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Differential antagonism of amylin's metabolic and vascular actions with amylin receptor antagonists.

Abstract
High affinity amylin binding sites are present in the rat nucleus accumbens. These sites bind [125I]amylin with an affinity of 27 pM and have high affinity for salmon calcitonin (sCT) and moderately high affinity for calcitonin gene related peptide (CGRP). N-terminally truncated peptides were tested for their ability to compete for [125I]amylin binding to these sites and to antagonize the metabolic and vascular actions of amylin. CGRP(8-37), sCT(8-32), and ac-[Asn30,Tyr32]sCT(8-32) (AC187) inhibited [125I]amylin binding to rat nucleus accumbens. Order of potency at inhibiting amylin binding (AC187 > sCT(8-32) > CGRP(8-37)) differed from the order of potency at inhibiting [125I]CGRP binding to SK-N-MC neuroblastoma cells (CGRP(8-37) > AC187 > sCT(8-32)) . AC187 was the most potent antagonist of amylin's effects on isolated rat soleus muscle glycogen metabolism, and it was more effective than either sCT(8-32) or CGRP(8-37) at reducing amylin-stimulated hyperlactemia in rats. In contrast, CGRP(8-37) was the most potent peptide at antagonizing amylin-induced hypotension in rats. Amylin's hypotensive actions appear to be mediated by a weak action at CGRP receptors, while its metabolic actions are mediated by receptors with a distinct antagonist profile. AC187 is a potent antagonist of amylin binding sites in nucleus accumbens and of amylin's metabolic actions.
AuthorsK Beaumont, C X Moore, R A Pittner, K S Prickett, L S Gaeta, T J Rink, A A Young
JournalCanadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 73 Issue 7 Pg. 1025-9 (Jul 1995) ISSN: 0008-4212 [Print] Canada
PMID8846395 (Publication Type: Journal Article)
Chemical References
  • Amyloid
  • Islet Amyloid Polypeptide
  • Lactates
  • Peptide Fragments
  • Peptides
  • Receptors, Islet Amyloid Polypeptide
  • Receptors, Peptide
  • AC 187
  • Lactic Acid
Topics
  • Amyloid (antagonists & inhibitors)
  • Animals
  • Blood Pressure (drug effects)
  • In Vitro Techniques
  • Islet Amyloid Polypeptide
  • Lactates (blood)
  • Lactic Acid
  • Male
  • Muscles (drug effects, metabolism)
  • Peptide Fragments
  • Peptides (pharmacology)
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Islet Amyloid Polypeptide
  • Receptors, Peptide (antagonists & inhibitors)

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