EFFECTS OF A NONPEPTIDE VASOPRESSIN ANTAGONIST (OPC-21268) ON CYTOSOLIC CA2+ CONCENTRATION IN VASCULAR AND CARDIAC MYOCYTES

A selective V1 antagonist, 1-{1-[4(3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-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 Ca2+ concentration ([Ca2+]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 [Ca2+]i of 133.6+/-10.9 nM to peak [Ca2+]i of 842.7+/-172.8 nM at 100 nM vasopressin, p<0.01) and then a small sustained increase in [Ca2+]i. After pretreatment of vascular smooth muscle cells with 1-mu-M OPC-21268, the effects of 100 nM vasopressin on [Ca2+]i 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 [Ca2+]i (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-mu-M) completely suppressed vasopressin-induced changes in peak systolic cell position and [Ca2+]i. These results suggest that vasopressin may increase vascular tone and may also cause a direct negative inotropic effect via V1 receptors and that this orally active V1 antagonist (OPC-21268) may have potential clinical usefulness.