Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin

<jats:p> The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor ( N<jats:sup>G</jats:sup>-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E<jats:sub>2</jats:sub> (UPGE<jats:sub>2</jats:sub>). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE<jats:sub>2</jats:sub>, and UNOx. Pretreatment with meclofenamate reduced UPGE<jats:sub>2</jats:sub> by 75% and reduced the effect of exenatide on UPGE<jats:sub>2</jats:sub> by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO. </jats:p>