Article preview from Peptides, Volume 22, Issue 11, November 2001, Pages 1809-1816.
Poadrenomedullin N-terminal 20 peptide (PAMP) is a hypotensive peptide derived from the precursor of adrenomedullin. We identified novel actions of proadrenomedullin N-terminal 20 peptide (PAMP) on blood glucose, food intake and gastric emptying after exogenous administration. PAMP elevated blood glucose levels after central injection in fasted mice. PAMP had affinity for bombesin (BN) receptor and the hyperglycemic effect of PAMP was blocked by a BN antagonist, indicating that the elevation of blood glucose after central administration of PAMP was mediated by BN receptor. Centrally administered PAMP inhibited food intake and gastric emptying in fasted conscious mice. However, studies using a BN antagonist and BN receptor knockout mice suggested that the inhibitory effects of PAMP on feeding and gastric emptying were mediated not via BN receptor but via another receptor specific for PAMP. In the present review, we summarize these effects of PAMP and report other novel actions of PAMP on body temperature and oxygen consumption. In addition, the mechanism underlying the cardiovascular functions of PAMP is discussed.
Proadrenomedullin N-terminal 20 peptide (PAMP) was found in the N-terminal portion of the precursor of adrenomedullin (AM) originally isolated from the human pheochromocytoma. Thereafter, PAMP was shown to exist throughout not only in peripheral organs such as the adrenal gland and vasculature but also in the central nervous system using immunoassay or molecular biological methods. AM is well known to lower blood pressure after peripheral administration. It has been reported that AM has inhibitory effects on food intake, gastric emptying and insulin secretion, and these actions on food intake and gastric emptying are mediated by calcitonin gene-related peptide (CGRP) receptor. However, except for the transient hypotensive effect of PAMP after peripheral administration, the biological actions of PAMP remain unclear. The specific binding sites for PAMP in rats using radioligand were abundant in the aorta and adrenal gland, followed by the lung, kidney, brain, spleen and heart. However, a receptor specific for PAMP has not been cloned despite much effort. In previous studies, we identified novel actions of PAMP on blood glucose, food intake and gastric emptying after central administration in mice. The aim of the present article is to review these effects of PAMP, to report other novel functions of PAMP and to discuss the mechanisms underlying its actions containing blood pressure.
We found that centrally administered PAMP (10–30 nmol/mouse) elevated blood glucose levels in fasted mice (Fig. 1-A). The elevation of blood glucose was potently elicited within 15 min after intra-cerebroventricular (i.c.v.) administration of PAMP and lasted for at least 60 min. Peripheral administration of PAMP also elevated blood glucose levels in fasted mice, as shown in Fig. 1-B.
AM was reported to have affinity for both CGRP 1 and AM receptor and several actions of AM were
We showed that PAMP dose-dependently decreased food intake after central administration at a dose of 3–30 nmol/mouse in fasted conscious mice (Fig. 2-A). The inhibitory effect of the highest dose of PAMP on feeding lasted for 24 h. PAMP-related peptides such as PAMP 9-20 and PAMP 12-20 also decreased food intake after i.c.v. injection in fasted mice, although the potencies of these
We investigated whether PAMP had other novel actions on body temperature and metabolism after central administration. I.c.v. of administration PAMP was performed as described previously. The cannula was implanted into the third cerebral ventricle of male ddY mice at 7 weeks old (SLC, Shizuoka Japan) under pentobarbital anesthesia. Each mouse was i.c.v. administered 4 μl artificial cerebrospinal fluid with PAMP one week after the implantation. Body temperature was measured by
Both PAMP and AM have hypotensive activity after peripheral administration through different mechanisms. While AM causes vasodilation by releasing nitro oxide release from endothelial cells, PAMP reduces norepinephrine overflow from peripheral sympathetic nerve endings of rat mesenteric arteries. CGRP 8-37,
In summary, the exogenous administration of PAMP elicits multiple biological actions on blood pressure, blood glucose, food intake, gastric emptying, body temperature, metabolism and anxiety. Further investigations might elucidate the physiological significance of PAMP in the regulations of these actions.
This work was partly supported by grants from Ministry of Education, Culture, Sports, Science and Technology of Japan to MY and AI, and a PROBRAIN grant from Bio-oriented Technology Research Advancement Institution to MY. We thank Dr. Keiji Wada and Dr. Etsuko Wada of National Institute of Neuroscience, NCNP (Tokyo Japan) for helpful collaboration.
