Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals

Abstract

Adrenomedullin 5 (AM5) is a new member of the calcitonin gene-related peptide (CGRP) family identified in teleost fish. Although its presence was suggested in the genome database of mammals, molecular identity and biological function of AM5 have not been examined yet. In this study, we cloned a cDNA encoding AM5 in the pig and examined its cardiovascular and renal effects. Putative mature AM5 was localized in the middle of prohormone and had potential signals for intermolecular ring formation and C-terminal amidation. The AM5 gene was expressed most abundantly in the spleen and thymus. Several AM5 genes were newly identified in the database of mammals, which revealed that the AM5 gene exists in primates, carnivores, and undulates but could not be identified in rodents. In primates, nucleotide deletion occurred in the mature AM5 sequence in anthropoids (human and chimp) during transition from the rhesus monkey. Synthetic mature AM5 injected intravenously into rats induced dose-dependent decreases in arterial pressure at 0 . 1-1 nmol/kg without apparent changes in heart rate. The decrease was maximal in 1 min and AM5 was approximately half as potent as AM. AM5 did not cause significant changes in urine flow and urine Na C concentration at any dose. In contrast to the peripheral vasodepressor action, AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate at 0 . 1-1 nmol. The increase reached maximum more quickly after AM5 (5 min) than AM (15-20 min). AM5 added to the culture cells expressing calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of the receptor activitymodifying proteins (RAMPs), the combination of which forms major receptors for the CGRP family, did not induce appreciable increases in cAMP production in any combination, although AM increased it at 10 K10 -10 K9 M when added to the CLR and RAMP2/3 combination. These data indicate that AM5 seems to act on as yet unknown receptor(s) for AM5, other than CLR/CTRCRAMP, to exert central and peripheral cardiovascular actions in mammals.

Centrally administered adrenomedullin 5 activates oxytocin-secreting neurons in the hypothalamus and elevates plasma oxytocin level in rats

“…Cui et al (2008) reported that microinjection of AM2 into the NTS elevates arterial pressure and heart rate in urethane-anesthetized rats. Furthermore, Takei et al (2008) reported that AM5 injected into the cerebral ventricle dose-dependently increased arterial pressure and heart rate in urethane-anesthetized rats. These results suggest that centrally administered AM5 is involved in the cardiovascular system in rats.…”

“…In pigs, the AM5 gene was expressed abundantly in the spleen and thymus, slightly in the adrenal and pituitary, and undetectable in the brain . However, it remains a possibility that AM5 may exist in some restricted regions of the pig brain because they examined only a small part of the pig brain, including the ventral hypothalamic area (including the SON, organum vasculosum laminae terminalis, and median eminence; Takei et al 2008). Further studies such as ISH and RT-PCR using different parts of the brain may reveal the existence of AM5 in the pig brain.…”

“…AM5 sequences are highly conserved within some mammalian species. Takei et al (2008) described that they identified AM5 sequences in the genome database of ungulates (artiodachtyls: pig, ox, and sheep; and perissodactyles: horse), carnivores (dog and cat), and primates (prosimians: Tupaia belangeri, and simians: Macaca mulatta), but they could not identify such sequences in the genome database of rodents (mice and rats). They also described that an AM5-like sequence exists in the human and chimpanzee, but the sequence changes in the middle of the mature peptide because of the deletion of two nucleotides.…”

Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels

“…The major effects of AM2 in mammals known to date are on cardiovascular and body fluid regulation, similar to AM. The recently identified AM5 also induces hypotension after peripheral injection and hypertension after intracerebroventricular administration in mammals, but the peripheral effects are less potent than AM (35).…”

Horizontal gene transfer of a vertebrate vasodilatory hormone into ticks

“…ADM-1 and -2 are widely conserved in all vertebrates. However, ADM-5 is conserved in fish, amphibians and reptiles but has been lost in birds and many mammals, for example, humans, chimpanzees, rats and mice 13 , due to the loss of functional constraints. ADM-1, -2 and -5 are all expressed as pre-proproteins and contain secretory signal peptides and internal processing sites.…”