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(1 H)- 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 less than 0.01) and then a small sustained increase in [Ca2+]i. After pretreatment of vascular smooth muscle cells with 1 microM 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 less than 0.05) and also produced reductions in peak systolic [Ca2+]i (from 962.2 +/- 76.4 to 751.2 +/- 70.5 nM, p less than 0.01) within 30 seconds. Pretreatment of ventricular myocytes with OPC-21268 (1 microM) 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.
Matsui
H
H
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Kohmoto
O
O
Hirata
Y
Y
Serizawa
T
T
D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009994:Osmolar Concentration; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D010880:Piperidines; D015363:Quinolones; D014667:Vasopressins; D001127:Arginine Vasopressin; C068644:OPC 21268; D002118:Calcium