Abstract 13956: Nalfurafine, an Orally Active, G Protein-Biased Kappa Opioid Receptor Agonist, Increases the Diuretic Response to Loop and Thiazide Diuretics and Limits Electrolyte Losses

Abstract

Nalfurafine, a G protein-biased kappa opioid receptor (KOR) agonist that produces analgesia and is devoid of CNS adverse effects, is used in Japan to treat pruritis in dialysis patients. Our lab has shown that in rats, IV nalfurafine produces a marked diuresis, antinatriuresis, antikaliuresis, and decrease in blood pressure. Here, we examined the cardiovascular and renal responses to IV and oral nalfurafine in combination with furosemide or hydrochlorothiazide (HCTZ). We hypothesized that combining nalfurafine with these diuretics would increase urine output, given its distinct mechanism of vasopressin inhibition, and limit electrolyte loss. Following chronic catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion, and after stabilization, were administered an IV bolus diuretic alone or in combination with nalfurafine. Mean arterial pressure (MAP), heart rate (HR), and urine output were recorded for 90-min. In a separate study, rats were placed in metabolic cages, and following 2-hour acclimation, were administered drug in a volume load (20 cc/kg) via oral gavage. Hourly urine samples were then collected for five hours. When compared to diuretic treatment alone, IV co-administration with nalfurafine significantly increased total urine output to furosemide and HCTZ while reducing the amount of sodium and potassium excreted (Table 1). Notably, MAP was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral co-administration of nalfurafine significantly increased the urine output to HCTZ and reduced the amount of sodium and potassium excreted, whereas combination with furosemide only limited the amount of sodium excreted (Table 1). Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, which may offer a new approach to treat several cardiovascular conditions.