Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice

Strecker, Thomas; Meßlinger, Karl; Weyand, Michael; Reeh, Peter W.

doi:10.1016/j.cardiores.2004.10.013

Cited by 37 publications

(27 citation statements)

References 33 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: 91%

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: 91%

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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“…Our data suggest that endogenous CGRP released from isolated mouse hearts by activation of TRPV1 by PC contributes, at least in part, to PC-induced cardiac protection. These results are consistent with reports by others showing that TVPV1, but not acidsensing channels (ASIC3) or B 2 receptors, mediates acidevoked CGRP release from mouse hearts (38). A cautionary note: Given the fact that sensory nerves also possess afferent function in vivo via sending signal to the central nervous system, the data obtained from the Langendorff in vitro model may merely reflect efferent function (neuropeptide release) of sensory nerves activated by TRPV1.…”

Section: Discussionsupporting

confidence: 81%

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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“…Furthermore, CGRP was seen as nephroprotective in hypertensive kidney damage in other publications (3,31). The release of neuronal peptides like CGRP is putatively dependent on the stimulation of transient receptor potential vanilloid type 1 (TRPV1) channels (30). But also in other organs, e.g., the liver, peptidergic afferent nerve fibers were able to release peptides to influence inflammatory and sclerotic processes (33).…”

mentioning

confidence: 99%

“…It is widely accepted that tissue injury, inflammation, and ischemia are accompanied by local tissue acidosis (16), and TRPV1 (29) as well as members of the acid-sensing ion channels (ASIC) family (8,42) have been described as putative transducers of peptidergic afferent nerves to interact with altered proton concentration. Are peptidergic afferent renal nerves sensible or perhaps very sensible to stimulation by an increased proton concentration possibly via TRPV1 receptors or ASIC (30)? Such a finding could suggest mechanisms to be studied further to putatively explain neurogenic CGRP release being so effective in ameliorating hypertensive kidney damage (3,31).…”

mentioning

confidence: 99%

Do distinct populations of dorsal root ganglion neurons account for the sensory peptidergic innervation of the kidney?

Ditting

Tiegs

Rodionova

et al. 2009

American Journal of Physiology-Renal Physiology

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Peptidergic afferent renal nerves (PARN) have been linked to kidney damage in hypertension and nephritis. Neither the receptors nor the signals controlling local release of neurokinines [calcitonin generelated peptide (CGRP) and substance P (SP)] and signal transmission to the brain are well-understood. We tested the hypothesis that PARN, compared with nonrenal afferents (Non-RN), are more sensitive to acidic stimulation via transient receptor potential vanilloid type 1 (TRPV1) channels and exhibit a distinctive firing pattern. PARN were distinguished from Non-RN by fluorescent labeling (DiI) and studied by in vitro patch-clamp techniques in dorsal root ganglion neurons (DRG; T11-L2). Acid-induced currents or firing due to current injection or acidic superfusion were studied in 252 neurons, harvested from 12 Sprague-Dawley rats. PARN showed higher acid-induced currents than Non-RN (transient: 15.9 Ϯ 5.1 vs. 0.4 Ϯ 0.2* pA/pF at pH 6; sustained: 20.0 Ϯ 4.5 vs. 6.2 Ϯ 1.2* pA/pF at pH 5; *P Ͻ 0.05). The TRPV1 antagonist capsazepine inhibited sustained, amiloride-transient currents. Forty-eight percent of PARN were classified as tonic neurons (TN ϭ sustained firing during current injection), and 52% were phasic (PN ϭ transient firing). Non-RN were rarely tonic (15%), but more frequently phasic (85%), than PARN (P Ͻ 0.001). TN were more frequently acid-sensitive than PN (50 -70 vs. 2-20%, P Ͻ 0.01). Furthermore, renal PN were more frequently acid-sensitive than nonrenal PN (20 vs. 2%, P Ͻ 0.01). Confocal microscopy revealed innervation of renal vessels, tubules, and glomeruli by CGRP-and partly SP-positive fibers coexpressing TRPV1. Our data show that PARN are represented by a very distinct population of small-tomedium sized DRG neurons exhibiting more frequently tonic firing and TRPV1-mediated acid sensitivity. These very distinct DRG neurons might play a pivotal role in renal physiology and disease.classification of neurons; capacitance; TRPV1 channels; ASIC; renal afferent nerve; rat NERVES CONTAINING NEUROPEPTIDES such as calcitonin gene-related peptide (CGRP) and substance P (SP) are important components of the sensory nervous system (13, 18). Although these afferent nerves until recently have been thought to sense stimuli in the periphery and transmit the information to the central nervous system, they also have an "efferent" local vasodilator function (10, 37). Acute administration of a CGRP receptor antagonist increases blood pressure in various models of hypertension, which indicates that this potent vasodilator plays a counterregulatory role to attenuate hypertension (12). Furthermore, CGRP was seen as nephroprotective in hypertensive kidney damage in other publications (3, 31). The release of neuronal peptides like CGRP is putatively dependent on the stimulation of transient receptor potential vanilloid type 1 (TRPV1) channels (30). But also in other organs, e.g., the liver, peptidergic afferent nerve fibers were able to release peptides to influence inflammatory and sclerotic processes (33). Hence, it is p...

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Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice

Abstract: We conclude that cardiac acidosis is a strong stimulus to release CGRP from the mouse heart. This effect seems to be primarily mediated through activation of TRPV1 receptors that are known to be expressed by slowly conducting nociceptive primary afferent nerve fibers.

Cited by 37 publications

References 33 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

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

Do distinct populations of dorsal root ganglion neurons account for the sensory peptidergic innervation of the kidney?

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