Conivaptan

Conivaptan (YM 087 free base) is an orally active dual vasopressin V_1a/V₂ receptor antagonist with K_i values of 0.48 nM and 3.04 nM for vasopressin V_1a receptor and V₂ receptor, respectively. Conivaptan competitively and reversibly blocks vasopressin-mediated antidiuresis, vasoconstriction, and cellular hypertrophy, while inhibiting CYP3A4. Conivaptan inhibits vasopressin-induced intracellular calcium, cAMP, and mitogen-activated kinase activation in vascular smooth muscle cells and cardiomyocytes. Conivaptan induces water diuresis while improving hemodynamics in heart failure models, reducing left ventricular end-diastolic pressure, vascular resistance, and organ weight. Conivaptan is used for research on hyponatremia and congestive heart failure^[1][2]. In Vitro:Conivaptan binds to vasopressin V_1a receptors (K_i = 0.48 nM) and vasopressin V₂ receptors (K_i = 3.04 nM) in a competitive and reversible manner, and shows almost no activity against vasopressin V_1b receptors^[1].

Conivaptan inhibits vasopressin-triggered intracellular calcium elevation in vascular smooth muscle cells (IC₅₀ = 1.16 nM) and simultaneously inhibits vasopressin-induced cAMP accumulation (IC₅₀ = 17.3 nM)^[1].

Conivaptan binds with high affinity to canine platelet V_1a receptors (K_i = 0.6 nM) and canine kidney V₂ receptors (K_i = 0.7 nM), binds to rhesus monkey liver V_1a receptors (K_i = 26 nM) and rhesus monkey kidney V₂ receptors (K_i = 10 nM), and inhibits AVP binding to human cloned V_1a receptors (K_i = 6.3 nM) and V₂ receptors (K_i = 1.1 nM) in COS1 cells.

Conivaptan inhibits AVP-induced increases in Ca²⁺ and cAMP in COS1 cells expressing human receptors, with IC₅₀ values of 2.0-14.3 nM; it inhibits AVP-induced Ca²⁺, mitogen-activated kinase, and protein synthesis in rat cardiomyocytes expressing V_1a receptors; and it inhibits AVP-induced proliferation and hypertrophy of vascular smooth muscle cells in growth-arrested rats^[1]. In Vivo:Conivaptan (0.3-3 mg/kg; p.o.; single administration) attenuates heart failure-induced elevation of left ventricular end-diastolic pressure and reduces lung and right ventricular weights, while producing a significant aquaretic effect that increases urine output by more than 10-fold in rats with congestive heart failure^[2].