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Am J Physiol Heart Circ Physiol 274: H1489-H1494, 1998;
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Vol. 274, Issue 5, H1489-H1494, May 1998

Endogenous calcitonin gene-related peptide modulates tachycardiac but not bradycardiac baroreflex in rats

Seungbum Kim1,2, Yasuyoshi Ouchi2, Hiromichi Sekiguchi1, Hideyuki Fujikawa1, Kazuyuki Shimada1, and Kinji Yagi1

1 Departments of Physiology and Cardiology, Jichi Medical School, Minamikawachi, Tochigi 329-04; and 2 Department of Geriatrics, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

Effects of intracisternally administered human calcitonin gene-related peptide (8-37) [hCGRP-(8---37)], an antagonist, and hCGRP, an agonist of the CGRP receptor in the rat central nervous system, on baroreflex sensitivity (BRS) were studied in conscious male rats. Each rat sequentially received intracisternally injected 0.9% saline and then hCGRP-(8---37) at doses of 1, 2.5, and 5 nmol in a volume of 10 µl at an interval of 15 min. Five minutes after each injection, sodium nitroprusside (SNP, 10 µg/kg) or phenylephrine hydrochloride (PE, 2 µg/kg) was intravenously administered to induce reflex tachycardia or bradycardia, respectively. Intracisternally administered hCGRP-(8---37) increased BRS of the reflex tachycardia induced by SNP in a dose-related manner but did not change the BRS after PE. Intracisternally injected hCGRP significantly decreased the BRS after SNP. The lowering effect of hCGRP on BRS after SNP was inhibited by hCGRP-(8---37) injected before hCGRP. These results suggest that endogenous CGRP in the lower brain stem is selectively involved in the tachycardiac but not the bradycardiac baroreflex and modulates the baroreflex in an inhibitory rather than facilitatory fashion.

calcitonin gene-related peptide antagonist; intracisternal; baroreflex sensitivity; heart rate

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

IMMUNOREACTIVE calcitonin gene-related peptide (CGRP) and its specific binding sites have been demonstrated to exist widely in the central nervous system of mammalian species (7, 21, 22, 25). The CGRP-immunoreactive (10, 22) and CGRP mRNA-containing (11) neurons have been found at the highest density in the lower brain stem and spinal cord. These CGRP-containing areas include the nucleus tractus solitarius, the nucleus ambiguus, the dorsal motor nucleus of the vagus, and the ventrolateral medulla. Neurons in these brain stem areas are known to be involved in the control of cardiovascular functions including an arterial baroreflex. Thus the possibility arises that CGRP released endogenously in these areas may modulate cardiovascular reflex functions. Consistent with this hypothesis, intracerebroventricularly administered CGRP has been shown to enhance discharge activity of the sympathetic nerve and, as a result, to increase heart rate and arterial blood pressure (6, 14). It is, however, unclear whether endogenous CGRP in these brain stem areas modulates the baroreflex functions.

It has been shown that a COOH-terminal fragment of human CGRP, namely hCGRP-(8---37), has an antagonistic effect on the CGRP receptor in the rat central nervous system (4, 26). The distribution profile of hCGRP-(8---37) binding sites in the rat brain stem has been demonstrated to be rather similar to that of hCGRP binding sites (26). In addition, hCGRP-(8---37) has been shown to have a potent antagonistic effect on the action of the endogenously released CGRP in the rat central nervous system (4). Thus hCGRP-(8---37) is a useful tool for testing the possibility that CGRP released endogenously in the brain stem modulates the baroreflex functions.

Systemically administered sodium nitroprusside (SNP) and phenylephrine (PE) produce baroreceptor reflex-mediated tachycardia and bradycardia, respectively (5). To test the hypothesis that CGRP released endogenously in the lower brain stem modulates the arterial baroreflex functions, the present study aimed at investigating the effects of intracisternally administered hCGRP-(8---37) and hCGRP on the baroreflex sensitivity (BRS), which is defined by a change in heart rate per unit change in arterial blood pressure, after an administration of SNP or PE in conscious male rats.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Animals. Male Wistar rats weighing 280-320 g were used. Two rats were housed in each cage in an animal room (lights on 8:00 AM to 8:00 PM, 23-25°C). The animals were allowed free access to food and drinking water and were maintained for at least 5 days before experiments.

