SYSTEMIC AND REGIONAL HEMODYNAMIC AND BIOLOGICAL EFFECTS OF A NEW KAPPA-OPIOID AGONIST, NIRAVOLINE, IN HEALTHY-VOLUNTEERS

We noninvasively investigated the effects of a single 30-min i.v. infu sion of a 2-mg dose of niravoline, a new selective rc-opioid agonist, on systemic and regional (brachial artery) hemodynamics, on plasma lev els of the main hormones regulating the cardiovascular system, on diur esis and on plasma and urinary osmolalities and electrolytes. This was a placebo-controlled, randomized, double-blind, crossover study perfo rmed in 12 healthy volunteers. Compared with placebo, niravoline induc ed a significant, early and potent diuresis, which peaked within 2 hr (urine output increased 2.4-fold) and lasted for 4 hr. Niravoline sign ificantly decreased, between 0 and 2 hr, urine osmolality (-71%) and s odium (-38%) and potassium (-29%) excretion and significantly increase d plasma osmolality and natremia, without changing kalemia. Niravoline induced a slight, but significant, increase in blood pressure (+8% at 0.5 hr), which disappeared within 2 hr. Because heart rate, stroke vo lume and cardiac output were not modified, this effect was due to an i ncrease in total peripheral resistance (+22% at 0.5 hr). Niravoline di d not modify brachial artery diameter and flow and corresponding vascu lar resistance. Niravoline tended to decrease plasma vasopressin level s and urinary excretion and significantly increased plasma levels of n orepinephrine (+44% at 0.5 hr), active renin (+22% at 1.25 hr), aldost erone (+52% at 1.25 hr) and atrial natriuretic factor (+20% at 2 hr). We conclude that niravoline induces a potent aquaretic effect associat ed with antinatriuresis and antikaliuresis. These main effects are acc ompanied by a stimulation of the sympathetic and renin-angiotensin sys tems and a slight and transient increase in blood pressure.