Dose response characteristics for the hyperglycemic, hyperlactemic, hypotensive and hypocalcemic actions of amylin and calcitonin gene-related peptide-I (CGRP alpha) in the fasted, anaesthetized rat.
Amylin, a 37 amino-acid peptide secreted from the pancreatic beta-cells, exerts marked effects on carbohydrate metabolism in intact rats. It has approximately 50% amino-acid identity with the calcitonin gene-related peptides (CGRP) as well as certain shared biological actions. In vivo potencies were determined for four responses (increases in plasma glucose, increases in plasma lactate, decreases in plasma calcium, and depression of arterial pressure). These responses were measured in fasted, lightly anaesthetized rats given single intravenous bolus injections of rat amylin or rat CGRP alpha at doses of 0.01, 0.1, 1, 10, 100 and 1000 micrograms (about 7 pmol/kg-700 nmol/kg). Control animals received an equal volume of saline. The order of potency for the different responses was as follows: (i) increase in plasma glucose concentration, amylin approximately 2 times more potent than CGRP (by ED50) with detectable responses occurring at doses 100-fold less; (ii) decrease in plasma total calcium concentration, CGRP of equal or greater potency than amylin; and (iii) decrease in arterial pressure, CGRP 44-fold more potent than amylin. An increase in plasma lactate occurred with amylin doses 1000-fold lower than the CGRP doses producing such effects. Saturation of the dose-dependent increase in lactate was not observed, so median effective doses (ED50) were not obtained. These results are consistent with the existence of separate receptor systems for amylin and CGRP. The effects of amylin on plasma glucose and lactate concentrations were demonstrable at doses of 0.1-1.0 micrograms (70-700 pmol/kg). These doses produced plasma levels that were within the concentration range previously reported for insulin-resistant rats, supporting the proposal that amylin is a physiologic endocrine regulator of carbohydrate metabolism in vivo.
Department of Physiology, Amylin Pharmaceuticals, Inc., San Diego, CA 92121.
A A
AA
Young
T J
TJ
Rink
M W
MW
Wang
D000682:Amyloid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000378:metabolism; D015592:Immunoradiometric Assay; D058228:Islet Amyloid Polypeptide; D007773:Lactates / Q000097:blood*; D019344:Lactic Acid; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000682:Amyloid; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D007773:Lactates; D019344:Lactic Acid; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium