(Hypertension. 1998;31:391.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Calcitonin Gene-Related Peptide Is a Depressor in Subtotal Nephrectomy Hypertension
From the Departments of Human Biological Chemistry and Genetics (S.C.S.), and Internal Medicine (S.C.S., H.Z., D.M.H., D.J.D.). University of Texas Medical Branch, Galveston, TX 77555-1065.
Correspondence to Scott C. Supowit, PhD, University of Texas Medical Branch, 8.104 Medical Research Building, Galveston, TX 77555-1065
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Abstract |
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We previously demonstrated that the neuronal expression of calcitonin gene-related peptide (CGRP), a potent vasodilator, is increased in deoxycorticosterone-salt-induced hypertension where it acts as a compensatory vasodilator to attenuate the elevated blood pressure. To determine whether CGRP is playing a similar role in subtotal nephrectomy-salt-induced hypertension, hypertension was induced in Sprague-Dawley rats (n=6) by subtotal nephrectomy and 1.0% saline drinking water. Control rats (n=6) were sham operated and given tap water to drink. CGRP(8–37), a CGRP receptor antagonist, was used to assess the hemodynamic role of CGRP in this setting. CGRP mRNA and peptide levels in dorsal root ganglia were also determined. Three weeks after either protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. CGRP(8–37) (3.2 or 6.4x104 pmol/L in 0.1 mL saline) and vehicle were administered intravenously to all rats. Baseline mean arterial pressure was higher in the subtotal nephrectomized rats compared with the controls (173±5 versus 113±5 mm Hg, P<.001). Vehicle administration did not change mean arterial pressure in either group, and CGRP(8–37) administration did not alter mean arterial pressure in the normotensive group. In contrast, CGRP(8–37) administration to the subtotal nephrectomized rats rapidly increased the already elevated mean arterial pressure at both the 3.2x104 pmol/L dose (7.8±1.1 mm Hg, P<.05) and the 6.4x104 pmol/L dose (9.6±0.8 mm Hg, P<.01). CGRP mRNA and peptide levels in the dorsal root ganglia were not significantly different between the two groups. These data suggest that in subtotal nephrectomy-salt-induced hypertension, CGRP may play a compensatory depressor role in an attempt to lower the elevated blood pressure.
Key Words: calcitonin gene-related peptide • blood pressure • hypertension, experimental • neuropeptides • genes • RNA
Abbreviations: CGRP = calcitonin gene-related peptide • DOC = deoxycorticosterone • DRG = dorsal root ganglia • iCGRP = immunoreactive CGRP • MAP = mean arterial pressure • SN = subtotal nephrectomy
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Introduction |
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Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide that is widely distributed in the central and peripheral nervous systems in mammals.1 CGRP is derived from the tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene and is produced almost exclusively in neuronal tissues.1,2 A prominent site of CGRP synthesis is the dorsal root ganglia (DRG), which contain the cell bodies of afferent sensory nerves that terminate peripherally on blood vessels and other tissues innervated by the sensory nervous system and centrally in laminae I/II of the dorsal horn of the spinal cord.3 Immunoreactive CGRP (iCGRP)-containing nerve fibers are widely distributed in the cardiovascular system. In blood vessels these nerves are found at the junction of the adventitia and the media passing into the muscle layer.1,4 In these nerve fibers, CGRP is often colocalized with substance P and other tachykinins.5
In vivo and in vitro studies have demonstrated that CGRP is a very potent vasodilator, approximately 100 to 1000 times more potent than other vasodilators such as adenosine, substance P, or acetylcholine.6–8 CGRP has been shown to dilate multiple vascular beds, with the coronary vasculature being a particularly sensitive target.9,10 Systemic administration of CGRP decreases blood pressure in a dose-dependent manner in normotensive animals and humans and in the spontaneously hypertensive rat (SHR).1,6,8 The primary mechanism responsible for this reduction in blood pressure is peripheral arterial dilation.1,2,10 These findings suggest that CGRP may play a significant role in regulating peripheral vascular tone and regional organ blood flow, both under normal physiological conditions and in the pathophysiology of hypertension.
