Am J Physiol Heart Circ Physiol 293: H2155-H2160, 2007.
First published July 27, 2007; doi:10.1152/ajpheart.00629.2007
0363-6135/07 $8.00
Calcitonin gene-related peptide-evoked sustained tachycardia in calcitonin receptor-like receptor transgenic mice is mediated by sympathetic activity
Thomas H. Kunz,1
Michelle Scott,2
Lars M. Ittner,1
Jan A. Fischer,1
Walter Born,1 and
Johannes Vogel2
1Research Laboratory, Orthopedic University Hospital Balgrist, and 2Institute of Veterinary Physiology, Vetsuisse-Faculty and Zürich Center of Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland
Submitted 1 June 2007
; accepted in final form 27 July 2007
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ABSTRACT
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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.
calcitonin gene-related peptide; sympathetic nervous system; baroreceptor reflex
- AND 
-CALCITONIN GENE-RELATED PEPTIDE (CGRP) are 37 amino acid neuropeptides derived from separate genes. -CGRP is widely distributed in the central and peripheral nervous system, whereas -CGRP is primarily located in enteric nerves and in the pituitary gland (1). -CGRP and -CGRP belong to the calcitonin (CT) family of peptides, which includes adrenomedullin (AM) and amylin (16). CGRP and AM are potent vasodilators (2) and exert positive chronotropic and inotropic effects on the heart. Distinct actions of CGRP and AM on the cardiovascular system remain to be delineated. This has been addressed in the present study in transgenic mice expressing a V5-tagged rat CT receptor-like receptor (CLR) under control of a smooth muscle -actin promoter, e.g., in the vascular musculature.
CGRP immunoreactive nerve fibers terminate in blood vessels, primarily small arteries. They are found at the junction of the adventitia and the media and extend into the muscle layer (11). These observations are consistent with the reported vasodilatory activity of CGRP. In the heart of several mammals, including man, CGRP innervates the atria and, to a limited extent, the ventricles (6, 12, 14). In the atria, CGRP-containing nerve fibres are found in the sino-atrial node, the atrio-ventricular node, and the conduction system. Systemic administration of CGRP in humans and rats has direct positive chronotropic action not blocked by labetalol (4, 9). Studies on the inotropic action of CGRP on the heart revealed conflicting results (1). In humans, labetalol suppressed the inotropic action of CGRP, indicating that it is secondary to reflex activation of the sympathetic nervous system (9). In the isolated perfused heart of guinea pigs, CGRP provoked increased contractile force not affected by the -adrenoceptor antagonist metoprolol (7).
Cardiovascular effects of AM have been studied in conscious sheep and rabbits (8, 17). AM, much like CGRP, provoked decreased blood pressure concomitant with increased heart rate and cardiac output. In a recent study in sheep, AM increased the cardiac sympathetic nerve activity (3). In the isolated rat heart, AM had a positive inotropic effect without affecting the heart rate (19).
Both CGRP and AM interact with the CLR that forms heterodimers with single transmembrane-domain receptor-activity-modifying proteins (RAMP). The three so far identified are RAMP1, -2, and -3, and they determine the ligand selectivity of the CLR (15). CGRP predominantly interacts with CLR/RAMP1, whereas AM is recognized when the CLR is associated with RAMP2 or -3. Thus the responsiveness of a given tissue to AM and/or CGRP depends on the levels of expression of the CLR and the corresponding RAMP.
In the present study, the effects of systemically administered CGRP and AM on arterial blood pressure and heart rate were investigated in transgenic mice expressing a V5-tagged rat CLR (V5-CLR) under the control of a smooth muscle -actin promoter in the vascular musculature. Littermates were used as control animals. Basal arterial pressure, heart rate, and the vasodilatory response to CGRP and AM were indistinguishable in V5-CLR transgenic and control mice. However, transgenic animals exhibited sustained tachycardia in response to CGRP but not to equal amounts of AM. The effects of CGRP were suppressed by the CGRP(8-37) antagonist and by the -adrenergic receptor-blocking agent propranolol but not by the ganglion-blocker hexamethonium. Thus CGRP likely increases the heart rate in transgenic mice through interaction with CLR/RAMP1 CGRP receptors localized on postganglionic sympathetic neurons and independent of the baroreceptor reflex.
