EFFECT OF YM087, A POTENT NONPEPTIDE VASOPRESSIN ANTAGONIST, ON VASOPRESSIN-INDUCED HYPERPLASIA AND HYPERTROPHY OF CULTURED VASCULAR SMOOTH-MUSCLE CELLS

We investigated the effects of YM087, a potent nonpeptide V-1A and V-2 vasopressin (AVP)-receptor antagonist, in binding and functional stud ies on rat vascular smooth-muscle cells (VSMCs). V-1A, AVP receptors o n VSMCs were characterized by using the radioligand [H-3]AVP. Specific binding of [H-3]AVP was time dependent, reversible, and saturable. A single class of high-affinity binding sites with the expected V-1A pro file was identified. YM087 showed high affinity for V-1A receptors wit h an inhibitory dissociation constant (K-i) value of 0.24 nM. In addit ion, YM087 potently and concentration-dependently inhibited AVP-induce d increase in intracellular free calcium concentration and activation of mitogen-activated protein kinase. When added to growth-arrested VSM Cs, AVP concentration-dependently induced hyperplasia and hypertrophy. YM087 prevented AVP-induced hyperplasia and hypertrophy of these cell s in a concentration-dependent manner. YM087 had no agonistic activity in any biological assays used. These results suggest that YM087 displ ays high affinity for V-1A receptors on VSMCs and high potency in inhi biting the AVP-induced physiological response, YM087 is a potent pharm acologic probe for investigating the physiologic and pathophysiologic roles of AVP in several diseases.