Abstract 536: Resiniferatoxin-induced Disorders in Glucose Homeostasis and Hypertension: Role of Trpv1-positive Sensory Nerves
Resiniferatoxin (RTX), an ultrapotent agonist of the transient receptor potential vanilloid 1 (TRPV1) channels, has been used to relieve pain in humans in clinical trials that are ongoing, completed, or terminated due to its unwanted side effects that have not been well understood. We test the hypothesis that RTX causes disorders in glucose homeostasis, renal functional and structural impairment, and hypertension via insulin receptor-mediated increases in sympathetic nerve activity. Male Wistar rats were injected with RTX (0.2 mg/kg, i.p.) or vehicle. Pancreatic and renal TRPV1 levels were decreased 4 weeks after RTX treatment, confirming effective and lasting treatment of RTX (p<0.05). RTX decreased plasma insulin levels (Control: 1.4±0.1 vs RTX: 0.8±0.1 ng/ml, p<0.05) but improved glucose tolerance (p<0.05). RTX increased the translocation of skeletal muscle glucose transporter 4 (Glut4) from cytosol to cell membrane indicated by increased membrane fraction but decreased cytosol fraction of Glut4 in RTX-treated rats (p<0.05). RTX increased levels of phosphorylated insulin receptor substrate 1 in sympathetic ganglia (Control: 0.43±0.04 vs RTX: 0.65±0.08, p<0.05), renal tyrosine hydroxylase contents, and urinary norepinephrine concentrations (Control: 352±70 vs RTX: 781±142 ng/day, p<0.05). When TRPV1 expressed in sensory neurons and their nerve endings innervating the kidney was knocked down by intrathecal (i.t) injection of TRPV1 shRNA, insulin (3nmol/kg, i.t.)-induced increases in efferent renal nerve activity were further enhanced (Control: 40±3 vs TRPV1 shRNA: 53±2, p<0.05). RTX decreased creatinine clearance (Control: 0.58±0.04 vs RTX: 0.46±0.04 ml/min/100 gbwt, p<0.05) and increased levels of plasma urea, urinary albumin, renal connective tissue growth factor, and systolic blood pressure (Control: 128±1 vs RTX: 143±2 mmHg, p<0.05). Thus, RTX treatment causes disorders in glucose homeostasis, renal functional and structural impairment, and hypertension, possibly via increasing sympathetic nerve activity resulting from enhanced stimulatory effects of the insulin receptors expressed in sympathetic nerves and weakened inhibitory effects of TRPV1-positive sensory nerves on sympathetic nerves.
- © 2013 by American Heart Association, Inc.