Blocking effects of V1 (OPC-21268) and V2 (OPC-31260) antagonists on the negative inotropic response to vasopressin in isolated dog heart preparations.
We investigated the effects of V1 IOPC-21268, 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone) and V2 (OPC-31260, 5-dimethylamino-1[4-(2-methylbensoylamino)benzoyl]-2,3,4,5-tetrahy dro-1H- benzazepine) vasopressin receptor antagonists on the negative inotropic response to arginine vasopressin (AVP) in the isolated perfused heart preparations of the dog. AVP (7.5-750 pmol) decreased the atrial and ventricular contractile force when the preparation was perfused with constant pressure or constant flow. AVP induced a small increase in sinus rate. Desmopressin, a selective vasopressin V2 agonist, did not change the sinus rate and atrial or ventricular contractile force. OPC-21268 (0.01-3 mumol) and OPC-31260 (0.01-1 mumol) induced a small negative inotropic effect. Both OPC-21268 and OPC-31260 inhibited the negative inotropic response to AVP in a dose-dependent manner. The doses of 50% inhibition (ID50) for OPC-21268 and OPC-31260 on the inotropic effect were 0.30 +/- 0.16 mumol and 0.084 +/- 0.034 mumol, respectively. Neither OPC-21268 nor OPC-31260 affected the acetylcholine-, adenosine- or norepinephrine-induced inotropic and chronotropic effects. It has been reported that the concentration of OPC-21268 that displaced 50% of specific AVP binding is 0.4 microM for V1 receptors and > 100 microM for V2 receptors and the concentration of OPC-31260 is 0.01 microM for V2 receptors and 1 microM for V1 receptors. We, therefore, suggest that AVP directly causes negative inotropic effects mediated at least in part by V1 receptors in the dog heart.
Furukawa
Y
Y
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Takayama
S
S
Ren
L M
LM
Sawaki
S
S
Inoue
Y
Y
Chiba
S
S
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001552:Benzazepines / Q000494:pharmacology*; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D017483:Receptors, Vasopressin / Q000187:drug effects*
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C068644:OPC 21268; C076251:mozavaptan; D003894:Deamino Arginine Vasopressin