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MATERIALS AND METHODS
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Chemicals.
Rat -CGRP, -CGRP(8-37), and AM were purchased from Bachem (Bubendorf, Switzerland). All the peptides were dissolved in isotonic saline (0.9% NaCl) immediately before use. Propranolol was from AstraZeneca (Inderal, 1 mg/ml lyophilized to 10 mg/ml) and hexamethonium from Sigma (Buchs, Switzerland, dissolved in isotonic saline to obtain 25 mg/ml).
Generation and characterization of CLR transgenic mice.
Four independent CLR founders were obtained by pronuclear injection of a transgene encoding the V5-CLR (Fig. 1A) into B6D2F1 x B6D2F1 oocytes (10). Founders and offspring were genotyped by PCR analysis of genomic DNA extracted from tail biopsies with transgene specific forward (5'-GGCCCTGGCCATGGAAGAAGG-3') and reverse (5'-TGGGACCATGGATGATGTAGAGG-3') primers. PCR products with a predicted size of 880 bp were identified with agarose gel electrophoresis (Fig. 1B). Expression of the V5-CLR in smooth muscle containing tissues was verified by Western blot analysis of extracts of indicated tissues with antibodies to V5 (Invitrogen, Carlsbad, CA) and with monoclonal smooth muscle -actin specific antibodies (Sigma) and secondary alkaline phosphatase-conjugated antibodies (Jackson ImmmunoResearch Laboratories, West Grove, PA) (Fig. 1C).
Surgery and experimental procedure.
All animal experiments conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85–23, Revised 1996), and institutional guidelines and were approved by the Kantonales Veterinäramt Zürich.
Four- to five-month-old CLR transgenic mice and control littermates were investigated. Anesthesia was induced with a mixture of 4% halothane, 70% N2O, and 26% O2 and maintained by reducing the inhaled halothane concentration to 1–1.5%. Body temperature was maintained at 37°C using a temperature-controlled heating pad. Catheters were inserted into the left femoral artery and vein for the analysis of pH, PCO2, PO2, and base excess (pHOx-Plus, Nova Biomedical, Waltham, MA) and for the recording of arterial blood pressure. The arterial catheter was connected to a piezo-electric pressure transducer connected to a bio-potential amplifier (Hugo Sachs Electronics, March, Germany), and the pressure signal was used to calculate the heart rate from peak to peak with a heart rate module (Hugo Sachs Electronics). The signals from the bio-potential amplifier and the heart rate module were digitized, recorded, and analyzed offline with the Power-Lab system (ADInstruments, Spechbach, Germany). After completion of surgery, the anesthesia was changed to intravenous ethomidate at an infusion rate of 7–10 µl/min, and 30 min later indicated amounts of peptides were administrated as 50-µl iv bolus injections of corresponding stock solutions. Cardiovascular parameters were monitored for 1 h after the injection of the reagents or until they returned to basal values. Changes in heart rate have been analyzed as area under the curve during the 5 min after the injection of the peptides. The maximal decrease in the arterial blood pressure was also evaluated.
One group of experimental animals was treated with a continuous infusion of propranolol (2 mg·kg–1·min–1) or hexamethonium (5 mg·kg–1·min–1) commencing 30 min before the injection of peptides.
Collection of sympathetic ganglia.
CLR transgenic mice and control littermates were transcardially perfused with ice-cooled 0.1 M phosphate buffer (PB; pH 7.4), and fixed with 4% paraformaldehyde in PB. The superior cervical ganglion was removed with the carotid bifurcation and immersed in 4% paraformaldehyde in PB for 2 h, cryoprotected in 20% sucrose in PB for 24 h at 4°C, and frozen at –20°C. Serial 10-µm sections of tissue specimens were obtained with a cryostat, mounted on Superfrost plus slides (Menzel-Glaser, Germany), and kept at –20°C until use.
Immunohistochemistry.
