INHIBITION OF VASOPRESSIN ACTION IN VASCULAR SMOOTH-MUSCLE BY THE V-1ANTAGONIST OPC-21268

In vascular smooth muscle cells arginine vasopressin acting through th e V-1 receptor increases intracellural Ca2+ leading to vasoconstrictio n. Recent studies have also shown that vasopressin activates mitogen-a ctivated protein kinase (MAP kinase), which may contribute to vasopres sin-induced hypertrophy of vascular smooth muscle cells. We examined t he ability of an orally active, nonpeptide selective V-1 antagonist (O PC-21268) to block vasopressin binding and postreceptor signaling in t hese cells. [H-3]Vasopressin binding at 2x10(-9) mol/L was half-maxima lly blocked at 10(-9) mol/L OPC-21268. To compare effects of OPC-21268 on binding and postreceptor signaling, we stimulated cells with 10(-8 ) mol/L vasopressin. At this vasopressin concentration, half-maximal i nhibition of binding occurred at 5x10(-9) mol/L OPC-21268. Half-maxima l inhibition of Ca2+ efflux or increases in intracellular free Ca2+ re quired higher concentrations of antagonist (10(-7) mol/L), and half-ma ximal inhibition of vasopressin-stimulated MAP kinase was observed onl y at 10(-6) mol/L OPC-21268. These results indicate that this agent se lectively blocks both vasopressin binding and postreceptor signaling i n vascular smooth muscle cells. The requirement of higher concentratio ns of OPC-21268 for blocking increases in intracellular Ca2+ and activ ation of MAP kinase suggests that binding to a fraction of V-1 recepto rs generates maximal levels of second messengers or the existence of s ubtypes of the V-1 receptor with differential affinity for this antago nist. These data have implications for the clinical use of this compou nd.