Prevention and Reversal of Furosemide-Induced Diuretic Resistance using the Kappa Opioid Receptor

Ashlyn Anderson, Juan Gao, Jacob Meariman, and Daniel R. Kapusta Pharmacology, LSU Health Sciences Center, New Orleans, LA

Heart failure patients with high levels of vasopressin (AVP) are associated with decreased responses to loop diuretics and poorer outcomes, yet the role of AVP in the development of diuretic resistance remains unclear. We hypothesized increased AVP secretion due to water loss may significantly contribute to diuretic resistance. Since kappa opioid receptor (KOR) agonists act centrally to inhibit AVP secretion and produce water diuresis, we predicted that KOR agonist administration can reverse or prevent furosemide diuretic resistance. To test our hypothesis, we measured changes in 5-hr urine output (metabolic cages; no water) in Sprague-Dawley rats following daily injection (9:00am) of saline (control day) and treatment with 1) furosemide only (F, 10mg/kg, i.p.; days 1-11), 2) furosemide + nalfurafine (F+N, 10ug/kg, i.p.; days 1-11) or 3) F (days 1-5) followed by F+N (days 6-11). After urine collection, rats received a 2nd drug treatment (2:00 pm) and were returned to home cages. The results showed that initial treatment (day 1) of rats with F alone and F+N markedly increased urine output. However, over days 6-10, urine output was significantly reduced (diuretic resistance) in rats that received continued F alone. Daily co-treatment of F+N beginning day 1 maintained a marked 5-hr diuresis for all 11 days. Further, delaying addition of nalfurafine coadministration with F until day 6 reversed established diuretic resistance as noted by a marked increase in diuresis over days 6-10 with F+N cotreatment. These findings demonstrate that addition of a KOR agonist to a treatment regimen is sufficient to either reverse or prevent furosemide induced diuretic resistance and potentially improve hyponatremia and hypokalemia associated with loop diuretics.