Superior cervical ganglion sections were pretreated with 0.3% H2O2, washed in PBS, and incubated for 2 h in 1.5% rabbit normal serum or 1.5% goat serum diluted in PBS containing 0.3% Triton X-100. The sections were then incubated with antibodies to tyrosine hydroxylase (Novus Biologicals, Littleton, CO; 1:10,000, 48 h) or to the V5 epitope-tag (Bethyl Laboratories, Montgomery, TX; 1:10,000, 1 h). Subsequently, the sections were incubated with biotinylated goat anti-rabbit or rabbit anti-goat IgG (1:200, 2 h) and further processed using the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA), according to the instructions of the manufacturer. The bound antibodies were visualized with 3,-3' diaminobenzidine-tetrahydrochloride (Sigma) as a chromogene. The sections were washed in PBS containing 0.3% Triton X-100 (10 min, 3 times) between incubations.
Statistics.
Data are presented as means ± SE and analyzed with the GraphPad PRISM 4 Software (version 4.01) using ANOVA and Students t-test for unpaired samples with Bonferroni correction. P values of <0.05 were considered significant.
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RESULTS
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Basal blood parameters.
pH, PCO2, PO2, base excess, and hematocrit measured in arterial blood before the administration of drugs and peptides did not differ between control and transgenic mice (Table 1).
Cardiovascular effects of CGRP.
Arterial blood pressure and heart rate were continuously recorded in anesthetized CLR transgenic mice and control littermates before and after intravenous injection of 2 nmol/kg CGRP. Basal arterial blood pressure and heart rate in CLR transgenic mice were 79 ± 2 mmHg and 361 ± 26 beats/min, respectively, and indistinguishable from 78 ± 5 mmHg and 369 ± 29 beats/min in control animals. Intravenous injection of 2 nmol/kg CGRP in CLR transgenic mice and control animals resulted in a comparable transient decrease in arterial blood pressure that returned to basal levels within 6 min of peptide administration (Fig. 2). However, the concomitant increased heart rate, estimated as area under the curve during the 5 min after injection of CGRP, was 3.7 times higher in CLR transgenic mice than in control animals. Moreover, in CLR transgenic mice, the heart rate remained elevated at 140 ± 8% of basal values at least 30 min after the administration of CGRP. This sustained elevation was not observed in control littermates.
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Fig. 2. Effect of intravenously administered calcitonin gene-related peptide (CGRP) alone, or CGRP(8-37) and CGRP, or AM in sequence on heart rate and arterial blood pressure. Representative tracings of heart rate and arterial blood pressure (top). Bottom left: mean changes in heart rate and blood pressure in control (wt; open bars) and CLR transgenic (tg; shaded bars) mice in response to intravenous injection of 2 nmol/kg CGRP. The maximal drop in arterial blood pressure was similar in wt and tg mice. The heart rate, estimated as area under the curve (AUC) during the 5 min after intravenous injection of CGRP, increased to higher levels in tg than in wt mice. Bottom right: changes in heart rate and arterial blood pressure in wt and tg mice in response to 2 nmol/kg CGRP or 20 nmol/kg AM in the presence of 2 µmol/kg CGRP(8-37) antagonist. The decrease in arterial blood pressure and the increase in heart rate evoked by CGRP were suppressed by CGRP(8-37). In contrast, CGRP(8-37) did not affect the AM-evoked drop in arterial blood pressure. Values are means ± SE; n = 5. *P < 0.05 vs. the response to CGRP in wt and tg mice in the presence of CGRP(8-37).
