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Cardiovascular Research 2005 65(2):405-410; doi:10.1016/j.cardiores.2004.10.013
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Copyright © 2004, European Society of Cardiology

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

Thomas Streckera,b, Karl Messlingera, Michael Weyandb and Peter W. Reeha,*

aDepartment of Physiology and Experimental Pathophysiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Universitätsstr. 17, D-91054 Erlangen, Germany
bCenter of Cardiac Surgery, Friedrich-Alexander-University of Erlangen-Nuremberg, Krankenhausstr. 12, D-91054 Erlangen, Germany

* Corresponding author. Tel.: +49 9131 852 2228; fax: +49 9131 852 2497. Email address: reeh{at}physiologie1.uni-erlangen.de

Received 2 May 2004; revised 10 October 2004; accepted 13 October 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objective: Calcitonin gene-related peptide (CGRP), a potent vasodilator released from a subset of sensory A{delta}- and C-fiber afferents, has been suggested to play a beneficial role in myocardial ischemia. The aim of the present study was to investigate some receptors possibly involved in the proton-mediated CGRP release from the heart.

Methods: CGRP release from freshly isolated hearts of mice lacking the capsaicin receptor (TRPV1–/–), the bradykinin receptor type 2 (B2–/–), or the acid-sensing ion channel type 3 (ASIC3–/–) and their wild-type littermates (TRPV1+/+, B2+/+, ASIC3+/+) were compared. Hearts were passed through a series of solutions based on oxygenated synthetic interstitial fluid (SIF). SIF buffered to pH 5.7 or 5.2 was used as an acidic test stimulus, and capsaicin (5 x 10–7 M) was finally applied as a positive control. All eluates were processed using an enzyme immunoassay (EIA) for measurement of CGRP concentrations.

Results: SIF at pH 5.7 and 5.2 caused significant increases in CGRP release in TRPV1+/+ but not in mice lacking the TRPV1 receptor. The same acid stimuli caused no significant differences in CGRP release between ASIC3+/+ and ASIC3–/– or between B2+/+ and B2–/–, respectively. Capsaicin caused massive CGRP release in all mouse genotypes with the exception of TRPV1–/–.

Conclusion: 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.

KEYWORDS Heart; Ischemia; CGRP release; TRPV1; ASIC3; Bradykinin receptor


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that is widely distributed in the central and peripheral nervous system, where it is preferably found in primary afferent A{delta}- and C-fibers [1,2]. Activation of these nerve fibers causes release of CGRP, which acts as a powerful vasodilator in the cardiovascular system as in other vascularized tissues [3,4]. Based on its vascular function, CGRP has been suggested to be involved in several pathophysiological conditions such as septic shock, hypertension, and myocardial ischemia [5,6]. In the cardiovascular system, it seems to primarily exert a protective function [7,8]. In cardiac tissues, CGRP-containing sensory nerves were found at a high density in the sinoatrial and atrioventricular nodes, the pericardium, the right atria, and in the adventitia of the coronary arteries [9,10], thus generally located at the surface of the heart, just below the epicardium.

In patients with acute myocardial infarction, an almost twofold increase in plasma CGRP was observed within 24 h of hospital admission [11]. In this context, CGRP may play a deleterious role, facilitating norepinephrine release from cardiac sympathetic nerve fibers [12], which may contribute to dysrhythmias and sudden cardiac death. Myocardial ischemia is characterized by low pH values, low oxygen and high extracellular potassium concentrations. Low pH and high potassium concentrations cause release of CGRP from the mouse heart in vitro, whereas hypoxia is not effective in stimulating CGRP release (unpublished data from our laboratory). During experimental perfusion of pig and guinea pig hearts with low pH solutions, mimicking one important aspect of ischemia, CGRP is released through activation of capsaicin-sensitive afferent nerves [13,14]. These afferents respond not only to capsaicin and low pH, but also to noxious heat, whereby the heat-threshold can drop below body temperature during tissue acidosis or inflammation.

