment assessment with concurrent positive and negative controls.…”

Section: Abbreviationsmentioning

confidence: 99%

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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. 2008

J Pharmacol Exp Ther

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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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“…Since olcegepant does not induce vasoconstriction per se, this CGRP receptor antagonist has been argued to be safer than triptans, particularly in migraineurs suffering from cardiovascular pathologies. However, it must be highlighted that CGRP has a protective function during coronary ischemia, which was blocked by olcegepant in a Langendorff rat heart model (Chai et al 2006). Thus, if these findings hold for humans as well, CGRP receptor antagonists, like the triptans, may also be contraindicated in patients with coronary artery disease.…”

Section: Cgrp Receptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts

Cited by 92 publications

References 36 publications

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

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

Current and prospective pharmacological targets in relation to antimigraine action

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