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(Hypertension. 1996;28:1041-1046.)
© 1996 American Heart Association, Inc.
Articles |
Catecholamine Release Mediates Pressor Effects of Adrenomedullin-(15-22) in the Rat
the Department of Pharmacology, Tulane University School of Medicine, New Orleans, La.
Correspondence to Philip J. Kadowitz, PhD, Department of Pharmacology SL83, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.
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Abstract |
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Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene–related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg IV increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene–related peptide and human amylin, human calcitonin gene–related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of
-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.
Key Words: adrenomedullin • catecholamines • receptors, adrenergic, alpha • species specificity
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Introduction |
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Adrenomedullin is a hypotensive peptide first isolated from human pheochromocytoma cells.1 Human adrenomedullin (hADM) is a 52–amino acid peptide with a disulfide bond that has a six-member ring structure similar to the ring structure in calcitonin gene–related peptide (CGRP) and pancreatic amylin.1 Adrenomedullin is present in the adrenal medulla, lung, and kidney; and plasma levels of the peptide are increased in disease states, such as congestive heart failure, gram-negative sepsis, hypertension, and renal failure.2 3 4 5 6 This peptide has been shown to possess vasodilator activity in a number of regional vascular beds in the cat, dog, and rat.3 7 8 9 10 11 12 13
The properties of the receptor with which adrenomedullin interacts are uncertain, and it has been reported in some organ systems that adrenomedullin interacts with the CGRP receptor.14 15 16 However, other reports have shown that blockade of the CGRP receptor does not alter responses to adrenomedullin.17 18 The mechanism by which adrenomedullin and CGRP induce vasodilation is related to the species and vascular bed studied, and it has been reported that adrenomedullin elicits its vasodilator action via a cAMP mechanism.15 19 20 However, it has also been shown that inhibition of nitric oxide synthase attenuates vasodilator responses to adrenomedullin in the rat hindlimb and pulmonary vascular bed and in the renal vascular bed of the dog, suggesting that a nitric oxide/cGMP–dependent mechanism is also involved in mediating responses to adrenomedullin.3 9 10 13
Recent studies have shown that N-terminal truncated forms of adrenomedullin possessing the six-member ring structure retain the hypotensive and vasodilator activities of the full-sequence peptide.8 11 12 19 21 These reports suggest that the N-terminal amino acids located before the ring structure are not necessary for the full expression of vasodilator activity. Similarly, the ring structure of CGRP is required for the full expression of vasodilator activity.11 19 Moreover, fragments of adrenomedullin, such as hADM-(22-52), which do not possess the ring structure, do not possess vasodilator activity.8 11 19 It has been reported recently that N-terminal fragments of adrenomedullin that contain the ring structure, hADM-(1-25) and hADM-(16-21), have pressor activity in the systemic vascular bed of the rat and that responses to these fragments are attenuated by phenoxybenzamine and adrenergic neuronal blocking agents.22
Although responses to hADM-(16-21) and hADM-(13-52) have been studied in the anesthetized rat, little if anything is known about responses to hADM-(15-22), hADM-(15-52), and hADM-(22-52). Furthermore, the effects of the human CGRP and human amylin ring structures, hCGRP-(1-8) and hAmylin-(1-8), have not been reported. Our purpose in the present study was therefore to investigate responses to hADM-(15-22), hADM-(15-52), and hADM-(22-52) and the role of adrenal catecholamines in mediating responses to the hADM ring structure.
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Methods |
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Thirty-nine Sprague-Dawley rats of either sex weighing 340 to 520 g were anesthetized with pentobarbital sodium (50 mg/kg IP) in accordance with institutional guidelines. Supplemental doses of pentobarbital were given as needed to maintain a uniform level of anesthesia. The trachea was cannulated, and the rats breathed room air or were ventilated with a rodent ventilator (model 683, Harvard Instruments) at a tidal volume of 2.4 to 2.6 mL at a rate of 30 to 35 breaths per minute. Catheters were inserted into the external jugular vein for intravenous administration of drugs and into the carotid artery for measurement of systemic arterial (aortic) pressure. Systemic arterial pressure was measured with a Statham P23 pressure transducer (Vigo-Spectramed) and recorded on a polygraph (model 7, Grass Instruments). Mean pressures were derived by electronic averaging.