The aim of the present work was to investigate the involvement of different acid-sensing receptor types in mediating CGRP release from the mouse heart. The capsaicin receptor (TRPV1) is a nonselective cation channel that is expressed in a major subset of cardiac sensory neurons with C and A{delta} fibers. TRPV1 is activated by noxious stimuli such as low pH, heat, and several toxins produced in divergent plants, of which capsaicin from hot peppers is the best known example [15]. Furthermore, it was shown that both spinal and vagal cardiac afferent neurons exhibit acid-evoked ion currents. Some properties of these large currents have been taken to identify them as being carried by acid-sensing ion channels (ASICs) and to distinguish them from the TRPV1 receptors. Especially the cloned acid-sensing ion channel type 3 (ASIC3) reproduces functional features of the channels that may underlie the large acid-evoked currents in cardiac afferent neurons [16].

Previous studies demonstrated that combined inflammatory mediators bradykinin, serotonin and prostaglandin E2 potentiated acid-induced inward currents in capsaicin-sensitive dorsal root ganglion (DRG) neurons from newborn rats. The data further suggested that the combination operates on the capsaicin receptor because the facilitation could be blocked by capsazepine, a competitive capsaicin antagonist [17]. Bradykinin effects on the TRPV1 receptor channel are mediated through the B2 bradykinin receptor that is coupled to the G-protein and essentially sensitized TRPV1 [18]. Bradykinin actions are potentiated at lower pH [12].

In the present study, genetically mutant mice lacking either TRPV1 or ASIC3 receptor channels or B2 receptors were used to examine the significance of these receptor systems for the proton-induced CGRP release from the isolated heart.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996), and the Animal Care Deputy of the University was informed about this ex vivo study.

2.1. Preparation
The experiments were performed on mice of either sex with body weights between 18 and 36 g derived from transgenic strains that were back-crossed to C57BL/6 mice (from Jackson Labs., USA) for at least six generations. Mice lacking the capsaicin receptor (TRPV1–/–) and their wild-type littermates (TRPV1+/+) and mice lacking the bradykinin receptor type 2 (B2–/–) together with their littermates (B2+/+) were bred in the animal house of our department. The initial breeding pairs were generous gifts from John B. Davis (Glaxo Smith Kline, Harlow, UK) and from Ray G. Hill (Merck, Sharpe and Dome, Harlow, UK), respectively. Conventional genotyping was performed using RT-PCR and published primers for the TRPV1 and B2 receptors genes [19,20]. Mice lacking the acid-sensing ion channel type 3 (ASIC3–/–) and their wild-type littermates (ASIC3+/+) were kindly provided by M. Lazdunski and R. Waldmann (Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Sophia Antipolis, Valbonne, France). All animals were housed at 24 °C and provided with standard mice chow and water ad libitum.

The animals were killed in a CO2 atmosphere. After quick thoracotomy, the complete heart was excised by cutting the central blood vessels. A thread was fixed to the aorta with which the heart could be handled without touching it. All preparations, that soon ceased to beat, were washed for 30 min at room temperature in synthetic interstitial fluid (SIF) containing (mmol/l): 108 NaCl, 3.48 KCl, 3.5 MgSO4, 26 NaHCO3, 1.67 NaH2PO4, 1.5 CaCl2, 9.6 sodium gluconate, 5.55 glucose, 7.6 sucrose [21], continuously gassed with 95% oxygen and 5% carbon dioxide, buffered at pH 7.4. For modified SIF buffered at pH 5.7 and 5.2, respectively, the NaHCO3 and NaH2PO4 were replaced by 1.62 mmol/l Na2HPO4 and 45.14 mmol/l citric acid. Fine adjustment of the pH was achieved by applying drops of HCl or NaOH. Capsaicin (Sigma) was dissolved in 98% ethanol as a 3 mM stock solution and diluted with SIF to a final concentration of 5 x 10–7 M.

