Partial agonist effect of the platelet-activating factor receptor antagonists WEB 2086 and WEB 2170 in the rat perfused heart.

摘要

1. WEB 2086 and WEB 2170 are potent platelet-activating factor (PAF) receptor antagonists and have been used widely as pharmacological tools to investigate the actions of PAF in a variety of biological systems. 2. Low concentrations of WEB 2086 and WEB 2170 blocked the vasoconstrictor action of PAF in the rat perfused heart. In this study, we observed that moderate concentrations of WEB 2086 and WEB 2170 increased the perfusion pressure in rat isolated hearts under constant flow perfusion. The vasoconstrictor actions of WEB 2086 and WEB 2170 were not observed with a structurally different PAF receptor antagonist, FR-900452. 3. To determine whether this vasoconstrictor action of WEB 2086 involved non-specific effects or was via the activation of PAF receptors, hearts were pretreated with 1000 pmol PAF or 50 microM FR-900452. These pretreatments attenuated the vasoconstrictor action of 1 microM WEB 2086, suggesting that the action of WEB 2086 may be mediated via PAF receptors. Pretreatment with the leukotriene receptor antagonist (L-649,923, 5 microM) and the leukotriene synthesis inhibitor (MK-886, 10 microM) that are known to block the vasoconstrictor action of PAF receptor activation also attenuated the vasoconstrictor action of WEB 2086. Pretreatment with PAF or MK-886 attenuated the vasoconstrictor action of 0.5 microM WEB 2170. 4. When PAF receptors were activated by PAF in the perfused heart, significant amounts of leukotriene C4 and leukotriene C4/D4/E4 were detected in the coronary effluent. However, no significant amount of these leukotrienes was detected in the coronary effluent when hearts were perfused with 1 microM WEB 2086 or 0.5 microM WEB 2170.(ABSTRACT TRUNCATED AT 250 WORDS)