2696-LB: Acute Sildenafil Administration Augments the Counterregulatory Response to Hypoglycemia in Rats

Introduction and Objective: Novel treatments that improve the counterregulatory response to hypoglycemia are needed. The counterregulatory response is dependent on nitric oxide (NO) signaling pathways in the hypothalamus. Since sildenafil can cross the BBB and enhance NO-mediated signaling, this study tested the hypothesis that acute sildenafil treatment would enhance the counterregulatory response to hypoglycemia. Methods: Male Sprague Dawley rats (2-4 months) underwent carotid-jugular cannulation. After recovery, animals were randomized to acute treatment with sildenafil (3 mg/kg IV) or saline vehicle administered 15 minutes prior to a 90-minute hyperinsulinemic (200 mU/kg/min) hypoglycemic (40-45 mg/dL) clamp (Fig 1A). The glucose infusion rate was adjusted to maintain target glycemia. Plasma counterregulatory hormones were measured during the clamp. Results: During hypoglycemia, sildenafil treated rats achieved a higher concentration of plasma norepinephrine (p<0.05)(Fig 1B). Consistent with an augmented counterregulatory response, sildenafil treatment significantly reduced the glucose infusion rate necessary to maintain hypoglycemia (two-way RM Anova Pinteraction= .001)(Fig 1C). Conclusion: These data indicate that acute sildenafil augments the counterregulatory hormonal response to hypoglycemia. This may reflect increased sympathetic activation, potentially mediated by NO-dependent pathways within the hypothalamus.