The Inhibitory Effect of Adrenomedullin in the Rat Ileum: Cross-Talk with β3-Adrenoceptor in the Serotonin-Induced Muscle Contraction

Abstract

In contrast to vascular muscles, the contribution of a hypotensive peptide adrenomedullin (AM) to the regulation of visceral smooth muscles is obscure. The content, synthesis, and effects of AM on the muscular tone in rat ileum were explored. It was found that there was immunoreactive AM (301 pg/mg of protein) and AM mRNA expression (162 fg/pg actin mRNA) in the ileum and that AM evoked relaxation in ileal strips (K i ϭ 0.85 nM) precontracted with serotonin. Antagonists of both AM (AM ) and calcitonin gene-related peptide ) receptors did not affect this AM-induced relaxation, whereas it was suppressed by a selective blocker of ␤ 3 -adrenoreceptor (SR 59230A). The AM-induced relaxation was accompanied by a production of cAMP. Antagonists of protein kinases A (KT 5720 and H-7) and an inhibitor of the ATP-dependent K ϩ -channels (glibenclamide) attenuated the effect of AM. We suggest that AM is a local regulator of the ileal tone, with an inhibitory action on muscle contraction. AM may activate the ␤ 3 -adrenoceptors, resulting in protein kinase A activation, which in turn opens the ATP-dependent K ϩ -channels.The hypotensive peptide, adrenomedullin (AM), was originally purified from both adrenal medulla and pheochromocytoma Kitamura and Eto, 1997;Jougasaki and Burnett, 2000). Two unique structures, a 6-amino acid ring with a disulfide bond and a C-terminal amide in the molecule of AM Hinson et al., 2000;Jougasaki and Burnett, 2000), are likely to determine its vasorelaxation properties. AM shares structural homology with the calcitonin gene-related peptide (CGRP), indicating that AM probably belongs to the CGRP superfamily (Kitamura and Eto, 1997;Hinson et al., 2000;Poyner et al., 2002). The signal transduction pathways have been studied in the greatest detail in the vasculature. A large body of experimental data shows AM synthesis in smooth muscle cells (Kitamura and Eto, 1997;Nishimura et al., 1997) and suggests that AM-induced vasodilation may be mediated by a specific receptor functionally coupled to adenylate cyclase (Eguchi et al., 1994a;Kitamura and Eto, 1997;Nussdorfer et al., 1997;Jougasaki and Burnett, 2000;Poyner et al., 2002). AM-specific receptors are not only found in smooth muscle cells, but also in endothelium cells (Kamitani et al., 1999). It has been reported that the binding of AM to the endothelial receptor can trigger the nitric oxide (NO)-cGMP pathway (Ikeda et al., 1996). Therefore, it is now widely accepted that at least two mechanisms appear to underlie the AM-induced relaxation in vascular muscles: 1) a direct action on vascular smooth muscle cells to increase cAMP (Eguchi et al., 1994a,b;Shimekake et al., 1995;Kitamura and Eto, 1997;Yoshimoto et al., 1998) and 2) an indirect action on endothelial cells to stimulate NO synthesis (Shimekake et al., 1995;Hinson et al., 2000;Jougasaki and Burnett, 2000).The results of mRNA blot analysis reported 10 years ago (Sakata et al., 1993) and later confirmed (Nishimura et al., 1997;Cameron and Fleming, 1998;Sakata et al., 1998) imply that r...

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

“…However three independent studie (35,36,37) ZAG is a naturally occurring ligand with selective agonist activity towards the 3-AR. Very few proteins display such activity, although the hypotensive peptide adrenomedullin may also activate 3-AR leading to relaxation of ileal muscle [41]. Since ZAG is much larger than the normal catecholamine agonists it is possible that activation occurs through allosteric modulation.…”

Possible Role of Adrenomedullin In the Pathogenesis of Tubal Ectopic Pregnancy

“…Unlike the rat oviduct in which ADM22-52 was an effective blocker (19), the effect of ADM on smooth muscle contraction frequency, basal tone, and amplitude were blocked by neither hADM22-52 nor hCGRP8-37. It is possible that this discrepancy is due to a species difference and that the effect of ADM on smooth muscle contraction in the human oviduct is not receptor mediated, like the ADM effect on contraction in the rat colon (20), or is mediated by some as-yet-unidentified receptors. It is important to note that ADM decreases the amplitude of contraction in the tEP, which must mean that the frequency is more important than the amplitude of contraction in embryo transport.…”

Adrenomedullin regulates intestinal physiology and pathophysiology

“…The presence of AM mRNA in visceral smooth muscle cells of the gastrointestinal tract [126] suggests that AM may be able to regulate contractile responses of visceral muscles. In 2004, Kravtsov et al [134] demonstrated for the first time that AM elicits relaxation of the rat ileum precontracted with serotonin, acetylcholine, and histamine in a concentration-dependent manner and through an elevation of cAMP in the ileal strips. Antagonists of both AM and CGRP receptors did not affect AMinduced relaxation, whereas it was completely inhibited by a selective blocker of b 3 -adrenoreceptor [134].…”

“…The digestive system is not an exception and both, AM and PAMP, are reported to be in the salivary glands, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, gall bladder, bile duct, and pancreas (Table 1) [ 83,126,127,133,134]. Taking into account the vastness of the subject, in this review, we will focus our attention on the stomach and the gut, while briefly summarizing information about the oral cavity, esophagus, and pancreas.…”