Examination Date
Spring 5-13-2026
Degree
Dissertation
Degree Program
Pharmacology and Experimental Therapeutics
Examination Committee
Daniel R. Kapusta (Research Mentor), Peter Winsauer, Dennis Paul, Ifechukwude Biose, Rajesh Mohandas
Abstract
The goal of this dissertation research was to investigate the contribution of vasopressin (AVP) in mediating diuretic resistance to prolonged use of the loop diuretic, furosemide, and determine if inhibition of AVP secretion using kappa opioid receptor (KOR) agonists can reduce diuretic resistance in a rat model of heart failure with preserved ejection fraction (HFpEF). The loop diuretic, furosemide, is the first line treatment to relieve congestion in patients with acute heart failure. Repeated use of furosemide can lead to the development of diuretic resistance, which is a failure to achieve a therapeutically desired increase in the renal excretion of sodium and water and reduction in edema despite a full dose of a loop diuretic.
Upregulation of renal sodium and water channels in response to diuretics is theorized to be a main contributor to resistance. Current treatment options for diuretic resistance require increasing the dosing regimen or the addition of a thiazide diuretic to enhance natriuresis, which often increases adverse events including hypokalemia, hyponatremia, and worsening renal function. Poor outcomes in acute heart failure are associated independently with elevated AVP levels and diuretic resistance. However, it remains unclear how increased AVP secretion caused by fluid loss contributes to the etiology of diuretic resistance.
KOR agonists such as nalfurafine and difelikefalin are compounds that act centrally to inhibit AVP release and consequently produce a free-water diuresis. Using a rat model of diuretic resistance to furosemide, we showed co-administration of nalfurafine or difelikefalin prevents and reverses established diuretic resistance to furosemide in a normal model (Sprague-Dawley) and model of HFpEF (ZSF1) rats. Co-treatment with KOR agonists did not alter urinary electrolyte excretion compared to furosemide alone but increased free water clearance and decreased urine osmolality, supporting the role of AVP in mediating resistance to loop diuretics. Furosemide administration increased levels of the activated form of NCC, which was reduced to untreated control levels during KOR agonist co-treatment. Accordingly, we hypothesize that water loss caused by the prolonged use of the loop diuretic furosemide produces a compensatory increase in circulating AVP that promotes water retention and contributes to diuretic resistance in heart failure.
Recommended Citation
Anderson, Ashlyn Y., "LOOP DIURETIC RESISTANCE AND THE EFFECTS OF VASOPRESSIN INHIBITION BY KAPPA OPIOID RECEPTOR AGONISTS IN HEART FAILURE WITH PRESERVED EJECTION FRACTION" (2026). School of Graduate Studies. 14.
https://digitalscholar.lsuhsc.edu/etd_sgs/14