Six adult cats, unselected as to sex, weighing 2.5 to 4.0 kg were sedated with 20 to 30 mg/kg ketamine hydrochloride IM and anesthetized with pentobarbital sodium (30 mg/kg IV) in accordance with institutional guidelines. Supplemental doses of pentobarbital were given as needed to maintain a uniform level of anesthesia. The experimental design with the cats was similar to that with the rats with the exception that the cats were ventilated with a different respirator (Harvard model 607) at a tidal volume of 40 to 60 mL and a rate of 15 to 22 breaths per minute.
In the first series of experiments, responses to intravenous injection of hADM, hADM-(15-22), hADM-(15-52), hADM-(22-52), human CGRP, hCGRP-(1-8), human amylin, and hAmylin-(1-8) were compared. In the second series of experiments, responses to intravenous injections of hADM-(15-22) were compared with responses to norepinephrine when doses were expressed on a nanomole basis to take molecular weight into account, and the time course of the pressor response to hADM-(15-22) was assessed. In the third series of experiments, the role of the adrenergic nervous system in mediating pressor responses to hADM-(15-22) was investigated. Responses to hADM-(15-22) were compared before and after administration of the -adrenergic receptor antagonist phentolamine in a dose of 1 mg/kg IV. Phentolamine decreased systemic arterial pressure from 124±5 to 112±7 mm Hg. The extent of -receptor blockade was assessed by comparing responses to norepinephrine. In a separate series of experiments, the effects of adrenergic nerve terminal depletion on responses to hADM-(15-22) 20 to 24 hours after administration of reserpine in a dose of 1.5 mg/kg IP were investigated. The extent of adrenergic neuronal blockade was assessed by comparing responses to the indirect-acting agonist tyramine in reserpine-pretreated and control animals. In the fourth series of experiments, the role of adrenal catecholamines was investigated, and pressor responses to intravenous injections of hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) were compared before and after bilateral adrenalectomy; the effects of hexamethonium and atropine were also investigated.
Synthetic hADM, hADM-(15-22), hADM-(15-52), hADM-(22-52), human CGRP, hCGRP-(1-8), hAmylin-(1-37), and hAmylin-(1-8) (Peptide Research Laboratories, Tulane Medical School, New Orleans, La) were dissolved in 0.9% NaCl. Norepinephrine hydrochloride, atropine sulfate, hexamethonium bromide, tyramine hydrochloride, DMPP (all from Sigma Chemical Co), reserpine phosphate (Serpasil), and phentolamine mesylate (CIBA-Geigy Corp) were dissolved in 0.9% NaCl. Agonists were injected in a random order. Drug solutions were prepared frequently and kept on crushed ice.
Responses were analyzed with one-way ANOVA and Scheffe's F test or a paired t test.23 A value of P<.05 was used as the criterion for statistical significance.
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Results |
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Responses to Analogues of hADM, Human CGRP, and Human Amylin
Intravenous injections of hADM, hADM-(15-52), and human CGRP induced dose-dependent decreases in systemic arterial pressure in the rat (Fig 1
). Intravenous administration of hADM-(22-52) and hAmylin-(1-37) in doses of 10 to 1000 nmol/kg had no significant effect on systemic arterial pressure in the rat (Fig 1).
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Intravenous injection of hADM-(15-22) in doses of 10 to 300 nmol/kg produced dose-dependent increases in systemic arterial pressure in the rat (Fig 1
); in three experiments in which heart rate was measured, the increase in systemic arterial pressure in response to the injections of 100 to 300 nmol/kg was associated with a decrease in heart rate. However, injection of the ring structures of human CGRP and human amylin, hCGRP-(1-8) and hAmylin-(1-8), had no significant effect on systemic arterial pressure when injected in doses of 10 to 1000 nmol/kg IV (Fig 1).
The time course of the increase in systemic arterial pressure in response to the 300 nmol/kg dose of hADM-(15-22) is shown in Fig 2. When molecular weight was taken into account, norepinephrine was approximately threefold more potent than hADM-(15-22) in increasing systemic arterial pressure (Fig 2B).
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Role of the Adrenergic Nervous System
The role of the adrenergic nervous system in mediating pressor responses to hADM-(15-22) was investigated (Fig 3). After treatment with the -receptor blocking agent phentolamine in a dose of 1 mg/kg IV, pressor responses to hADM-(15-22) were significantly attenuated compared with control responses (Fig 3A). Pressor responses to norepinephrine were significantly decreased after administration of phentolamine, whereas responses to angiotensin II were not altered significantly (Fig 3A). After treatment with reserpine in a dose of 1.5 mg/kg IP, pressor responses to hADM-(15-22) were significantly reduced compared with control responses (Fig 3B). After treatment with reserpine, pressor responses to the indirect-acting agonist tyramine were significantly attenuated, and responses to norepinephrine were significantly greater than control (Fig 3). In addition, administration of the angiotensin type 1 receptor antagonist DuP 753 in a dose of 100 µg/kg IV and the nonselective endothelin-A/endothelin-B receptor antagonist bosentan in a dose of 5 mg/kg IV had no significant effect on the pressor response to hADM-(15-22) (data not shown).
