Similar coronary vascular effects in the rat perfused heart of platelet-activating factor structural analogues with agonist and antagonist properties.

Abstract

1. Selective blockade of platelet-activating factor (PAF) receptor subtypes by PAF receptor antagonists has been demonstrated. However, selective activation of PAF receptor subtypes by PAF receptor agonists has not been reported. 2. When structural analogues of PAF that have been shown to possess either agonist or antagonist effects were administered by a bolus injection in the rat perfused heart, they all showed agonist effects. Lower amounts produced vasodilation while higher amounts produced vasodilation followed by vasoconstriction. These coronary vascular effects were typical of that observed with PAF. Lyso-PAF did not show the same typical pattern of coronary vascular effect, confirming that the detergent effect of PAF structural analogues did not play a role in the coronary vascular effects. Other PAF antagonists, CV-6209 and WEB 2170, also did not produce the PAF-like response in the rat perfused heart. 3. The coronary vascular effects of hexanolamine-PAF (H-PAF, putative antagonist) and ethanolamine-PAF (E-PAF, agonist) were further studied. Pretreatment with FR-900452 (a PAF receptor antagonist) or MK-886 (a leukotriene synthesis inhibitor) significantly reduced the vasodilator and vasoconstrictor effects of H-PAF and E-PAF. 4. Pretreatment of rat perfused hearts with low concentrations of H-PAF and E-PAF blocked the response to PAF administration in a dose- and time-dependent manner. However, the pretreatment with either H-PAF or E-PAF did not result in a coronary vascular effect expected of a PAF receptor agonist. These results were compatible with H-PAF and E-PAF behaving as PAF receptor antagonists. 5. In summary, our results demonstrate that several PAF structural analogues possess agonist action in the rat perfused heart. Like the coronary vascular effects of PAF, the effects of H-PAF and E-PAF were blocked by a PAF antagonist (FR-900452) and a leukotriene synthesis inhibitor (MK-886). This suggests that both H-PAF and E-PAF mediate their effect through activation of PAF receptors with a subsequent release of leukotrienes that produced vasodilatation and vasoconstriction. Furthermore, pretreatment of perfused hearts with these compounds blocked the response to PAF in these hearts. Thus these compounds can also behave like a PAF receptor antagonist. This latter action may be due to a gradual receptor inactivation or desensitization by the pretreatment of H-PAF and E-PAF through a PAF receptor agonist effect rather than being a PAF receptor antagonist.