Vasodilator Effect of Adrenomedullin and Calcitonin Gene-Related Peptide Receptors in Rat Mesenteric Vascular Beds

doi:10.1006/bbrc.1993.2241

Biochemical and Biophysical Research Communications

Volume 196, Issue 1, 15 October 1993, Pages 245-251

https://doi.org/10.1006/bbrc.1993.2241 Get rights and content

Abstract

The effect of adrenomedullin, a novel peptide of 52 amino acids, on vascular tone was investigated in the perfused rat mesenteric vascular bed. In the vasculature contracted with methoxamine, perfusion of adrenomedullin (10⁻¹¹-10⁻⁷M) caused a concentration-dependent decrease in perfusion pressure due to vasodilation. Additionally, a bolus infusion of adrenomedullin (300 and 500 pmol) produced a long-lasting vasodilator response, which was not affected in the presence of atropine (10⁻⁷M) and propranolol (10⁻⁷M). However, this response was inhibited in the presence of CGRP[8-37] (10⁻⁶M), an antagonist for CGRP receptor. These results suggest that adrenomedullin induces nonadrenergic and noncholinergic vasodilation in which CGRP receptors may be involved.

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Cited by (308)

Adrenomedullin – Current perspective on a peptide hormone with significant therapeutic potential
2020, Peptides
Citation Excerpt :
ADM is a crucial player in the cardiovasculature, regulating blood flow and pressure as well as vascularization [12,125]. Early studies on the effect of ADM on vascular smooth muscle cells, as well as the kidney and vascular bed of rats demonstrated its potent vasodilatory effect and found it to be mediated by cAMP signaling as well as nitric oxide released from the endothelium [12,126–128]. It was also reported that intravenous (i.v.) administration of ADM had a reductive effect on the blood pressure in humans [129].
The peptide hormone adrenomedullin (ADM) consists of 52 amino acids and plays a pivotal role in the regulation of many physiological processes, particularly those of the cardiovascular and lymphatic system. Like calcitonin (CT), calcitonin gene-related peptide (CGRP), intermedin (IMD) and amylin (AMY), it belongs to the CT/CGRP family of peptide hormones, which despite their low little sequence identity share certain characteristic structural features as well as a complex multicomponent receptor system. ADM, IMD and CGRP exert their biological effects by activation of the calcitonin receptor-like receptor (CLR) as a complex with one of three receptor activity-modifying proteins (RAMP), which alter the ligand affinity. Selectivity within the receptor system is largely mediated by the amidated C-terminus of the peptide hormones, which bind to the extracellular domains of the receptors. This enables their N-terminus consisting of a disulfide-bonded ring structure and a helical segment to bind within the transmembrane region and to induce an active receptor confirmation. ADM is expressed in a variety of tissues in the human body and is fundamentally involved in multitude biological processes. Thus, it is of interest as a diagnostic marker and a promising candidate for therapeutic interventions. In order to fully exploit the potential of ADM, it is necessary to improve its pharmacological profile by increasing the metabolic stability and, ideally, creating receptor subtype-selective analogs. While several successful attempts to prolong the half-life of ADM were recently reported, improving or even retaining receptor selectivity remains challenging.
Natural and synthetic peptides in the cardiovascular diseases: An update on diagnostic and therapeutic potentials
2019, Archives of Biochemistry and Biophysics
Citation Excerpt :
A substantial number of studies have been performed in cell, animal model, and humans revealing that AM is involved in mechanisms regulating or modulating biological functions through its pleiotropic actions. AM have potent vasorelaxant effect in cardiovascular cells [214,215], while causes vasodilatation and hypotension in experimental animals [216–218]. AM has been shown to be a powerful dilator in human coronary arteries [219], and also causes potent vasodilation of arteries and veins in the pulmonary circulation [220–222].
Several peptides play an important role in physiological and pathological conditions into the cardiovascular system. In addition to well-known vasoactive agents such as angiotensin II, endothelin, serotonin or natriuretic peptides, the vasoconstrictor Urotensin-II (Uro-II) and the vasodilators Urocortins (UCNs) and Adrenomedullin (AM) have been implicated in the control of vascular tone and blood pressure as well as in cardiovascular disease states including congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Therefore these peptides, together with their receptors, become important therapeutic targets in cardiovascular diseases (CVDs). Circulating levels of these agents in the blood are markedly modified in patients with specific CVDs compared with those in healthy patients, becoming also potential biomarkers for these pathologies. This review will provide an overview of current knowledge about the physiological roles of Uro-II, UCN and AM in the cardiovascular system and their implications in cardiovascular diseases. It will further focus on the structural modifications carried out on original peptide sequences in the search of analogues with improved physiochemical properties as well as in the delivery methods. Finally, we have overviewed the possible application of these peptides and/or their precursors as biomarkers of CVDs.