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Role of Adrenal Catecholamines
The role of adrenal catecholamines in mediating pressor responses to hADM-(15-22) was investigated (Fig 4). After bilateral adrenalectomy, pressor responses to hADM-(15-22) were significantly reduced compared with control responses obtained before adrenalectomy (Fig 4). After bilateral adrenalectomy, pressor responses induced by the nicotinic agonist DMPP were significantly reduced (Fig 4). Bilateral adrenalectomy did not alter pressor responses to norepinephrine (data not shown).
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In another series of experiments, the effect of nicotinic and muscarinic receptor blockade on responses to hADM-(15-22) was investigated (Fig 5). The nicotinic blocking agent hexamethonium in a dose of 5 mg/kg IV had no significant effect on the increase in systemic arterial pressure in response to hADM-(15-22), whereas the pressor response to the nicotinic agonist DMPP was significantly reduced (Fig 5). Subsequent administration of the muscarinic antagonist atropine in a dose of 1 mg/kg IV resulted in no significant change in the pressor responses to hADM-(15-22) and no further change in the pressor response to DMPP (Fig 5).
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Responses to hADM-(15-22) in the Cat
Injections of hADM-(15-22) in doses up to 1000 nmol/kg IV had no significant effect on systemic arterial pressure in the cat (Fig 6). Injections of hADM-(1-52) in doses of 0.1 to 3 nmol/kg IV produced dose-related decreases in systemic arterial pressure in the cat that were similar to responses obtained in the rat (Fig 6).
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Discussion |
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The results of the present investigation show that the ring structure of hADM, hADM-(15-22), increases systemic arterial pressure in the rat; whereas hADM-(1-52) and hADM-(15-52) caused similar decreases in systemic arterial pressure, and hADM-(22-52) had no measurable activity when injected in doses of up to 1000 nmol/kg IV. The ring structure of human CGRP, hCGRP-(1-8), had no measurable activity; whereas the full-sequence peptide hCGRP-(1-37) was more potent than hADM-(1-52) in decreasing systemic arterial pressure in the rat. hAmylin-(1-37) and the ring structure hAmylin-(1-8) produced no significant changes in systemic arterial pressure in the rat. In terms of relative pressor activity, the ring structure hADM-(15-22) was approximately threefold less potent than norepinephrine, and pressor responses to hADM-(15-22) were reduced by the
-receptor antagonist phentolamine. Pressor responses to hADM-(15-22) were reduced by reserpine in a dose that attenuated pressor responses to tyramine and enhanced the pressor response to norepinephrine, suggesting that increases in systemic arterial pressure in response to the adrenomedullin ring structure were mediated by the release of catecholamines and the activation of -adrenergic receptors. We investigated the site of catecholamine release by studying the effects of adrenalectomy and found that after bilateral adrenalectomy, pressor responses to hADM-(15-22) and to the nicotinic agonist DMPP were reduced significantly. Adrenalectomy did not affect the pressor response to norepinephrine; the results of these experiments suggest that the pressor response to hADM-(15-22) is in large part due to the release of catecholamines from the adrenal gland. We investigated the role of nicotinic receptor activation in mediating the response to hADM-(15-22) and found that after treatment with hexamethonium in a dose that attenuated the pressor responses to the nicotinic agonist DMPP, the increase in systemic arterial pressure in response to hADM-(15-22) was not altered. Atropine had no significant effect on the pressor response to hADM-(15-22). The results of experiments with hexamethonium and atropine suggest that the release of catecholamines from the adrenal medulla in response to hADM-(15-22) does not depend on a cholinergic mechanism.