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Intravenous injection of 2 µmol/kg of the CGRP(8-37) antagonist had no effect on systemic blood pressure in transgenic and control mice. However, it suppressed the decrease in arterial blood pressure in response to CGRP to a similar extent in control and CLR transgenic animals (Fig. 2). The CGRP evoked increase in heart rate in CLR transgenic mice was also lowered by CGRP(8-37) to values comparable to those of control mice. The CGRP antagonist did not affect the moderate CGRP-induced increase in heart rate observed in control mice. The evidence for CGRP-specific effects on arterial pressure in control and transgenic animals and on the heart rate in CLR transgenic mice was supported by additional observations. Administration of up to 10 times higher amounts of salmon CT than of CGRP did not affect arterial blood pressure or heart rate in CLR transgenic mice and control littermates (not shown). Moreover, 10 times higher amounts of AM than of CGRP were required to obtain a modest decrease in arterial blood pressure in control (not shown) and transgenic mice that was not blocked by CGRP(8-37). Taken together, the results indicate that the higher and prolonged elevation of the heart rate in CLR transgenic mice in response to systemically administered CGRP is mediated by the CLR/RAMP1 CGRP receptor. The sustained CGRP evoked increase in heart rate is unlikely to result from the transient decrease in arterial blood pressure.
Effect of propranolol and hexamethonium on the action of CGRP.
The enhanced chronotropic action of CGRP was further investigated in CLR transgenic mice and control littermates receiving a constant infusion of the -adrenergic receptor blocking agent propranolol or the ganglionic blocker hexamethonium (Fig. 3). Treatment of control and CLR transgenic mice with propranolol lowered the arterial blood pressure to 40–50 mmHg. Intravenous injection of 2 nmol/kg CGRP in propranolol-treated mice led to a further transient drop in arterial blood pressure indistinguishable in control and CLR transgenic mice and similar to that seen in the absence of propranolol. Importantly, the CGRP evoked increase in heart rate observed in untreated control and CLR transgenic mice was blocked by propranolol. These findings are consistent with activation of the sympathetic nervous system in CLR transgenic mice by intravenous CGRP rather than by a direct action of CGRP on the heart. Our finding that hexamethonium had no effect on the CGRP-evoked heart rate response in CLR transgenic mice supports this interpretation and points to a direct action of CGRP on postganglionic neurons.
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Fig. 3. Effect of propranolol and hexamethonium treatment on the CGRP-evoked changes in heart rate and arterial blood pressure. Top left: representative tracings of heart rate and arterial blood pressure before and after intravenously injected CGRP (2 nmol/kg) in wt and tg mice treated with propranolol (2 mg·kg–1·min–1). Basal arterial blood pressure in wt and tg mice was lower than in untreated mice (see Fig. 2, top left). Bottom left: CGRP injection during propranolol infusion resulted in comparable arterial blood pressure decreases in tg and wt mice. However, the effect on heart rate, estimated as AUC of recordings during the 5 min after intravenous injection of CGRP, was abolished, suggesting a CGRP-dependent mechanism upstream of the sino-atrial node independent of the parasympathetic nervous system. Top right: representative tracings of heart rate and arterial blood pressure before and after intravenous injection of CGRP (2 nmol/kg) in wt and tg mice infused with hexamethonium (5 mg·kg–1·min–1). Bottom right: during hexamethonium treatment, the effect of CGRP on heart rate and arterial blood pressure was indistinguishable from that seen in untreated animals (see Fig. 2, left). This suggests that CGRP exerts its effect on postganglionic neurons. Values are means ± SE; n = 5. *P < 0.05 vs. controls.
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Immunohistochemistry.
Sympathetic ganglia have been identified through staining with antibodies to tyrosine hydroxylase (Fig. 4). V5 staining in sections from CLR transgenic mice localized the CLR to cell bodies. Interestingly, nerve fibers did not stain with antibodies to the V5-CLR.
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Fig. 4. Immunoreactive tyrosine hydroxylase (TH) and V5-CLR in sections of the superior cervical ganglion. Top: TH staining in sections from control (TH-wt) and CLR transgenic mice (TH-tg). Note stained cell bodies and unstained nerve fibers (arrowhead). Bottom: V5 staining of ganglia sections of control (V5-wt) and CLR transgenic mice (V5-tg). In CLR transgenic mice, the cell bodies were stained in contrast to the nerve fibers leaving or entering the ganglion (arrowheads). Bar = 50 µm.