2.2. Sampling and stimulus application
Hearts were incubated for periods of 5 min in a series of Eppendorf tubes each filled with 250 µl of solutions mentioned below and placed in a thermostatic shaking bath at 36.5 °C. The 1st and the 2nd incubation (baseline) was in buffered SIF (pH 7.4) followed by the stimulation solution consisting of phosphate buffered SIF of pH 5.7 or 5.2, followed by another SIF (pH 7.4), and, finally, 5 x 10–7 M capsaicin in SIF (pH 7.4) was applied for a positive control. Samples of 100 µl from each solution were collected immediately after 5 min incubation and stored on ice in micro test tubes that had been prefilled with 20 µl of the fivefold concentrated commercial EIA-buffer, cotaining an ample mixture of peptidase inhibitors (SPIbio, France).

2.3. Enzyme immunoassays
For measurements of CGRP concentrations, an enzyme immunoassay (EIA) was used (Cayman, distributed by SPIbio, France). The minimum detection limit for CGRP of the assay was 2 pg/ml. The intra- and inter-assay coefficients of variation were 15–20% for basal release and 10–15% for the higher values of stimulated CGRP release. Standard curves were run with graded CGRP concentrations in SIF.

2.4. Data analysis
The concentrations of CGRP were calculated as pg/ml incubation fluid. The CGRP concentration from the second incubation period was taken to normalize the data in each experiment. Mean ± S.E.M. from groups of identical types of experiments were computed. An analysis of variance (ANOVA) for repeated measurements extended post-hoc by the least significant difference (LSD) test was performed using the nonnormalized values. Significance was assessed at the 5% level (p<0.05).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
Isolated hearts of genetically different mice were used to measure basal and proton-stimulated CGRP release. In all mutant strains (TRPV1–/–, ASIC3–/–, B2–/–) and in their wild-type littermates (TRPV1+/+, ASIC3+/+, B2+/+) the mean basal CGRP release was between 23 pg/ml and 27 pg/ml (Table 1) and was stable from the first to the second control sample. From each animal the second control value of basal CGRP concentration was taken as baseline value to normalize the individual data.


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  		Table 1 CGRP release in isolated hearts of different mice TRPV1–/–, ASIC3–/–, and B2–/– and in their wild-type littermates TRPV1+/+, ASIC3+/+, and B2+/+ caused by stimulation with low pH of 5.2 and 5.7 and capsaicin at 5 x 10–7 mmol/l (mean ± S.E.M.)

 
In all wild-type groups, the stimulation by acidic buffers caused 2.4- to 3.6-fold increases in CGRP release which were not significantly different for pH 5.7 and pH 5.2, suggesting that pH 5.7 was already supramaximal for stimulating cardiac CGRP release. The recovery after acid stimulation was complete within the subsequent 5-min incubation. The acid stimuli caused significant increases in cardiac CGRP release in wild-type TRPV1+/+ mice but not in mice lacking the TRPV1 receptor (TRPV1–/–; Table 1). Likewise, capsaicin (5 x 10–7 M) as a positive control stimulus caused significant increases in CGRP release only in TRPV1+/+ but not in TRPV1–/– (Table 1 and Fig. 1A and B). The vehicle of capsaicin containing 0.05% ethanol was not effective in releasing CGRP (n=4, not shown). Interestingly, all capsaicin responses in all responsive mouse groups were consistently smaller following the stronger acid stimulus (pH 5.2) than the weaker one (pH 5.7), which indicates heterologous desensitisation by protons of the capsaicin receptor channel.


Figure 1
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  		Fig. 1 CGRP release (normalized data, mean ± S.E.M.) caused by stimulation of (A) isolated mice heart with the intact capsaicin receptor type 1 (TRPV1+/+): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5 x 10–7 mmol/l. (B) Mice hearts lacking the capsaicin receptor type 1 (TRPV1–/–): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5 x 10–7 mmol/l. (n=6 in all experiments; *P<0.05, ANOVA and LSD test, applied to the raw data).