Alterations in enteric calcitonin gene-related peptide in patients with colonic diverticular disease: CGRP in diverticular disease
2019, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Within the digestive system, CGRP fibers innervate a multitude of targets (epithelia, muscle cells, neuronal elements) (Sternini et al., 1992), providing a morphological basis for the range of biological activities exerted by this peptide. In the alimentary tract CGRP exerts multidirectional action and has a prominent role in sensory and pain conduction (Russell et al., 2014), vasodilation (Nuki et al., 1993), immune response (Assas et al., 2014), absorption and secretory activity (Barada et al., 2000). Major targets of CGRPergic innervation are the intrinsic plexuses (Cottrell et al., 2012; Makowska and Gonkowski, 2018; Sternini et al., 1992), and in animal studies, CGRP was demonstrated to induce peristaltic reflexes (Grider, 1994, 2003; Grider et al., 2006), increase the peristaltic threshold (Holzer et al., 1989), relax intestinal smooth muscle cells (Katsoulis and Conlon, 1989; Takaki et al., 1989), induce phasic contractile activity (Holzer et al., 1989; Maggi et al., 1996, 1997) and excite myenteric neurons (Palmer et al., 1986).
Diverticular disease (DD) is one of the most prevalent diseases of the large bowel. Lately, imbalance of neuro-muscular transmission has been recognized as a major etiological factor for DD. Neuronal calcitonin gene-related peptide (CGRP) is a potent gastrointestinal smooth muscle relaxant shown to have a widespread effect within the alimentary tract. Nevertheless, CGRPergic innervation of the enteric ganglia has never been considered in the context of motility impairment observed in DD patients.
Changes in CGRP and calcitonin receptor-like receptor (CRLR) abundance within enteric ganglia were investigated in sigmoid samples from symptomatic and asymptomatic DD patients using quantitative fluorescence microscopy. CGRP effect on gastrointestinal smooth muscle was investigated using organ bath technique.
We found CGRP levels within the enteric ganglia to be declined by up to 52% in symptomatic DD patients. Conversely, CRLR within the enteric ganglia was upregulated by 41% in symptomatic DD. Longitudinal smooth muscle displayed an elevated (+10.5%) relaxant effect to the exogenous application of CGRP in colonic strips from symptomatic DD patients. Samples from asymptomatic DD patients consistently showed intermediate values across different experiments.
In conclusion, the present study demonstrates that CGRPergic signaling is subject to alteration in DD. Our results suggest that a hypersensitization mechanism to gradually decreasing levels of CGRP-IR nerve fibers takes place during DD progression. Alterations to CGRPergic signaling in DD disease may have implications for physiological abnormalities associated with colonic DD.
Mechanism of adrenomedullin 2/intermedin mediated vasorelaxation in rat main pulmonary artery
2018, Peptides
Adrenomedullin 2/intermedin (AM2/IMD) is a member of calcitonin related gene peptide family and an important nitric oxide mediated vasorelaxant in various vascular beds. However, the mechanism of post receptor-interaction is not clear and may differ depending on tissue type and species. In this study, we aimed to investigate the exact mechanism and the role of BK_Ca and calcium channels on the vasorelaxant effect of AM2/IMD in rat PA. Changes in the AM2/IMD-mediated vasorelaxation were evaluated in the presence of various inhibitors. CGRP_(8-37) (10⁻⁶ M), L-NAME (10⁻⁴ M), ODQ (10⁻⁵ M), SQ22536 (10⁻⁴ M), H89 (10⁻⁶ M), TEA (10⁻² M), iberiotoxin (3 × 10⁻⁷ M), and verapamil (10⁻⁵ M), all partly or completely inhibited the vasorelaxation. The relaxation was also abolished by removal of the endothelium, or in KCl precontracted PAs. AM2/IMD did not elicit vasorelaxation in the Ca²⁺-free conditions. However, the vasorelaxation was not inhibited with AM_(22-52) (10⁻⁶ M), 4-AP (3 × 10⁻³ M), glibenclamide (10⁻⁵ M), apamin (3 × 10⁻⁷ M), TRAM-34 (10⁻⁵ M), and La⁺³ (10⁻⁴ M). AM2/IMD −induced changes in intracellular calcium levels and isometric force were monitored simultaneously in fura-2-loaded, endothelium-intact PAs. The AM2/IMD-induced increase in intracellular Ca²⁺ concentration was inhibited in the presence of iberiotoxin and verapamil, whereas no change was observed with La³⁺ incubation. Our data suggest that the cAMP/PKA pathway is one of the important pathways AM2/IMD-induced vasorelaxation. AM2/IMD acts through activation of endothelial BK_Ca and subsequently causes hyperpolarization of the endothelial cell membrane. The hyperpolarization induces Ca²⁺ influx, which leads to NO production and subsequent vasorelaxation.
Adrenomedullin has no effect on segmental bone defect healing but increases bone mineral density in rat model
2023, Acta Orthopaedica et Traumatologica Turcica
Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure
2022, Biomolecules

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Regular ArticleVasodilator Effect of Adrenomedullin and Calcitonin Gene-Related Peptide Receptors in Rat Mesenteric Vascular Beds

Abstract

Regular Article
Vasodilator Effect of Adrenomedullin and Calcitonin Gene-Related Peptide Receptors in Rat Mesenteric Vascular Beds