Surgical procedures. A stainless steel guide cannula was attached to the cisterna magna according to Bouman and Van Wimersma Greidanus (2) and Lai et al. (15) with reference to an atlas of the rat brain (17). Briefly, each rat was anesthetized with pentobarbital sodium (50 mg/kg body wt ip) and placed in a stereotaxic instrument (Narishige, Tokyo, Japan). The skull was exposed from the bregma to the occipital crest. A hole was made with a dental drill on the midline immediately rostral to the interparietal occipital suture. Through this hole, the tip of a 23-gauge stainless steel guide cannula was lowered 7 mm into the cisterna magna below at an angle of 70° to the skull surface. The guide cannula was fixed to two jeweler's screws attached to the skull with dental cement. The position of the cannula tip within the cisterna magna was verified by cerebrospinal fluid spilled out spontaneously through the upper end of the cannula. The cannula was then sealed with a 30-gauge obturator until the day of experiments. Five to seven days after the surgery for attachment of the guide cannula, the rat was anesthetized again with pentobarbital sodium. A polyethylene catheter (PE-50 tubing) was inserted to the left femoral artery for monitoring arterial blood pressure (BP) and heart rate (HR), and another catheter was attached to the right jugular vein for drug administrations. About 20-24 h after the catheterization, the arterial catheter in the conscious rat was connected to a strain-gauge transducer (P10 EZ, Statham) to record BP and HR on a thermal pen recorder (NEC San-Ei, Tokyo, Japan) throughout the experiments.

Experimental protocols. To determine the baseline levels of mean arterial blood pressure (MAP) and HR, recordings of BP were made in the conscious rat for more than 5 min without manipulations. Either a peptide solution or the vehicle (0.9% NaCl) in a volume of 10 µl was then injected into the cisterna magna through a 30-gauge needle attached to a Hamilton syringe. The dose of intracisternally injected hCGRP or hCGRP-(8---37) (Peptide Institute, Osaka, Japan) in the present experiments was 1, 2.5, or 5 nmol per rat. We determined this dose for the intracisternal injection on the basis that intracerebroventricular administration of hCGRP at a dose of 0.1-3.0 nmol (6, 14) or intrathecal administration of CGRP at a dose of 0.72-8.6 nmol (18) has been shown to be effective in producing a cardiovascular response in rats. Five minutes after the intracisternal injection, SNP (Wako Pure Chemicals, Osaka, Japan) or PE (Sigma, St. Louis, MO) dissolved in 0.9% NaCl was injected into the right jugular vein at a dose of 10 or 2 µg · 0.5 ml-1 · kg-1, respectively. These doses were determined according to the reported experiments in which the dose of SNP or PE appropriate for inducing depressor or pressor changes, which in turn activate baroreceptor reflex, was between 1 and 32 µg/kg for SNP (3) and between 1 and 4 µg/kg for PE (5), respectively. Altered MAP and HR after SNP or PE returned to baseline levels within 5 min. Therefore, a pair of injections of the peptide solution and SNP or PE as a single trial were repeated at an interval of 15 min in increasing peptide doses. To test two CGRP analogs in combination, hCGRP-(8---37) and then hCGRP were intracisternally injected successively at identical doses. BRS was calculated for each trial as a peak change in HR per unit change in MAP after SNP or PE on the basis of BP and HR values measured on the recorder.

Statistics. Data were expressed as means ± SE and analyzed using the method of analysis of variance. When statistical significance was noted, the difference between two groups was further analyzed using the Newman-Keuls test. Student's t-test for paired data was also used when appropriate.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Effects of intracisternally administered hCGRP-(8---37) on reflex tachycardia. The rats were injected intracisternally with hCGRP-(8---37) or the vehicle. Intracisternally administered hCGRP-(8---37) did not significantly alter the baseline levels of MAP and HR. In the rats that had received intracisternal hCGRP-(8---37), intravenously administered SNP transiently decreased BP for ~1 min and increased HR as a result of tachycardiac baroreflex. Figure 1 shows a sample record of the tachycardiac baroreflex after SNP. The magnitude of the peak decrease in MAP was not significantly different between the depressor response after intracisternally injected saline and that after hCGRP-(8---37). The magnitude of the peak increase in HR after SNP, however, was significantly larger in the reflex response after intracisternal hCGRP-(8---37) than in that after the vehicle (Table 1).


