L-649,923: an antagonist of cardiac and vascular leukotriene D4 receptors.

The capacity of L-649,923--sodium (beta S, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)-ga mma- hydroxy-beta-methylbenzene butanoate--to block vascular receptors of leukotriene D4 (LTD4) was examined in the conscious rat. Hindquarter (HQ), renal, and mesenteric blood flow and vascular resistance were evaluated in the conscious rat chronically equipped with miniaturized Doppler probes for organ blood flow measurement by directional pulsed Doppler technique. In addition, cardiac output was measured by thermodilution technique in conscious rats equipped with minithermistors in the ascending aorta. Systemic hemodynamic variables, mean arterial pressure, and heart rate were monitored through femoral catheters. LTD4 (1 or 10 micrograms/kg) produced a marked dose dependent increase in the mesenteric vascular resistance associated with a marked decrease in blood flow whereas no consistent effects were demonstrated in the renal circulation. LTD4, at 1 microgram/kg, increased the HQ blood flow whereas the higher dose of LTD4 produced a biphasic response: an early increase followed by a decrease in blood flow. Infusion of LTD4, 3 micrograms/kg per min over 10 min decreased cardiac output and increased total peripheral resistance. L-649,923 (10 or 30 mg/kg, i.v.) effectively blocked the LTD4-induced mesenteric constriction and the second phase of HQ vasoconstriction but did not modify the LTD4 induced HQ vasodilation. L-649,923 also effectively attenuated the cardiac effects of LTD4 infusion. These studies suggest that L-649,923 could preserve cardiac and vascular functions in pathologic states mediated by cysteinyl leukotrienes, such as traumatic or endotoxin shock.