Effect of a selective V1 vasopressin receptor antagonist on the sequelae of endotoxemia in the conscious rat.
The following studies were designed to evaluate the efficacy of a potent and selective AVP V1 receptor antagonist ([1-beta-mercapto-beta, beta-cyçlopentamethyleneproprionic acid, 2-(O-methyl)tyrosine-8-arginine vasopressin]; AVPRA) in limiting the sequelae of endotoxemia. At 0.5 and 1.0 hr after intravenous injection of 30 mg/kg S. enteritis endotoxin (LPS) to male Sprague-Dawley rats, AVP plasma concentrations were increased to 171 +/- 20 and 100 +/- 24 pg/ml, respectively, and were significantly greater than the vehicle control values of 1 pg/ml. Injection of LPS was accompanied by the following: a decreased survival rate (20%) with a mean survival time of 21.6 +/- 6 hr (n = 10), an increased heart rate (+ 84 +/- 22 bpm), a reduced circulating platelet count (23% of initial), and an acute hemoconcentration that was maximal at 30 min after injection of LPS. In a separate group of conscious rats, it was determined that AVPRA (1-100 mg/kg/hr) produced a dose-dependent, parallel and rightward shift in the AVP vasopressor dose-response curve: the highest dose of AVPRA (i.e., 100 micrograms/kg/hr) produced approximately a 1,000-fold shift in the AVP dose-response curve. Administration of AVPRA (1-100 micrograms/kg/hr) beginning 15 min prior to the injection of LPS and continuing for 6 hr did not significantly limit any of the sequelae produced by endotoxemia. These results suggest that, in this model, acute administration of a potent V1 AVP antagonist (AVPRA) is not sufficient to prevent the cardiovascular sequelae and mortality associated with endotoxemia.
Egan
J W
JW
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania 19406.
Jugus
M
M
Kinter
L B
LB
Lee
K
K
Smith
E F
EF
D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood* / Q000494:pharmacology / Q000031:analogs & derivatives; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006400:Hematocrit; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012477:Salmonella enteritidis; D014115:Toxemia / Q000097:blood / Q000503:physiopathology*
D004731:Endotoxins; D001127:Arginine Vasopressin; C025043:vasopressin, 1-(1-mercaptocyclohexaneacetic acid)-2-(O- methyl-L-tyrosine)-8-L-arginine-