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DISCUSSION
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The present study introduces transgenic mice that express the rat CLR under the control of a smooth muscle -actin promoter in vascular tissue and, unexpectedly, also in the superior cervical ganglion. The transgenic mice responded to intravenously injected CGRP with an increased heart rate of higher amplitude and longer duration than control littermates. Interestingly, hypotension provoked by intravenous CGRP was indistinguishable in CLR transgenic and control mice. Apparently, expression of the transgenic rat CLR in the vascular smooth muscle cell layer, a known target of CGRP, did not increase the sensitivity to CGRP or AM. Counterregulation of increased CGRP or AM sensitivity in vascular smooth muscle cells as a result of downregulation of CGRP or AM receptor signaling in CLR transgenic mice or inadequate expression of RAMP1 or -2 cannot be ruled out. The CGRP(8-37) antagonist was ineffective when administered alone. But the hypotensive effect of CGRP was suppressed in both transgenic and control mice by CGRP(8-37). Importantly, the antagonist lowered the increased positive chronotropic action in transgenic animals. In contrast, equal amounts of AM were ineffective in all mice. Thus the observed chronotropic and hypotensive effects in transgenic and wild-type animals are specific for CGRP. Altogether, the results indicate a predominantly baroreflex-independent positive chronotropic action of intravenously administered CGRP in CLR transgenic mice. This is in line with observations in the rat where over 10-fold higher doses of CGRP than those used here provoked long-lasting tachycardia in the face of a transiently decreased arterial pressure (5).
The long-lasting increased heart rate in CLR transgenic mice may be mediated by a direct action of CGRP on the sino-atrial node or by modulation of the activity of the sympathetic nervous system. To test these hypotheses, we treated the mice with propranolol or hexamethonium. The CGRP-evoked tachycardia was blocked by propranolol, indicating CGRP signaling upstream of the sino-atrial node. In contrast, hexamethonium did not affect the CGRP-evoked increased heart rate. These findings, together with the immunohistochemical localization of the V5-CLR in the superior cervical ganglion, point to the expression of CGRP receptors in postganglionic neurons of transgenic mice and imply unexpected and, as of yet, unexplained activity of the otherwise smooth muscle tissue-specific -actin promoter.
Endogenous CGRP receptors have been localized in sympathetic ganglia (13, 20). Moreover, Seyedi et al. (18) demonstrated a CGRP-provoked release of norepinephrine from isolated sympathetic nerves of the guinea pig heart. In the dog, positive inotropic action of intravenous CGRP was attributed to sympathetic activation brought about through interaction of CGRP with receptors in stellate ganglia (13). This effect was blocked by the -adrenergic blocking agent timolol but not by the ganglionic blocking agent hexamethonium. These findings, much like those of the present study, indicate direct actions of CGRP on the heart mediated through the sympathetic nervous system.
In conclusion, intravenous CGRP provoked tachycardia of higher amplitude and longer duration in CLR transgenic mice compared with nontransgenic littermates. This effect was blocked by propranolol but not by hexamethonium, suggesting a baroreceptor reflex-independent positive chronotropic action of CGRP on the heart of CLR transgenic mice. The effects are mediated by CLR/RAMP1 CGRP receptors expressed on postganglionic sympathetic neurons. This is in accordance with the observed expression of the transgene-derived CLR in the superior cervical ganglion. These findings together with the previously reported inotropic action of CGRP in the dog indicate that CGRP modulates the cardiac output in part through stimulation of myocardial sympathetic activity. The activation of the sympathetic nervous system is a defensive mechanism inhibiting the impact of vasodilation and hypotension.
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GRANTS
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This study was supported by a grant of the Swiss National Science Foundation to W. Born, a grant from the Zürich Center of integrative Human Physiology (ZIHP) to J. Vogel, the University of Zürich, and the Schweizerische Verein Balgrist.
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ACKNOWLEDGMENTS
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Present address of L. M. Ittner: Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, NSW 2050, Australia.
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FOOTNOTES
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Address for reprint requests and other correspondence: W. Born, Laboratory for Orthopedic Research, Orthopedic Univ. Hospital Balgrist, Univ. of Zürich, Forchstrasse 340, 8008 Zurich, Switzerland (e-mail: wborn{at}research.balgrist.ch)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Copyright © 2007 by the American Physiological Society.
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ABSTRACT
MATERIALS AND METHODS