Adrenomedullin was first isolated from human pheochromocytoma cells,1 and hADM is a 52–amino acid peptide with a disulfide bond and six-member ring structure similar to the ring structure in CGRP and pancreatic amylin (Fig 7). Adrenomedullin possesses vasodepressor activity in the systemic vascular bed of the rat and vasodilator activity in a number of regional vascular beds in the cat, dog, and rat.1 3 8 9 10 11 12 13 14 17 18
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Studies in the rat have shown that hADM-(13-52), which contains the six-member ring structure, possesses vasodepressor activity similar to that seen with the full-sequence peptide.21 The present data show that hADM-(15-52) produces dose-dependent decreases in systemic arterial pressure similar to that induced by hADM-(1-52), whereas hADM-(22-52) lacks significant activity. These data suggest that the 14 N-terminal amino acids are not necessary for the full expression of the vasodepressor activity of hADM, whereas the amino acids that comprise the ring structure are essential for the vasodepressor response. These data are in agreement with previous studies showing that N-terminal analogues of hADM, which retain the ring structure of hADM, possess vasodepressor activity, whereas analogues that lack the ring structure do not have activity.8 11 12 19 21
The present data showing that hADM-(15-22), which comprises the ring structure of hADM, produces dose-dependent increases in systemic arterial pressure in the rat are in agreement with a previous study in which hADM-(16-21), a smaller ring structure analogue, was shown to increase systemic arterial pressure in the rat.22 The data with the hADM ring structure analogues hADM-(16-21) and hADM-(15-22) provide support for the concept that these small hADM fragments containing the six-member ring structure have novel pressor activity in the rat. The results of the present experiments extend the work of previous studies by demonstrating the role of a noncholinergic mechanism in the release of catecholamines from the adrenal gland in the mediation of the pressor response to hADM-(15-22). Although hADM-(15-22) has pressor activity in the rat, the peptide has little or no effect on systemic arterial pressure in the cat when injected in doses of up to 1000 nmol/kg IV, whereas hADM-(1-52) and hADM-(15-52) had similar depressor activity in both species. The results of experiments in the rat and cat show that there are marked species differences with regard to the effects of hADM-(15-22) on systemic arterial pressure. The absence of an effect of hADM-(15-22) in the cat may suggest that hADM-(15-22) receptors are not present in the adrenal gland of the cat. Data from the present study in the rat and cat provide evidence in support of the hypothesis that responses to the adrenomedullin ring structure depend on the species.
It has also been reported that important species differences exist with regard to the mechanism by which hADM-(1-52) induces vasodilation.13 Inhibition of nitric oxide synthase attenuates vasodilator responses to hADM in the pulmonary and hindquarters vascular beds of the rat and in the renal vascular bed of the dog.9 10 13 However, vasodilator responses to hADM are not affected by nitric oxide synthase inhibitors in the feline pulmonary circulation13 and hindlimb vascular bed of the cat (unpublished observations, 1996).
The present study demonstrates that the ring structure of human CGRP, hCGRP-(1-8), possesses no activity in the systemic vascular bed of the rat when injected in doses of up to 300 nmol/kg IV. Furthermore, human amylin and hAmylin-(1-8) had no effect on systemic arterial pressure in the rat. These data suggest that although human CGRP, human amylin, and hADM possess similar structural features, especially in the ring structure, the three truncated analogues have very different effects on systemic arterial pressure in the rat.
In summary, hADM-(15-52) possesses vasodepressor activity similar to that of hADM-(1-52) in the systemic vascular bed of the rat, whereas hADM-(22-52) lacks activity when injected in doses of up to 300 nmol/kg IV. The ring structure of hADM, hADM-(15-22), increases systemic arterial pressure in the rat but not in the cat. The ring structures of human CGRP and human amylin, hCGRP-(1-8) and hAmylin-(1-8), respectively, had no effect on systemic arterial pressure in the rat. hADM-(15-22) was threefold less potent than norepinephrine, and the present results suggest that the increase in systemic arterial pressure in response to hADM-(15-22) is mediated by the activation of -adrenergic receptors by catecholamines released from the adrenal medulla. These data suggest that hADM-(15-22) is another novel peptide that releases catecholamines from the adrenal gland by a noncholinergic mechanism. The physiological importance of the results with hADM-(15-22) is uncertain; however, adrenomedullin is synthesized in the adrenal gland, and it is possible that hADM-(15-22) could alter vascular tone by releasing catecholamines from the adrenal medulla.
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Acknowledgments |
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These studies were supported by National Institutes of Health (NIH) grants HL-15580 and HL-09474 and a grant from the American Heart Association, Louisiana Affiliate. Hunter C. Champion was supported by NIH grant HL-09474. The authors thank Janice Ignarro for editorial assistance.
Received June 3, 1996;
first decision July 9, 1996; first decision July 24, 1996;
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Nossaman BD, Feng CJ, Kaye AD, DeWitt BJ, Coy DH, Murphy WA, Kadowitz PJ. Pulmonary vasodilator responses to adrenomedullin are reduced by nitric oxide synthase inhibitors in the rat but not in the cat. Am J Physiol. 1996;270:L782-L789.
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