Nalfurafine Combined with Standard‐of‐Care Diuretics Increases Diuresis and Limits Electrolyte Losses

Abstract

Kappa opioid receptor (KOR) agonists produce a variety of beneficial effects, including a water diuresis, but their translation into the clinic has been hindered by psychotomimetic adverse effects. Nalfurafine is a novel, G protein biased KOR agonist that has been shown to produce several desired effects of KOR agonists, while avoiding central adverse effects. To more fully explore the clinical potential of this drug, this study examined the cardiovascular and renal responses to i.v. nalfurafine alone or in combination with the clinically used diuretics: furosemide, hydrochlorothiazide (HCTZ), and amiloride. Following chronic instrumentation, conscious Sprague-Dawley rats were continuously infused i.v. with isotonic saline; after stabilization, rats were administered i.v. bolus nalfurafine, diuretics, diuretics combined with nalfurafine, or vehicle, and mean arterial pressure (MAP), heart rate (HR), and urine output were recorded for 90 min. IV nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and decrease in MAP without eliciting a change in HR. As compared to diuretic treatment alone, co-administration of nalfurafine notably increased the total urine output to furosemide and HCTZ while reducing the amount of sodium and potassium excreted. When combined with amiloride, nalfurafine also increased the diuresis and decreased the amount of sodium excreted. In contrast to these diuretics administered alone, MAP was reduced with nalfurafine combination therapy. Together, these findings demonstrate that nalfurafine has a clinically important action to augment the diuresis to classical diuretics without causing excessive loss of electrolytes characteristic of these drugs. Combination therapy of nalfurafine with loop/thiazide diuretics may offer a new approach to treat several cardiovascular conditions such as hypertension, volume overloaded states, and electrolyte abnormalities.