Insulin- and glucagon-independent effects of calcitonin gene-related peptide in the conscious dog.
Calcitonin gene-related peptide (CGRP) causes vasodilation in many vascular beds, resulting in hypotension and tachycardia. The current studies were conducted in overnight-fasted conscious dogs to determine the effect of different CGRP dosages on carbohydrate metabolism and catecholamine release resulting from hemodynamic changes. During a pancreatic clamp, dogs received intraportal infusions of CGRP at 13, 26, and 52 (n = 3) or 52, 105, and 210 pmol x kg(-1) x min(-1) (n = 4; 60 minutes at each rate). Blood pressure decreased (P < .05) and the heart rate and hepatic blood flow (HBF) increased a maximum of 100% and 30%, respectively (P < .05). For the five CGRP infusion rates, arterial plasma epinephrine increased approximately 1.3-, 2.4-, 7.4-, 12-fold, and eightfold basal, respectively; norepinephrine increased about 2.3-, 3.3-, 4.1-, 4.6-, and 4.8-fold basal, respectively; and cortisol increased about twofold, 3.4-fold, fivefold, sixfold, and 6.2-fold basal, respectively. At CGRP infusion rates of 52 pmol x kg(-1) x min(-1) or higher, increases (P < .05) occurred for plasma glucose, endogenous glucose production (EndoRa), and net hepatic uptake of gluconeogenic substrates (maximum change, 24 mg/dL, 1.3 mg x kg(-1) x min(-1), and 9.9 micromol x kg(-1) x min(-1), respectively). Arterial blood glycerol concentrations increased only a maximum of 30%. At the two highest CGRP infusion rates, glycerol returned to basal concentrations and arterial plasma nonesterified fatty acids (NEFAs) decreased. The increased net hepatic uptake of gluconeogenic substrates during CGRP infusion was sufficient to account for 49% to 58% of the increase in EndoRa. CGRP has no apparent direct effects on hepatic carbohydrate metabolism, but the catecholamines, at levels similar to those observed during CGRP infusion, stimulate hepatic glycogenolysis. Therefore, some factor(s) other than CGRP, probably an increase in circulating catecholamine concentrations, would appear to be responsible for at least 42% to 51% of the increase in EndoRa.
Moore
M C
MC
Department of Molecular Physiology & Biophysics, and Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.
Lin
D W
DW
Colburn
C A
CA
Goldstein
R E
RE
Neal
D W
DW
Cherrington
A D
AD
D000409:Alanine / Q000097:blood; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000097:blood; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000502:physiology*; D007659:Ketones / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009638:Norepinephrine / Q000097:blood
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007659:Ketones; D019344:Lactic Acid; D005934:Glucagon; D005947:Glucose; D015740:Calcitonin Gene-Related Peptide; D000409:Alanine; D005990:Glycerol; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine