Abstract 084: Selective Renal Afferent Denervation Enhances Diuretic and Natriuretic Response to Glucagon-like Peptide-1 in Rats With Heart Failure

Abstract

Glucagon-like peptide-1 (GLP-1), incretin hormone, has diuretic and natriuretic effects and its receptor agonist reduces cardiovascular events. The present study was designed to determine whether GLP-1-induced diuresis is regulated by renal nerve in the rats with a coronary ligation model of heart failure (HF). Our immunohistochemistry and immunoblotting studies demonstrate that GLP-1 receptors were expressed in the renal pelvic wall, densely innervated by afferent renal nerves (ARN). Basal ARN activity (ARNA) was increased in HF compared to normal rats (1.3 ± 0.2* vs. 0.6 ± 0.1 μV·s). GLP-1 (3μM) infused into left renal pelvis increased ipsilateral ARNA in both normal and HF rats. The change in basal ARNA and the maximum ARNA represented as percent activation by injection of capsaicin (transient receptor potential V1 receptor agonist, 100μM) were higher in HF than in normal rats (ΔARNA 227 ± 27%* vs. 131 ± 26%, and ARNAmax 64.2 ± 3.4%* vs. 45.1 ± 6.6%). Intravenous infusion of GLP-1 (1μg/kg/min) for 30 min increased renal urine flow and sodium excretion in normal rats and these effects were blunted in HF (Urine flow 1577 ± 122* vs. 1981 ± 101 μl/gkw, Sodium excretion 221 ± 19* vs. 284 ± 15 μEq/gkw). GLP-1-induced diuresis and natriuresis were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves in both normal and HF rats. The degree of diuretic and natriuretic responses to GLP-1 were greater in HF than in normal rats (increased % rate: Urine flow 167%* vs. 135%, Sodium excretion 169%* vs. 150%). Selective afferent renal denervation (A-RDN) was performed by bilateral perivascular application of capsaicin (33mM) on the renal nerves. Ten days after A-RDN, there was an enhanced diuretic and natriuretic response to GLP-1 in both normal and HF rats. These effects were greater in HF than in normal rats (increased % rate: Urine flow 187%* vs. 130%, Sodium excretion 147%* vs. 138%). Urine flow and sodium excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN in both groups. Taken together our results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via ARN activation. GLP-1-induced diuresis and natriuresis enhanced by RDN have potential therapeutic implication for HF.