We previously reported that during the onset phase of deoxycorticosterone-salt (DOC-salt)-induced hypertension in the rat, CGRP mRNA accumulation was significantly increased in DRG, and, correspondingly, iCGRP levels were markedly elevated in laminae I/II of the spinal cord compared with that of normotensive controls.9 We later showed that intravenous administration of the specific CGRP receptor antagonist CGRP(8–37) produced significant increases in the already elevated mean arterial pressure (MAP) in the DOC-salt hypertensive rats but not in the controls.10 These data suggest that the increase in CGRP expression in the DRG is a compensatory vasodilator mechanism to attenuate the elevated blood pressure. This finding is in agreement with an earlier study involving hypertensive humans that showed an increase in circulating CGRP levels both in individuals with primary aldosteronism and in subjects placed on high-versus low-salt diets.11
Because these data and other reports suggest that CGRP (and substance P)12 may act as counterregulatory vasodilators in salt-dependent hypertension, the purpose of this study was to examine the effect of endogenous CGRP on blood pressure and heart rate in subtotal nephrectomy (SN)-salt induced hypertension, another model of low-renin, salt-dependent hypertension. In addition, we also quantified CGRP mRNA and iCGRP levels in DRG from the hypertensive and normotensive control groups of animals.
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Methods |
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Animals
A total of 12 male Sprague-Dawley rats (Harlan, Houston, TX), initially weighing 150 g, were studied. The protocols were approved by the institutional Animal Care and Use Committee. For the surgical procedures, the rats were anesthetized with ketamine and xylazine (80 and 4 mg/kg IP, respectively). SN-hypertension was induced in six animals by the total removal of the right kidney and approximately 25% of the left kidney (upper and lower poles). They received 1% saline to drink ad libitum. Six sham-operated animals that received tap water instead of 1% saline were used as the controls. The tail-cuff method (Narco Bio-Systems, Austin, TX) was used to record systolic blood pressures before the surgeries and every 2 to 4 days thereafter. The animals were studied 18 to 20 days after the surgical procedures.
Blood Pressure and Heart Rate Determinations
Human 
-CGRP(8–37) was synthesized by standard solid-phase T-BOC chemistry. CGRP(8–37) was dissolved in saline and has been previously shown to block the hypotensive effects of exogenously administered human -CGRP (Phoenix Pharmaceuticals, Belmont, CA) in normal rats.10 For the present studies, each rat was anesthetized as described above. The left carotid artery was cannulated for continuous measurement of MAP and heart rate with a pressure transducer linked to a recorder (Gould Instruments, Valley View, OH). The right jugular vein was also cannulated for infusion of either vehicle (saline) or CGRP(8–37). Hemodynamic studies were performed approximately 3 hours after surgery, with the rats fully awake and unrestrained.
Hybridization Probes, RNA Isolation and Analysis, and Radioimmunoassay
The -CGRP hybridization probe was a 1.4-kb Sau3A rat genomic restriction fragment containing CGRP exons 5 and 6.2 This probe hybridizes to both - and ß-CGRP mRNA species. The 18S rRNA hybridization probe was a 1.15-kb BamHI-EcoRI restriction fragment of the mouse 18S rRNA gene.13 The DNA inserts were purified by agarose gel electrophoresis and subsequently labeled with [-32P]dCTP using a random hexanucleotide DNA labeling kit (Amersham, Arlington Heights, IL).
After the hemodynamic studies, the rats were deeply anesthetized by infusion of ketamine and xylazine (100 and 5 mg/kg) through the jugular vein catheter. The rats were then killed by decapitation and the cervical, thoracic, and lumbar DRG from each animal were immediately dissected and frozen in liquid nitrogen. For each animal, the DRG on one side of the spinal cord were separated from those on the other side of the cord such that half of the DRG were used for CGRP mRNA analysis and the other half for CGRP peptide quantification. To determine relative CGRP mRNA levels, total cellular RNA was isolated from the DRG by the guanidine-isothiocyanate method.14 The RNA samples were subjected to electrophoresis on denaturing formaldehyde-agarose gels.15 The fractionated RNAs were transferred to nylon membranes and hybridized with the 32P-labeled CGRP DNA probe. As a control, the CGRP probe was removed from the membrane which was then hybridized with the 18S rDNA probe. After hybridization, the membranes were washed and exposed to Kodak X-Omat x-ray film (Eastman Kodak Co., Rochester, NY) at -70°C with an intensifying screen. After autoradiography, the relative levels of CGRP mRNA and 18S rRNA were quantified by computerized scanning laser densitometry.
To determine iCGRP content in the DRG from the experimental and control rats, we used a commercially available rabbit-anti-rat CGRP radioimmunoassay kit (Phoenix Pharmaceuticals). This antibody has 100% cross-reactivity with rat -CGRP and 79% with rat ß-CGRP. There is no cross-reactivity with rat amylin, calcitonin, somatostatin, or substance P. The assay was performed as recommended by the supplier and the total protein content in each sample was determined by the Bradford method (Bio-Rad, Hercules, CA).