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  		Fig. 1.   Sample records of tachycardiac baroreflex responses induced by intravenous (iv) sodium nitroprusside (SNP) in same rat pretreated intracisternally (ic) with human calcitonin gene-related peptide (8---37) [hCGRP-(8---37)] or vehicle. The magnitude of a decrease in mean arterial blood pressure (MAP) in response to iv SNP after ic hCGRP-(8---37) was similar to that after vehicle. The magnitude of an increase in heart rate (HR) as a result of baroreflex was apparently larger after hCGRP-(8---37) than after vehicle. BP, blood pressure; bpm, beats/min.

                              
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  		Table 1.   Effects of intracisternally injected hCGRP-(8---37) on tachycardiac baroreflex responses after intravenous SNP

As shown in Fig. 2, intracisternally administered hCGRP-(8---37) increased BRS in a dose-related fashion. Mean BRS after intracisternal hCGRP-(8---37) at the dose of 5 nmol was 144% of the mean BRS observed after an intracisternally injected vehicle.


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  		Fig. 2.   Baroreflex sensitivity (BRS) of tachycardiac reflex responses induced by iv injected SNP. Intracisternally administered hCGRP-(8---37) increased BRS in a dose-related manner. Data are means ± SE for 10 rats. Each rat received ic vehicle (0.9% saline) and hCGRP-(8---37) at sequential doses of 1, 2.5, and 5 nmol. * P < 0.05, ** P < 0.01 compared with data after vehicle.

Effects of intracisternally administered hCGRP-(8---37) on reflex bradycardia. The animals were injected intravenously with PE 5 min after an intracisternal injection of hCGRP-(8---37) or the vehicle. PE increased MAP transiently and decreased HR as a result of bradycardiac baroreflex. Intracisternally administered hCGRP-(8---37) did not significantly change the peak magnitude of the pressor response to intravenous PE or the peak decrease in HR (Table 2). As a result, intracisternally administered hCGRP-(8---37) did not significantly alter the BRS estimated for the reflex bradycardia after PE, as shown in Fig. 3.

                              
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  		Table 2.   Effects of intracisternally injected hCGRP-(8---37) on bradycardiac baroreflex responses after intravenous PE


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  		Fig. 3.   BRS of bradycardiac responses induced by iv injected phenylephrine (PE) was not significantly altered by ic administered hCGRP-(8---37). Data are means ± SE for 8 rats.

Effects of intracisternally administered hCGRP on the reflex tachycardia. To examine whether an activation of CGRP receptors located in the lower brain stem results in a suppression of the BRS of tachycardiac reflex response after SNP, we injected rats intracisternally with hCGRP at the doses of 0, 1, 2.5, and 5 nmol and observed the effect of this peptide on the BRS of tachycardiac reflex response after SNP. Intracisternally administered hCGRP lowered the baseline level of MAP and elevated the level of HR (Table 3). Increases in HR after the peptide was administered averaged 45 beats/min at a dose of 1 nmol, 56 beats/min at 2.5 nmol, and 86 beats/min at 5 nmol.

                              
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  		Table 3.   Effects of intracisternally injected hCGRP on tachycardiac baroreflex responses after intravenous SNP

In the rats that had received intracisternal hCGRP, intravenously injected SNP decreased MAP and increased HR as a result of tachycardiac baroreflex. The peak amplitude of the depressor response to SNP was not statistically significant between the responses after hCGRP at any dose and those after the vehicle. The peak amplitude of the reflex tachycardia after SNP, however, was significantly smaller after the peptide than after the vehicle (Table 3). As a result, the BRS determined for each reflex tachycardia was significantly lower after intracisternally administered hCGRP than after the vehicle, showing the apparent suppressive effect of hCGRP on the tachycardiac BRS (Fig. 4).


