Nitrergic contribution to gastric relaxation induced by glucagon-like peptide-1 (GLP-1) in healthy adults.
The incretin glucagon-like peptide-1 (GLP-1), which is used to treat diabetes mellitus, delays gastric emptying by inhibiting vagal activity. GLP-1 also increases fasting and postprandial gastric volume in humans. On the basis of animal studies, we hypothesized that nitric oxide mediates the effects of GLP-1 on gastric volumes. To assess the effects of nitrergic blockade on GLP-1-induced gastric accommodation in humans, in this double-blind study, 31 healthy volunteers were randomized to placebo (i.e., saline), GLP-1, or the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine acetate (L-NMMA; 4 mg.kg(-1) x h(-1)) alone or with GLP-1. Thereafter, 16 additional subjects were randomized to GLP-1 alone or together with a higher dose of L-NMMA (10 mg/kg bolus plus 8 mg.kg(-1).h(-1) infusion). Gastric volumes (fasting pre- and postdrug, postprandial postdrug) were measured by (99m)Tc-single-photon-emission computed tomography imaging. GLP-1 increased (P = 0.04) fasting gastric volume by 83 +/- 16 ml (vs. 17 +/- 11 ml for placebo) and augmented (P < or = 0.01) postprandial accommodation by 688 +/- 165 ml (vs. 542 +/- 29 ml for placebo). L-NMMA (low dose) alone did not affect fasting or postprandial gastric volume. L-NMMA (low dose) did not attenuate the effect of GLP-1 on gastric volumes. In contrast, L-NMMA (high dose) did not affect fasting volume but blunted GLP-1-mediated postprandial accommodation (postprandial change = 494 +/- 37 ml, P < or = 0.01 vs. GLP-1 alone). These data are consistent with the hypothesis that nitric oxide partly mediates the effects of GLP-1 on postprandial but not fasting gastric volumes in humans.
Andrews
Christopher N
CN
Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905, USA.
Bharucha
Adil E
AE
Camilleri
Michael
M
Low
Phillip A
PA
Seide
Barbara
B
Burton
Duane
D
Baxter
Kari
K
Zinsmeister
Alan R
AR
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D004311:Double-Blind Method; D005215:Fasting; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019518:Postprandial Period; D013270:Stomach / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; D002395:Catecholamines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052216:Glucagon-Like Peptide 1; D019001:Nitric Oxide Synthase