Statistical Analysis
Statistical significance was determined by the Student’s t test or where appropriate by ANOVA followed by the Tukey-Kramer multiple comparisons test. The acceptable level of significance was P<.05.
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Effects of CGRP(8–37) on Blood Pressure in SN-Salt-Induced Hypertensive and Normotensive Control Rats
Fig 1 shows that SN (n=6) and 1% saline produced a rapid and significant increase in the systolic blood pressure that was maintained throughout the treatment period. As expected, the sham-operated (n=6) rats that received tap water to drink remained normotensive. On days 18 to 20 after the initiation of each protocol, rats had arterial (for continuous MAP recording) and intravenous (for drug administration) catheters surgically implanted and were studied in a fully awake and unrestrained state. Baseline MAP was markedly higher in the SN-hypertensive rats compared with the controls (173±5 versus 113±5 mm Hg, P<.001). Administration of saline (0.1 mL IV) did not significantly change MAP in either group (SN rats 2.0±0.9 versus controls 2.8±0.5 mm Hg). Likewise, as shown in Fig 2, the effects of bolus intravenous administration of two different doses of CGRP(8–37) (3.2x104 or 6.4x104 pmol/L in 0.1 mL) on MAP in the control group were similar to those observed with saline alone, which did not significantly alter the blood pressure. In contrast, the infusion of CGRP(8–37) to the SN-hypertensive rats rapidly (the MAP increase began approximately 15 to 20 seconds after antagonist administration) produced a further increase of the already elevated MAP at both the lower (7.8±1.1 mm Hg, P<.05) and higher (9.6±0.8 mm Hg, P<.01) doses. The pressor activity of CGRP(8–37) was relatively short-lived, lasting approximately 60 seconds for the lower dose and 90 seconds for the higher dose. The values shown in this figure represent the peak responses, which lasted approximately 8 seconds and 15 seconds for the lower and higher doses, respectively. This transient effect of CGRP(8–37) has been observed by us and other investigators who have used this antagonist for in vivo hemodynamic studies and most likely reflects the rapid proteolysis of this peptide in the circulation.10,16,17 As part of these experiments, we also measured heart rate, which was not significantly changed by the CGRP antagonist in either of the groups. These results suggest that in SN-induced hypertension, CGRP is playing a compensatory depressor role to minimize the blood pressure increase.
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Analysis of CGRP mRNA and iCGRP Content in DRG from SN-Hypertensive and Control Rats
To determine whether neuronal CGRP expression was enhanced in the SN-salt hypertensive rats, CGRP mRNA and iCGRP levels were quantified in the DRG taken from the rats used in the hemodynamic experiments described above. Fig 3 is a representative Northern blot demonstrating the levels of both the 1.2-kb CGRP mRNA species (- and ß-CGRP) and 18S rRNA present in the DRG RNA samples. Scanning laser densitometric analysis of the autoradiographs was then performed to quantify the hybridization signals for CGRP mRNA and 18S rRNA. When the values for CGRP mRNA levels were normalized to those for 18S rRNA to control for possible differences in loading of the RNA samples between the groups, there were no detectable differences in DRG CGRP mRNA content between the SN-hypertensive and control rats (Fig 4). Similar results were obtained when the values for the CGRP mRNA signals were normalized to those of the glyceraldehyde-3-phosphate dehydrogenase mRNA (unpublished observations).
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A CGRP-specific radioimmunoassay was then used to determine iCGRP levels in the DRG from the two groups of rats. The results from this experiment were consistent with those from the RNA analysis and showed no significant differences in DRG iCGRP content between the two groups (SN-hypertensive 0.62±0.04 versus control 0.67±0.08 pg iCGRP/µg total protein). These data indicate that the depressor effect of CGRP observed in the SN-hypertensive rats does not result from the enhanced neuronal (DRG) expression of CGRP, as seen in the DOC-salt model, but is instead mediated through an unidentified mechanism.
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These results demonstrate that the infusion of a potent and specific CGRP receptor antagonist increased further the elevated blood pressure in SN-hypertensive rats but did not produce a detectable effect in the normotensive control rats. This action of CGRP(8–37) is not simply the result of salt loading, because we previously reported that in sham-operated rats on 1% saline, when compared with sham-operated rats that received tap water, there was no change in the blood pressure during the 3-week treatment period and the pressor effect of CGRP(8–37) was not observed.10 These data are consistent with the hypothesis that in this model of experimental hypertension, CGRP is acting as a compensatory depressor in an attempt to counteract the blood pressure increase. This interpretation must be qualified by the fact that we have not yet determined whether the pressor effect of CGRP receptor blockade would be diminished in a time-dependent manner if the blood pressure was pharmacologically normalized in these animals. We cannot rule out the possibility that the effect of CGRP on blood pressure is secondary to some other effect engendered by the SN. We do not think this is likely, because we demonstrated in earlier studies with the DOC-salt hypertensive rats that control animals which underwent a uninephrectomy, with or without saline-drinking water, did not exhibit a pressor response after administration of the CGRP receptor antagonist.10 In light of this caveat, the present findings are consistent with those that we previously reported in DOC-salt hypertensive rats10 and in NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension during pregnancy.18 The magnitude and duration of the hypertensive effect of CGRP(8–37) was quite similar in all three models. The inability of CGRP(8–37) to alter blood pressure in the control rats implies that CGRP does not participate in the regulation of systemic blood pressure in the normotensive state but does not rule out a role for CGRP in the modulation of regional organ blood flow under normal physiological conditions. It has been well documented that CGRP participates in the regulation of regional organ blood flow in the gut,19 and it has been reported that in studies in which CGRP(8–37) was used in normal rats, CGRP was responsible for approximately 30% of basal coronary blood flow.20
Our data suggest that there may be two different mechanisms by which CGRP exerts its compensatory vasodilator effect. During the onset phase (4 weeks) of DOC-salt hypertension, we observed a severalfold increase in CGRP mRNA accumulation in the DRG and iCGRP in the spinal cord when compared with the normotensive controls. Because CGRP(8–37) administration produced an increase in MAP only in the hypertensive rats, it seems that the enhancement of neuronal CGRP synthesis, and presumably release, is responsible for the observed depressor activity of this neuropeptide. In the present study, and in our earlier experiments with the hypertensive pregnant rats, endogenous CGRP was also shown to play a counterregulatory role; however, CGRP expression in the DRG was not significantly altered in these hypertensive rats when compared with the normotensive controls. It should be noted, however, that we cannot completely rule out a small but real change in DRG CGRP expression between the SN-hypertensive and normotensive groups. Based on our previous studies, both in vivo9,18,21 and in vitro,22–24 it is unlikely that any change in CGRP expression <1.5-fold would be statistically significant given the number of animals in each group. If there was, in fact, no change in CGRP in the hypertensive rats, then one possible mechanism to explain the depressor effect of CGRP is an increased vascular responsiveness to this peptide. Although there are supporting data demonstrating an altered vascular sensitivity to CGRP in one model of hypertension,25 our current data do not permit further speculation along these lines.
Our results also agree with the findings of Kohlmann et al,12 who showed that the acute inhibition of the substance P receptor (NK-1) increased blood pressure in the salt-dependent DOC-salt and SN models of hypertension. Substance P is colocalized with CGRP in many perivascular sensory nerve fibers, and the release of these two neuropeptides is regulated by many of the same factors.1,5 These investigators also demonstrated a similar action of the substance P antagonist in the salt-dependent 1 kidney-1 clip model but not the salt-independent 2 kidney-1 clip rats. With regard to CGRP, we are unable to comment on these latter two models of hypertension because we are not aware of any studies on the hemodynamic actions of CGRP(8–37) or whether there are any alterations in neuronal CGRP expression in these settings. Taken together, these data suggest that in the DOC-salt and SN-hypertensive rats, both CGRP and substance P are acting as compensatory vasodilators in response to the increase in blood pressure. With regard to the depressor role of substance P in these two models, it is not known whether there are any significant changes in the expression or vascular sensitivity to this tachykinin.
Kohlmann et al12 also demonstrated that the substance P receptor antagonist did not increase MAP in the SHR, and other investigators have shown that there is a decrease in the circulating levels of substance P in this genetic, salt-independent model of hypertension.26 We have also reported that in the SHR there was a significant decrease in CGRP mRNA accumulation in the DRG and a reduction in iCGRP content in the spinal cord in comparison to Wistar-Kyoto control rats.21,27 Preliminary studies using CGRP(8–37), conducted in our laboratory, also showed that endogenous CGRP does not play a depressor role in the SHR (unpublished observations). Therefore, it is possible that in SHR, a decrease in vasodilator activity caused by the downregulation of CGRP (and substance P) could contribute to the development and maintenance of the high blood pressure.
