Influence of asimadoline, a new kappa-opioid receptor agonist, on tubular water absorption and vasopressin secretion in man

Aims The purpose of the study was to investigate the effects of asimadoline , a new kappa-opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects. Methods In a placebo-controlled, randomised, double-blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoli ne, in 24 healthy volunteers. Two hour control urine collections were follo wed by 2 h postdose urine collections and subsequently 2.5% saline was give n i.v, at a rate of 0.3 ml min(-1) kg(-1) during another 2 h urine collecti on. Blood was obtained hourly. Arginine-vasopressin (AVP), atrial natriuret ic peptide (alpha-hANP), endothelin (ET-1) and cAMP were determined by r.i. a. or ELISA. Results GC-MS measurements revealed C-max values of asimadoline in plasma r anging from 18 ng ml(-1) at the 1 mg dose, 91 ng ml(-1) at the 5 mg dose, t o 214 ng ml(-1) at the 10 mg dose after an average of 1.1-1.4 h. Without ef fects on blood pressure, heart rate, GFR or urine electrolyte excretion, ur ine volume increased after 1-2 h after administration of 5 and 10 mg asimad oline from 3.3 +/- 1.3 to 5.6 +/- 1.4 (P < 0.05) and from 3.2 +/- 1.6 to 5. 5 +/- 2.2 ml min(-1) (P < 0.01), respectively. C-H2O rose from 0.2 +/- 1.5 to 2.0 +/- 1.6 (P < 0.05) and from 0.6 +/- 1.6 to 3.0 +/- 1.6 ml min(-1) (P < 0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose horn 46 +/- 23 to 25 +/- 15 fmol min(-1) (P < 0.05) without and from 410 +/ - 206 to 181 +/- 125 fmol min(-1) (P < 0.05) with stimulation by 2.5% salin e. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six o f eight subjects during the 2.5% saline infusion. Changes in the alpha-hANP or ET-1 systems were not affected by asimadoline. Conclusions Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression o f AVP secretion was observed only at the highest dose level of 10 mg of asi madoline.