 
In mice lacking the acid-sensing ion channel type 3 (ASIC3–/–) and their wild-type littermates (ASIC3+/+), the acid stimuli significantly increased CGRP release which was not different between the two genotypes (Table 1 and Fig. 2A and B). Likewise, stimulation with capsaicin (5 x 10–7 M) caused no significant differences in CGRP release between both types.


Figure 2
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  		Fig. 2 CGRP release (normalized data, mean ± S.E.M.) caused by stimulation of (A) isolated mice heart with the intact acid-sensing ion channel type 3 (ASIC3+/+): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5x10–7 mmol/l. (B) Mice hearts lacking the acid-sensing ion channel type 3 (ASIC3–/–): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5 x 10–7 mmol/l. (n=6 in all experiments; *P<0.05, ANOVA and LSD test, applied to the raw data).

 
In mice lacking the B2 receptor (B2–/–), the increased CGRP release caused by pH 5.2 or 5.7 and by capsaicin (5 x 10–7 M) appeared to be smaller than in mice with the intact B2 receptor (B2+/+), but this tendency was not significant (Table 1, Fig. 3A and B).


Figure 3
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  		Fig. 3 CGRP release (normalized data, mean ± S.E.M.) caused by stimulation of (A) isolated mice heart with the intact bradykinin receptor type 2 (B2+/+): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5 x 10–7 mmol/l. (B) Mice hearts lacking the bradykinin receptor type 2 (B2–/–): pH 5.2 (bullet) and 5.7 (lhblk) followed by capsaicin 5 x 10–7 mmol/l. (n=6 in all experiments; *P<0.05, ANOVA and LSD test, applied to the raw data).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The present preparation of the isolated mouse heart, without coronary perfusion, relied on the fact that all CGRP expressing nerve fibers terminate next to the epicardial surface [22] which can be assumed to be well supplied with oxygen by superfusion as well as reached by the acid buffer solutions. Support for this assumption is provided by the observations of stable baseline release of CGRP and of prompt response to and recovery from acid stimulation. In consequence, the present results are in good agreement with previous ones obtained from acid stimulation of the perfused guinea pig heart [13,14]. The acid effect seems to be primarily mediated through activation of TRPV1 receptors that are known to be located on nociceptive primary afferent nerve fibers [23]. Ischemia-induced cardiac acidosis appears to be an essential condition inducing pain during cardiac hypoxia. In previous studies on DRG neurones from the rat and on C-fibre afferents in the guinea pig heart, the competitive capsaicin antagonist capsazepine inhibited not only capsaicin-evoked CGRP release but also CGRP release induced by low pH, which indicates a common release mechanism [24]. It is known that capsazepine as well as capsaicin bind to the capsaicin receptor channel TRPV1 which is also activated by protons and noxious heat [19]. We conclude from the present knockout results that TRPV1 receptor channels are major players in the proton-dependent CGRP release. Neuropeptide release is known to depend on an increase in free intracellular Ca++, which in primary afferent nerve endings is subserved by the opening of voltage-gated Ca++ channels [25]. Since TRPV1 receptors are unspecific cation channels, they are not only effective in depolarizing primary afferents but also show considerable Ca++ conductance by themselves; their opening is likely to be particularly effective with respect to CGRP release.