Although it is not unexpected that at least in some models of experimental hypertension there is a compensatory depressor response to the elevated blood pressure, there is accumulating evidence that perivascular sensory nerve fibers are involved in this antihypertensive mechanism(s). In this study as well as our previous experiments using the DOC-salt model and L-NAME-treated pregnant rats, given the rapid onset (15 to 20 seconds) of the hypertensive effect of CGRP(8–37) and because the antagonist probably does not penetrate the central nervous system, it is likely that most of the pressor activity of CGRP(8–37) seen in these studies results from a direct interaction of the antagonist with peripheral vascular CGRP receptors (probably CGRP receptor type I). Support for this conclusion is provided by radioligand binding and functional studies which showed that CGRP(8–37) is a competitive inhibitor of CGRP binding and that the type I CGRP receptor displays the highest sensitivity to this antagonist.28–30 This receptor subtype has been shown to be the predominant CGRP receptor present in the heart and peripheral blood vessels.29,30 In addition, it is well documented that the CGRP(8–37) can inhibit the vasodilator and hypotensive effects evoked by exogenously administered or endogenously released CGRP in vivo.10,16–18,31
Other studies suggest that it is the capsaicin-sensitive class of sensory neurons that participates in this antihypertensive response. The neurotoxin capsaicin, when administered neonatally, results in a selective destruction of a large subpopulation of small diameter, mainly unmyelinated CGRP (and substance P)-containing primary afferents.32 It has been shown that the induction of DOC-salt hypertension in capsaicin-pretreated and control rats resulted in an increase in blood pressure that was more rapid in onset and of greater magnitude in the capsaicin-pretreated animals.33 These same animals also received intravenous administration of capsaicin which produces a massive acute release of CGRP and substance P. In these experiments, the systemic administration of this neurotoxin produced a much larger hypotensive effect in the hypertensive control animals when compared with those that had received neonatal capsaicin. Therefore, the ablation of a significant number of CGRP (and substance P)-producing sensory neurons seems to markedly attenuate the sensory neuropeptide-mediated depressor response and exacerbates the development of hypertension in the DOC-salt rat.
Taken together, results from these multiple studies strongly support the hypothesis that afferent neurons, whose primary function is the transmission of sensory information from peripheral tissues to the spinal cord, can also regulate vascular tone and regional organ blood flows through the efferent release of neuropeptides (CGRP, substance P) from primary afferent nerve terminals.1,5,34,35 Numerous studies performed in vivo and in vitro using either sensory nerve preparations or primary cultures of DRG neurons have shown that local factors such as nerve growth factor,36 vascular wall tension,5,34 bradykinin/prostaglandins,37 endothelin,38 as well as interactions with the sympathetic nervous system39 can modulate the release of CGRP and substance P. Moreover, using primary cultures of adult rat DRG neurons we have demonstrated that nerve growth factor22 or bradykinin/prostaglandins23 can upregulate CGRP synthesis and release, whereas glucocorticoids22 or 2-adrenoreceptor agonists24 can attenuate the stimulatory effects of nerve growth factor on CGRP. Therefore, alterations in these factors, some of which are known to occur in hypertension, may mediate any changes seen in neuronal CGRP expression and release. Furthermore, in certain hypertensive states, changes in as yet unidentified factors could alter the sensitivity of the vasculature to CGRP (and substance P). Thus, vascular tone may be modulated by changes in the expression and release of CGRP and/or by alterations in vascular responsiveness to this neuropeptide.
In summary, the results presented herein suggest that in SN-induced hypertension CGRP is playing a compensatory depressor role to partially counteract the increase in blood pressure in the absence of any detectable change in CGRP expression in the DRG. Although it is tempting to speculate that the mechanism of this effect is through an increase in the vascular responsiveness to CGRP, further studies are necessary to evaluate this possibility. These studies, together with those using the DOC-salt and SHR models, are also consistent with the hypothesis that the ability of CGRP (and substance P) to partially counteract the increased blood pressure is strongly influenced by the salt-dependence of the hypertensive state. The mechanism(s) of this phenomenon is not known. However, our studies with the nonsalt-dependent hypertensive L-NAME-treated pregnant rats suggest that other factors may influence the antihypertensive actions of these vasodilator neuropeptides.
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Acknowledgments |
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These studies were supported by National Institutes of Health grant HL-44277. We thank Rhoda Thompson for excellent secretarial assistance.
Received September 17, 1997; first decision October 20, 1997; accepted October 28, 1997.
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