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  		Fig. 4.   Intracisternally administered hCGRP suppressed BRS of tachycardiac reflex responses to iv injected SNP. * P < 0.05, ** P < 0.01 compared with data after vehicle. Data are means ± SE for 7 rats.

Blocking action of intracisternal hCGRP-(8---37) on the effect of intracisternally injected hCGRP. To determine whether the augmentative effect of hCGRP-(8---37) on the BRS of reflex tachycardia after SNP was due to its specific antagonistic actions on the CGRP receptor, we injected rats intracisternally with both hCGRP-(8---37) and hCGRP and observed the tachycardiac reflex after SNP. Successive intracisternal injections of hCGRP-(8---37) and hCGRP slightly lowered the baseline level of MAP and elevated the level of HR, though the change in the baseline level of MAP or HR was not statistically significant (Table 4).

                              
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  		Table 4.   Effects of intracisternally injected hCGRP-(8---37) and hCGRP on tachycardiac baroreflex responses after intravenous SNP

In the rats that had received both hCGRP-(8---37) and hCGRP intracisternally, intravenously injected SNP transiently decreased MAP and, as a result of baroreflex, increased HR. The peak amplitude of changes in MAP or HR after SNP was not significantly different between the responses observed after both peptides were injected intracisternally and those observed after the vehicle. Consequently, the BRS calculated for each trial was not significantly different between the tachycardiac responses to SNP after the peptide administrations and the responses after the vehicle (Fig. 5). These results demonstrate that intracisternal hCGRP-(8---37) blocked the suppressive effects of intracisternal hCGRP on the tachycardiac reflex after SNP, because hCGRP decreased the BRS of tachycardiac reflex after SNP significantly (Fig. 4).


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  		Fig. 5.   Effects of combined administrations of hCGRP-(8---37) and hCGRP on BRS of tachycardiac reflex responses to iv injected SNP. Data are means ± SE for 7 rats.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

It has been shown that the medulla oblongata and the spinal cord contain a considerable amount of CGRP and its binding sites in rats (8, 10, 12, 22). Although the amino acid sequence of an hCGRP molecule is different from that of rat CGRP in 4 of 37 amino acid residues, hCGRP and hCGRP-(8---37) have been shown to bind competitively to CGRP receptors in the rat central nervous system and have an agonistic and antagonistic effects on the receptor in rats, respectively (4, 26). It has been demonstrated that hCGRP administered intrathecally at the level of thoracic segments increases HR in rats (18). It is, therefore, possible that the site of action of the hCGRP injected into the cisterna magna might have been at CGRP receptors in the spinal cord rather than those in the medulla oblongata. In the present experiments, however, HR was not significantly altered after hCGRP was injected intracisternally at a dose of 1 or 2.5 nmol but was significantly altered after the peptide was injected at a dose of 5 nmol (Table 3). Therefore, a decrease in magnitude of reflex tachycardia was observed after hCGRP was injected intracisternally at a dose of 1 or 2.5 nmol and, as a result, a decrease in BRS (Fig. 4) is suggested to be due to an activation of CGRP receptors in the medulla oblongata. A significant increase in HR after the peptide at a dose of 5 nmol may reflect the consequence of activation of CGRP receptors in the spinal cord as well.

In contrast, intracisternally injected hCGRP(8---37) did not significantly alter the baseline level of MAP or HR but augmented the BRS of tachycardiac baroreflex after intravenously injected SNP (Table 1 and Fig. 2). These results may indicate that CGRP is released in the rat lower brain stem not in a tonic but in a baroreflex activity-dependent fashion. In other words, a reduced baroreceptor input to the medulla as a result of decreased MAP after SNP is suggested to activate the neural pathway that increases sympathetic outflow, resulting in tachycardia on one hand, and the neural pathway that releases CGRP in the brain stem, bringing about a suppression of the reflex tachycardia on the other hand.

