An adrenomedullin fragment retains the systemic vasodepressor activity of rat adrenomedullin
Abstract
The present study was undertaken to investigate the effects of human adrenomedullin, a newly discovered peptide present in normal human plasma, as well as a fragment of adrenomedullin, on systemic hemodynamics in the anesthetized rat. Intravenous (i.v.) bolus injections of rat adrenomedullin, rat adrenomedullin-(11–50), human adrenomedullin, and human adrenomedullin- (13–52) decreased mean systemic arterial pressure in a dose-dependent manner. Since rat adrenomedullin and human adrenomedullin did not decrease cardiac output, the decreases in systemic arterial pressure reflect dose-dependent reductions in systemic vascular resistance. The systemic vasodepressor responses to similar doses of the adrenomedullin fragments studied and to their respective parent adrenomedullin peptides were similar. The present data demonstrate that the entire adrenomedullin molecule is not required for full systemic vasodilator activity in vivo suggesting that rat adrenomedullin-(11–50) or a structurally similar peptide, if formed endogenously, could mediate the hemodynamic properties of adrenomedullin in vivo. Since rat adrenomedullin had significantly greater systemic vasodilator activity than human adrenomedullin at similar doses in the rat, the present data suggest that adrenomedullin has greater systemic vasodilator activity in its native species and that limited changes in the peptide's sequence confer markedly different vascular activity in vivo.
References (8)
- Y. Ishiyama et al.
Hemodynamic effect of a novel hypotensive peptide, human adrenomedullin, in rats
Eur. J. Pharmacol.
(1993) - K. Kitamura et al.
Adrenomedullin: A novel hypotensive peptide isolated from human pheochromocytoma
Biochem. Biophys. Res. Commun.
(1993) - K. Kitamura et al.
Cloning and characterization of cDNA encoding: a precursor for human adrenomedullin
Biochem. Biophys. Res. Commun.
(1993) - J. Sakata et al.
Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide
Biochem. Biophys. Res. Commun.
(1993)
Cited by (20)
Cell and molecular biology of the multifunctional peptide, adrenomedullin
2002, International Review of CytologyAdrenomedullin (AM) is a recently discovered regulatory peptide involved in many functions including vasodilatation, electrolyte balance, neurotransmission, growth, and hormone secretion regulation, among others. This 52-amino acid peptide is expressed by specific cell types in many organs throughout the body. A complex receptor system has been described for AM; it requires at least the presence of a seven-transmembrane-domain G-protein-coupled receptor, a single-transmembrane-domain receptor activity modifying protein, and a receptor component protein needed to establish the connection with the downstream signal transduction pathway, which usually involves cyclic-AMP. In addition, a serum-binding protein regulates the biological actions of AM, frequently by increasing AM functional attributes. Changes in levels of circulating AM correlate with several critical diseases, including cardiovascular and renal disorders, sepsis, cancer, and diabetes. Whether AM is a causal agent, a protective reaction, or just a marker for these diseases is currently under investigation. New technologies seeking to elevate and/or reduce AM levels are being investigated as potential therapeutic avenues.
Effects of adrenomedullin on rat cerebral arterioles
1997, European Journal of PharmacologyThe effects of adrenomedullin on isolated rat intracerebral arterioles were investigated and compared with those of calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin produced dose-dependent vasodilation (maximum dilation 27.1±2.1% at 3×10−7 M, median effective dose (EC50) 1.6×10−9 M). CGRP produced similar vasodilation (19.8±4.1%) at 10−7 M with a lower EC50 of 2.8×10−11 M. Amylin did not cause vasodilation at concentrations up to 10−6 M. Adrenomedullin-induced vasodilation was significantly suppressed by CGRP-(8–37). These data suggest that adrenomedullin is a potent vasodilator for arterioles in the cerebral microcirculation that acts through CGRP receptors.
Comparison of responses to rat and human adrenomedullin in the hindlimb vascular bed of the cat
1997, Regulatory PeptidesResponses to rat (r) adrenomedullin (ADM) and human (h) ADM were compared in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intra-arterial injections of rADM and hADM in doses of 0.03–1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, rADM was similar to hADM. The time course of the vasodilator response and the recovery half times (T1/2) for the vasodilator response to rADM and hADM were not significantly different. Decreases in hindlimb perfusion pressure in response to rADM and hADM were not altered by the calcitonin gene-related peptide receptor antagonist, rCGRP(8–37), at the same time, vasodilator responses to calcitonin gene-related peptide (CGRP) were significantly reduced. The T1/2 of the vasodilator response to rADM and hADM were significantly greater after administration of the cAMP-selective, type IV phosphodiesterase inhibitor, rolipram. These data demonstrate that decreases in hindlimb perfusion pressure in response to rADM and hADM are similar and that vasodilator responses to rADM are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. These data further suggest that decreases in hindlimb perfusion pressure in response to rADM are mediated by smooth muscle increases in cAMP levels.
Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors
1997, Neuroscience and Biobehavioral ReviewsVAN ROSSUM, D. U.-K. HANISCH AND R. QUIRION. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. NEUROSCI BIOBEHAV REV 21(5)649–678, 1997.—Calcitonin gene-related peptide (CGRP) is a neuropeptide discovered by a molecular approach over 10 years ago. More recently, islet amyloid polypeptide or amylin, and adrenomedullin were isolated from human insulinoma and pheochromocytoma respectively, and revealed between 25 and 50% sequence homology with CGRP. This review discusses findings on the anatomical distributions of CGRP mRNA, CGRP-like immunoreactivity and receptors in the central nervous system, as well as the potential physiological roles for CGRP. The anatomical distribution and biological activities of amylin and adrenomedullin are also presented. Based upon the differential biological activity of various CGRP analogs, the CGRP receptors have been classified in two major classes, namely the CGRP1 and CGRP2 subtypes. A third subtype has also been proposed (e.g. in the nucleus accumbens) as it does not share the pharmacological properties of the other two classes. The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors. The receptors identified thus far for CGRP and related peptides belong to the G protein-coupled receptor superfamily. Indeed, modulation of adenylate cyclase activity following receptor activation has been reported for CGRP, amylin and adrenomedullin. Furthermore, the binding affinity of CGRP and related peptides is modulated by nucleotides such as GTP. The cloning of various calcitonin and most recently of CGRP1 and adrenomedullin receptors was reported and revealed structural similarities but also significant differences to other members of the G protein-coupled receptors. They may thus form a new subfamily. The cloning of the amylin receptor(s) as well as of the other putative CGRP receptor subtype(s) are still awaited. Finally, a broad variety of biological activities has been described for CGRP-like peptides. These include vasodilation, nociception, glucose uptake and the stimulation of glycolysis in skeletal muscles. These effects may thus suggest their potential role and therapeutic applications in migraine, subarachnoid haemorrhage, diabetes and pain-related mechanisms, among other disorders. © 1997 Elsevier Science Ltd.
Adrenomedullin: Localization in the gastrointestinal tract and effects on insulin secretion
1996, Regulatory PeptidesAdrenomedullin is a novel hypotensive adrenal polypeptide originally isolated from a human pheochromocytoma and is structurally related to calcitonin gene-related peptide and islet amyloid polypeptide. Using immunocytochemistry, the occurrence of adrenomedullin in the adrenal gland and gastro-entero-pancreatic region in the rat was examined and its effect on insulin secretion from isolated rat islets was determined. Adrenomedullin-like immunoreactivity occurred in noradrenaline- and adrenaline-producing cells in the adrenal gland. Gastrointestinal endocrine cells, with increased density distally, displayed adrenomedullin-like immunoreactivity; these cells constituted a subpopulation of the enterochromaffin (serotonin-containing) cells. Co-localization of adrenomedullin with somatostatin, glicentin, gastrin/cholecystokinin, peptide YY or islet amyloid polypeptide was not encountered. Adrenomedullin-immunoreactive cells were not observed in the pancreatic islets. At 1, 10 and 100 nmol/l, adrenomedullin stimulated insulin release from isolated rat islets in the presence of 3.3 mmol/l glucose (P < 0.05) and at 100 nmol/l, the peptide potentiated insulin secretion also in the presence of 8.3 mmol/l glucose (P < 0.05). These findings suggest that, besides being an adrenal hypotensive peptide, adrenomedullin may be a gut hormone with a potential insulinotropic function.
The purpose of the present study was to determine the effects of adrenotensin, a newly described product of the ADM gene, on cat pulmonary arterial (PA) rings. Under resting conditions, adrenotensin increased tension of PA rings in a concentration-dependent manner. Although addition of diphenhydramine, ONO-3708, phentclamine, methysergide, atropine, and meclofenamate did not alter the contractile response to adrenotensin, removal of the endothelial cell layer significantly reduced this response. Moreover, precontraction of PA rings with adrenotensin selectively attenuated the pulmonary vasorelaxant response to ADM but not to other vasodilator substances, including isoproterenol, pinacidil, nifedipine, and adenosine. The present data suggest that adrenotensin acts in an endothelium-dependent manner to contract PA rings. Moreover, the present data suggest that adrenotensin may act in a modulatory manner to influence vasorelaxation in response to ADM, a sister proADM product.