An involvement of acid-sensing ion channels type 3 (ASIC3) in the proton-stimulated CGRP release from the mouse heart could not be confirmed in the present study. Acid-sensing ion channels (ASICs) have been identified as kinetically distinct, Na+- and Ca2+-permeable channels in neurons that are gated by low pH and blocked by the diuretic drug amiloride [26]. They constitute a proton-sensitive subfamily of channels within the larger family of epithelial sodium channels and degenerin channels of Caenorrhabditis elegans [27]. At present, the ASIC family has five members in rat and mouse: ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 [25]. Particularly, ASIC3 matches the functional properties of a channel that underlies the large acid-evoked inward currents in cultured cardiac sensory neurons, and it has been associated to cardiac ischemic and inflammatory pain [16,28]. It was shown that low levels of endogenous nerve growth factor (NGF), which is a mediator in inflammatory pain, are responsible for basal ASIC3 expression, and high NGF levels as during inflammation increase ASIC3 expression in parallel to the development of neuronal hypersensitivity as associated with hyperalgesia [29]. In our experiments, neither pH 5.7 nor pH 5.2 stimulation showed any difference in CGRP release between ASIC3–/– and ASIC3+/+ hearts. This is at variance with the electrophysiological results of Lazdunski's [29] and McCleskey's [16] groups from which a role of ASIC3 receptor channels in controlling neuropeptide release could be inferred. Our preparation of the isolated heart monitors the function of sensory nerve terminals, whereas the electrophysiological works use the DRG cell in culture as a model of its nerve endings. Latest with the advent of TRPV1 knockout mice, however, it became evident that there are major discrepancies between the cellular model and the real nerve endings which match the behavioral phenotype of the animal more closely [30,31]. At the pH values used, TRPV1 generates a slowly activating sustained inward current [32], which effectively depolarizes neurons, introducing calcium and releasing CGRP. ASIC3, on the other hand, would induce a sustained current only at pH levels lower than 5, whereas pH 5.7 and 5.2 generate rapidly inactivating ASIC3 currents that would not last for the 5 min duration of the pH stimuli used in the present work.

A role for the B2 receptors in the proton-stimulated CGRP release from the mouse heart could not be shown in the present study. In previous studies, it was found that disruption of the gene that encodes for the constitutive B2 receptor causes left ventricular hypertrophy, hypertension, myocardial damage, and cardiac failure [20]. This development is quite similar to the pathological changes observed in the hypertensive hypertrophic cardiomyopathy in man that may indicate an essential role of kinins and the B2 receptor in the preservation of myocardial structure and function [33,34]. On the other hand, bradykinin and the B2 receptor cause a tonic sensitization of primary afferent nociceptors which includes enhanced release of neuropeptides as shown in several tissue preparations as well as in the isolated guinea pig heart. The capsaicin receptor TRPV1 is a prominent molecular target of the sensitising action of bradykinins through the B2 receptor. Thus, in view of the predominant role of TRPV1 in acid-sensing, a tonic facilitatory role of kinins and the B2 receptor appeared possible but could not be demonstrated in the present study. There were small but not significant differences in stimulated CGRP release between B2–/– and the wild-type mice B2+/+. These differences might become relevant under pathological conditions as shown by a number of studies using these bradykinin B2 receptor knockout mice [35].

In conclusion, we have shown a predominant role for TRPV1 receptors in acid-evoked CGRP release from the mouse heart, whereas ASIC3 and B2 receptors were shown to play no obvious role in this response. TRPV1 receptors can be assumed to be important in nociception and thus might be a useful pharmaceutical target for treating ischaemic cardiac pain, if the mechanisms are similar in human as in mouse heart. However, in view of the potentially important vasodilatory and cardioprotective function of CGRP, TRPV1 blockade may be of disadvantage in ischemic heart disease. For clarification of these options, the mechanisms deserve further investigations.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
The authors would like to thank Mrs. B. Vogler, Mrs. M. Schulte, Mrs. J. Schramm, Mrs. I. Izydorczyk, and Mrs. A. Kuhn for their excellent technical assistance. The work was supported by the Deutsche Forschungsgemeinschaft (SFB 353, B3 and B12) and the Wilhelm-Sander-Stiftung.


   Notes
 
Time for primary review 16 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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