Primary afferent fibers originating from baroreceptors send input signals to neurons in the nucleus tractus solitarius (NTS) of the medulla (16). CGRP and its binding sites have been shown to exist in the NTS (8, 10, 12, 22). If the CGRP receptors on NTS neurons were the sites of action of intracisternally administered hCGRP-(8---37), the peptide would be expected to alter the BRS of both tachycardiac baroreflex after SNP and bradycardiac baroreflex after PE. In the present experiments, however, intracisternally injected hCGRP-(8---37) changed selectively the BRS of tachycardiac baroreflex after SNP but not that of bradycardiac baroreflex after PE. In the bradycardiac baroreflex after PE, intracisternally administered hCGRP-(8---37) also did not alter the BRS after PE at a high dose of 5 µg/kg (data not shown). Thus CGRP receptors on NTS neurons could not be the site of antagonistic actions of intracisternally administered hCGRP-(8---37) in the present experiments. Consistent with this notion, it has been demonstrated that hCGRP injected in the NTS did not significantly change MAP, HR, or the baroreflex response to aortic nerve stimulation in anesthetized rats (13).

It has been shown that the NTS neurons that receive the afferent neural signals originating from the arterial baroreceptors project to the nucleus ambiguus (23). Discharge activity of the nucleus ambiguus neurons enhance the efferent activity of the cardiac vagus and, in turn, decrease HR. The nucleus ambiguus has been shown to contain CGRP and its binding sites. This reflex pathway, however, could not be responsible for the effects of CGRP released endogenously in a reflex activity-dependent manner on the BRS of tachycardiac reflex, because it has been suggested that the bradycardiac but not the tachycardiac baroreflex response is selectively mediated by the cardiac vagus nerve (5).

It has been shown that the NTS neurons that receive input signals originating from the arterial baroreceptors also project to neurons in the caudal ventrolateral medulla (cVLM) (1). The cVLM neurons in turn inhibit spontaneously discharging activity of the rostral ventrolateral medulla (rVLM) in a tonic fashion (1). The spontaneously active rVLM neurons have been shown to excite sympathetic preganglionic neurons in the spinal cord (19). This intramedullary reflex pathway has been claimed to mediate selectively tachycardiac baroreflex due to a decrease in MAP (1). CGRP and its binding sites have been demonstrated in both the cVLM and rVLM (8, 10, 12, 22). Thus these two possible sites are considered for the location of CGRP-producing neurons that modulate tachycardiac baroreflex. The present results suggest that CGRP was released only when the tachycardiac baroreflex was induced by a reduction in MAP after SNP and that the endogenously released peptide reduces an increase in sympathetic outflow during the tachycardiac reflex. A reduction in MAP after SNP is expected to reduce discharge activities of both the NTS neurons projecting to the cVLM and the cVLM neurons that project to the rVLM. Consequently, the level of tonic activity of rVLM neurons should be augmented by disinhibition. The most likely explanation that satisfies all these conditions is that CGRP-producing rVLM neurons receive tonic inhibitory synaptic inputs from the cVLM neurons, releasing CGRP from axon terminals in the rVLM by disinhibition as the cVLM inputs are reduced due to a decrease in MAP, and that the released CGRP suppresses discharge activity of spontaneously active rVLM neurons, resulting in a reduced BRS of tachycardiac baroreflex. Inconsistent data have been reported concerning the modulatory action of CGRP on excitable cells. It has been demonstrated that CGRP applied to the rVLM in a slice preparation enhances discharge activity of spontaneously active rVLM neurons (24) and that CGRP applied to the dorsal root ganglion neurons activates Ca2+ channels of the neuronal membrane (20). However, CGRP receptors, as activated by CGRP, have been shown to increase the intracellular concentration of cAMP, which in turn suppresses the excitability of rat cortical neurons in culture (27) or vascular smooth muscle cells (9). The present results are consistent with the view that CGRP, at least that involved in the tachycardiac reflex after SNP, has an inhibitory modulatory effect on neuronal excitability.

