Effects of a Nonpeptide Vasopressin Antagonist (OPC-21268) on Cytosolic Ca Concentration in Vascular and Cardiac Myocytes

A selective V, antagonist, l-{l-[4(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(l//)-quinolinone (OPC-21268), which is nonpeptide and orally effective, has been recently synthesized. We studied the effects of vasopressin and OPC-21268 on cell contraction with a video motion detector and cytosolic Ca concentration ([Ca]i) by using indo-1 in cultured rat vascular smooth muscle cells and cultured chick embryo ventricular myocytes. Exposure of cultured vascular smooth muscle cells to vasopressin (1-100 nM) dose-dependently produced an initial transient increase (from control level [Ca]j of 133.6± 10.9 nM to peak [Ca], of 842.7±172.8 nM at 100 nM vasopressin,p<0.01) and then a small sustained increase in [Ca],. After pretreatment of vascular smooth muscle cells with 1 /*M OPC-21268, the effects of 100 nM vasopressin on [Ca]| were abolished. Exposure of ventricular myocytes to 100 nM vasopressin slightly but significantly decreased peak systolic cell position (-8.7±3.7%, p<0.05) and also produced reductions in peak systolic [Ca], (from 962.2±76.4 to 751.2±70.5 nM, p<0.01) within 30 seconds. Pretreatment of ventricular myocytes with OPC-21268 (1 /xM) completely suppressed vasopressininduced changes in peak systolic cell position and [Ca]j. These results suggest that vasopressin may increase vascular tone and may also cause a direct negative inotropic effect via V, receptors and that this orally active V, antagonist (OPC-21268) may have potential clinical usefulness. (Hypertension 1992;19:730-733)