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Abstract: TH-OR94

Treatment of Diuretic Resistance with a Kappa Opioid Agonist, an Inhibitor of Central Vasopressin Secretion

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Anderson, Ashlyn Y., LSU Health New Orleans, New Orleans, Louisiana, United States
  • Gao, Juan, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Johnson, Kara, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Denys, Ian Bart, LSU Health New Orleans, New Orleans, Louisiana, United States
  • Beckendorf, Luke E., LSU Health New Orleans, New Orleans, Louisiana, United States
  • Meariman, Jacob K., LSU Health New Orleans, New Orleans, Louisiana, United States
  • Kapusta, Daniel R., LSU Health New Orleans, New Orleans, Louisiana, United States
Background

Prolonged use of furosemide for treatment of congestive heart failure can produce adverse effects including hypokalemia, hyponatremia, and diuretic resistance. We hypothesized that due to diuretic-induced excretion of water, increased vasopressin (AVP) secretion may be a key compensatory mechanism contributing to diuretic resistance. Since kappa opioid receptor (KOR) agonists act centrally to inhibit AVP secretion and produce water diuresis, we predicted that administration of difelikefalin, a KOR agonist, will reverse diuretic resistance to furosemide without enhancing urinary sodium/potassium excretion.

Methods

To test this, changes in 5-hr urine output (metabolic cages; no water) were measured daily in Sprague-Dawley rats following injection (9:00am) of saline (day 0) and furosemide (10 mg/kg, i.p.; days 1-5). Over days 6-10 rats were administered either, furosemide, furosemide + difelikefalin (F+D, 20 µg/kg, i.p.; days 6-10), or furosemide + tolvaptan (F+T, 1 mg/kg, i.p.) an AVP V2 receptor antagonist. After urine collection, rats received a 2nd drug treatment (2:00 pm) and were placed in home cages.

Results

Initial treatment (day 1) of rats with furosemide evoked a marked increase in urine output (V), urinary sodium excretion (UNaV), and urinary potassium excretion (UKV), with the magnitude of each greatly reduced by day 5 (day1:day5; V, 10.5±0.6 vs 5.6±0.4 ml/5hrs; UNaV, 971±55 vs 396±23 µEq/5hrs; UKV, 250±14 vs 193±20 µEq/5hrs). Over days 6-10, 5-hr urine output remained reduced throughout furosemide treatment (diuretic resistance). Combination treatment with either difelikefalin or tolvaptan over days 6-10 reversed diuretic resistance as noted by a sustained increase in V without increasing UNaV compared to furosemide alone (day 10, V; F, 5.6±0.2 ml/5hrs; F+D, 10.1±0.77 ml/5hrs; F+T, 11.1±0.9 ml/5hrs). Further, tolvaptan but not difelikefalin increased UKV over days 6-10.

Conclusion

These findings demonstrate that AVP plays a major role in mediating diuretic resistance to furosemide. Further, we show that combination therapy with a KOR agonist (difelikefalin) can reverse and potentially prevent diuretic resistance while improving loop diuretic induced hypokalemia and hyponatremia. (LSUHSC Research Enhancement Program)