In the present experiments, intracisternally administered hCGRP reduced the BRS of tachycardiac reflex in response to SNP (Table 3 and Fig. 4). The results suggest that CGRP released endogenously in these areas partially, but not fully, activates CGRP receptors during the reflex response. Intracisternally administered hCGRP-(8---37) increased the BRS of the tachycardiac reflex. In addition, intracisternal hCGRP-(8---37) inhibited the suppressive effects of hCGRP on the BRS of tachycardiac reflex. These data demonstrate that the observed increase after hCGRP-(8---37) in the tachycardiac BRS was attributed to a specific antagonistic action of hCGRP-(8---37) on the CGRP receptor in the medulla oblongata. Thus the present results suggest that endogenous CGRP released in the lower brain stem in a baroreflex activity-dependent fashion selectively suppresses the BRS of tachycardiac but not bradycardiac baroreflex.

    ACKNOWLEDGEMENTS

This work was supported by Grant-in-Aid No. 06770036 for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

    FOOTNOTES

Address for reprint requests: S. Kim, Dept. of Geriatrics, Univ. of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan.

Received 3 October 1997; accepted in final form 29 January 1998.

    REFERENCES
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Abstract
Introduction
Methods
Results
Discussion
References

1.   Agarwal, S. K., and F. R. Calaresu. Monosynaptic connection from caudal to rostral ventrolateral medulla in the baroreceptor reflex pathway. Brain Res. 555: 70-74, 1991[Medline].

2.   Bouman, H. J., and T. B. Van Wimersma Greidanus. A rapid and simple cannulation technique for repeated sampling of cerebrospinal fluid in freely moving rats. Brain Res. Bull. 4: 575-577, 1979[Medline].

3.   Crofton, J. T., L. Share, and D. P. Brooks. Pressor responsiveness to and secretion of vasopressin during the estrous cycle. Am. J. Physiol. 255 (Regulatory Integrative Comp. Physiol. 24): R1041-R1048, 1988[Abstract/Free Full Text].

4.   Dennis, T., A. Fournier, A. Cadieux, F. Pomerleau, F. B. Jolicoeur, S. St. Pierre, and R. Quirion. hCGRP8-37, a calcitonin gene-related peptide antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery. J. Pharmacol. Exp. Ther. 254: 123-128, 1990[Abstract/Free Full Text].

5.   Ferrari, A. U., A. Daffonchio, F. Albergati, and G. Mancia. Inverse relationship between heart rate and blood pressure variabilities in rats. Hypertension 10: 533-537, 1987[Abstract/Free Full Text].

6.   Fisher, L. A., D. O. Kikkawa, J. E. Rivier, S. G. Amara, R. M. Evans, M. G. Rosenfeld, W. W. Vale, and M. R. Brown. Stimulation of noradrenergic sympathetic outflow by calcitonin gene-related peptide. Nature 305: 534-536, 1983[Medline].

7.   Gibson, S. J., J. M. Polak, S. R. Bloom, I. M. Sabate, P. M. Mulderry, M. A. Ghatei, G. P. McGregor, J. F. B. Morrison, J. S. Kelly, R. M. Evans, and M. G. Rosenfeld. Calcitonin gene-related peptide immunoreactivity in the spinal cord of man and of eight other species. J. Neurosci. 4: 3101-3111, 1984[Abstract].

8.   Inagaki, S., S. Kito, Y. Kubota, S. Girgis, C. J. Hillyard, and I. MacIntyre. Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains. Brain Res. 374: 287-298, 1986[Medline].

9.   Ishikawa, M., Y. Ouchi, and H. Orimo. Effect of calcitonin gene-related peptide on cytosolic free Ca2+ level in vascular smooth muscle. Eur. J. Pharmacol. 246: 121-128, 1993[Medline].

10.   Kawai, Y., K. Takami, S. Shiosaka, P. C. Emson, C. J. Hillyard, S. Girgis, I. MacIntyre, and M. Tohyama. Topographic localization of calcitonin gene-related peptide in the rat brain: an immunohistochemical analysis. Neuroscience 15: 747-763, 1985[Medline].

11.   Kresse, A., D. M. Jacobowitz, and G. Skofitsch. Detailed mapping of CGRP mRNA expression in the rat central nervous system: comparison with previous immunocytochemical findings. Brain Res. Bull. 36: 261-274, 1995[Medline].

12.   Kruger, L., P. W. Mantyh, C. Sternini, N. C. Brecha, and C. R. Mantyh. Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites. Brain Res. 463: 223-244, 1988[Medline].

