vasopressin--1-(1-mercaptocyclohexaneacetic-acid)-2-(o--methyl-l-tyrosine)-8-l-arginine- and Toxemia

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.

Topics: Animals; Arginine Vasopressin; Blood Pressure; Dose-Response Relationship, Drug; Endotoxins; Heart Rate; Hematocrit; Male; Platelet Count; Rats; Rats, Inbred Strains; Salmonella enteritidis; Toxemia