13.   Kubo, T., and M. Kihara. Modulation of the aortic baroreceptor reflex by neuropeptide Y, neurotensin and vasopressin microinjected into the nucleus tractus solitarii of the rat. Naunyn Schmiedebergs Arch. Pharmacol. 342: 182-188, 1990[Medline].

14.   Kuo, T.-F., Y. Ouchi, S. Kim, K. Toba, and H. Orimo. The role of activation of the sympathetic nervous system in the central pressor action of calcitonin gene-related peptide in conscious rats. Naunyn Schmiedebergs Arch. Pharmacol. 349: 394-400, 1994[Medline].

15.   Lai, Y.-L., P. M. Smith, W. J. E. Lamm, and J. Hildebrandt. Sampling and analysis of cerebrospinal fluid for chronic studies in awake rats. J. Appl. Physiol. 54: 1754-1757, 1983[Abstract/Free Full Text].

16.   Palkovits, M., and L. Zaborszky. Neuroanatomy of central cardiovascular control. Nucleus tractus solitarii: afferent and efferent neuronal connections in relation to baroreceptor reflex arc. Prog. Brain Res. 47: 9-34, 1977[Medline].

17.   Paxinos, G., and C. Watson. The Rat Brain in Stereotaxic Coordinates. San Diego, CA: Academic, 1986.

18.   Rochford, J., K. Yashpal, and J. L. Henry. Intrathecal administration of calcitonin gene-related peptide (CGRP) increases heart rate and decreases arterial pressure in the urethane anesthetized rat. Brain Res. Bull. 25: 809-816, 1990[Medline].

19.   Ross, C. A., D. A. Ruggiero, D. H. Park, T. H. Joh, A. F. Sved, J. M. Fernandez-Pradal, J. M. Saavedra, and D. J. Reis. Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J. Neurosci. 4: 474-494, 1984[Abstract].

20.   Ryu, P. D., G. Gerber, K. Murase, and M. Randic. Calcitonin gene-related peptide enhances calcium current of dorsal root ganglion neurons and spinal excitatory synaptic transmission. Neurosci. Lett. 89: 305-312, 1988[Medline].

21.   Skofitsch, G., and D. M. Jacobowitz. Autoradiographic distribution of 125I-calcitonin gene-related peptide binding sites in the rat central nervous system. Peptides 6: 975-986, 1985[Medline].

22.   Skofitsch, G., and D. M. Jacobowitz. Calcitonin gene-related peptide: detailed immunohistochemical distribution in the central nervous system. Peptides 6: 721-745, 1985[Medline].

23.   Stuesse, S. L., and S. E. Fish. Projection to the cardioinhibitory region of the nucleus ambiguus of rat. J. Comp. Neurol. 229: 271-278, 1984[Medline].

24.   Sun, M.-K., and P. G. Guyenet. Effects of vasopressin and other neuropeptides on rostral medullary sympathoexcitatory neurons "in vitro." Brain Res. 492: 261-270, 1989[Medline].

25.   Tschopp, F. A., H. Henke, J. B. Petermann, P. H. Tobler, R. Janzer, T. Hökfelt, J. M. Lundberg, C. Cuello, and J. A. Fisher. Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary. Proc. Natl. Acad. Sci. USA 82: 248-252, 1985[Abstract/Free Full Text].

26.   Van Rossum, D., D. P. Menard, A. Fournier, S. St. Pierre, and R. Quirion. Binding profile of a selective calcitonin gene-related peptide (CGRP) receptor antagonist ligand, [125I-Tyr]hCGRP8-37, in rat brain and peripheral tissues. J. Pharmacol. Exp. Ther. 269: 846-853, 1994[Abstract/Free Full Text].

27.   Zona, C., D. Farini, E. Palma, and F. Eusebi. Modulation of voltage-activated channels by calcitonin gene-related peptide in cultured rat neurons. J. Physiol. (Lond.) 433: 631-643, 1991[Abstract/Free Full Text].

AJP Heart Circ Physiol 274(5):H1489-H1494
0363-6135/98 $5.00 Copyright © 1998 the American Physiological Society


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