Antagonism of vasoconstriction induced by platelet‐activating factor in guinea‐pig perfused hearts by selective platelet‐activating factor receptor antagonists

Self Cite

1 The involvement of prostacyclin (PGI2) in the vasodilator responses to acetylcholine (ACh), A23187 and bradykinin (Bk) has been investigated in guinea-pig, isolated, Krebs-perfused hearts. 2 ACh (0.01-lOnmol), A23187 (0.1-1.Onmol) and Bk (0.3-lOpmol) each elicited dose-related and shortlasting (-2 min) reductions in perfusion pressure. Larger maximal responses were obtained in preparations with coronary vascular tone elevated by platelet-activating factor (100 pmol) than in preparations at basal perfusion pressure. 3 Bk and A23187 elicited dose-related increases in the generation of PGI2 as measured by its chemically-stable breakdown product, 6-oxo-PGFg. Indomethacin (2.8 uM) prevented both basal and the stimulated generation of 6-oxo-PGF,., whereas the magnitudes of the vasodilator responses were unaffected. 4 Attempts to identify the release of vasodilator materials by on-line superfusion bioassay of cardiac effluent were unsuccessful, indicating a possible role for a labile vasodilator such as endothelium-dependent relaxing factor (EDRF). In addition, the inhibitors of EDRF action/ production, mepacrine (3yM) or diethylcarbamazine (300pM), attenuated vasodilator responses to ACh without altering those to the endothelium-independent vasodilator, verapamil (1 nmol). 5 Haemoglobin (10pM) reduced vasodilator responses to ACh, Bk and verapamil and abolished those induced by A23187. Inhibition of the endothelium-independent vasodilator, verapamil, was significantly less than that for the other compounds. 6 The present data indicate the existence of an indomethacin-resistant vasodilator mechanism in the coronary microcirculation in response to ACh, A23187 and Bk. EDRF is a candidate for mediating these responses; however, a direct vasodilator action of these substances cannot be excluded.

Section: Introductionsupporting

confidence: 80%

Vasodilator actions of acetylcholine, A23187 and bradykinin in the guinea‐pig isolated perfused heart are independent of prostacyclin

Stewart

Piper

1988

Self Cite

“…Piper & Stewart (1986& Stewart ( , 1987 showed that indomethacin attenuated the increase in perfusion pressure in rat and guinea-pig isolated hearts following bolus injections of PAF. It had also been reported that indomethacin blocked the coronary vasoconstriction produced by intracoronary injection of PAF in the pig heart in vivo (Feuerstein et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

Interaction of vasoactive substances released by platelet‐activating factor in the rat perfused heart

Man

1991

1 The coronary vascular effects of platelet-activating factor (PAF) have been intensively studied and it has been proposed that they are mediated by the release of vasoactive substances. In this study, a cascade perfusion model using two rat perfused hearts was developed to investigate the properties of PAF-released vasoactive substances and the interplay of these substances. The properties of the vasoactive substances after an injection of PAF (100pmol) in the rat perfused heart were examined by collecting the effluent from the first heart for the perfusion of a second (recipient) heart. The presence of vasoconstrictor substances in the effluent was characterized by an increase in the perfusion pressure of the recipient heart. 2 Previous exposure of the recipient heart of PAF (100pmol) abolished the response of the heart to subsequent administration of PAF, but did not affect the response of the recipient heart to the effluent. This suggested that the coronary vasoconstrictor response of the recipient heart was not due to the presence of PAF in the effluent but to other vasoactive substances. 3 Pretreatment of the recipient heart with the leukotriene receptor antagonist, L-649,923 (5pM), partially reduced the vasoconstrictor effect of the effluent. Pretreatment of the first heart with indomethacin (2.8 pM) also partially reduced the vasoconstrictor effect of the effluent. The combination of indomethacin pretreatment of the first heart and L-649,923 pretreatment of the recipient heart completely abolished the vasoconstrictor effect of the effluent suggesting that both prostaglandins and leukotrienes are involved in the vasoconstrictor effect of the effluent. 4 Pretreatment of both hearts with L-649,923 or the first heart with the leukotriene synthesis inhibitor (MK-886, 10pUM) completely abolished the vasoconstrictor effect of the effluent. This suggested that the indomethacin sensitive vasoconstrictor component of the effluent might be regulated by leukotrienes in the first heart. However, infusion of leukotrienes (LTB4, LTC4 and LTD4) to the first heart did not reproduce this vasoconstrictor component of the effluent in the recipient heart. 5 In conclusion, our study demonstrated through the use of a leukotriene receptor antagonist, a leukotriene synthesis inhibitor and a cyclo-oxygenase inhibitor that the vasoconstrictor effect of the effluent of the rat perfused heart after an injection of PAF is mediated by leukotrienes and prostaglandins. The ability of leukotriene receptor blockade and inhibition of leukotriene synthesis to mimic the effect of indomethacin indicates that the production and/or release of cyclo-oxygenase products in the effluent by PAF can be modulated by leukotrienes. The inability of exogenously applied leukotrienes to modulate the production and/or the release of cyclo-oxygenase products in the effluent suggests that the PAF-induced production of prostaglandins may be mediated by intracellular leukotrienes or at sites not accessible to exogenously applied leukotrienes.

“…However, the results of these studies are diverse. PAF was shown to cause vasoconstriction in the guinea-pig perfused heart (Levi et al, 1984;Piper & Stewart, 1987) and in the rat perfused heart (Piper & Stewart, 1986). In contrast, intracoronary injection of PAF to anaesthetized dogs produced only increases in coronary flow and this effect was reduced after the removal of circulating platelets (Jackson et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of the coronary vascular effects of platelet‐activating factor in the rat perfused heart

Kinnaird

Man

1991

1In a previous study it was demonstrated that bolus injections of platelet-activating factor (PAF) in the rat perfused heart resulted in coronary vasodilatation, vasoconstriction or the combination of both, depending on the amount of PAF that was injected. In the present study, the mechanisms of these coronary vascular effects of PAF in the rat perfused heart were investigated. 2 Pretreatment of the rat perfused heart with the PAF antagonists FR-900452 or BN-52021 did not affect the vasodilator effect of PAF but eliminated the vasoconstrictor effect of PAF. FR-900452 had no effect on the vasoconstrictor response to leukotriene C4 (LTC4) or LTD4. 3 The cyclo-oxygenase inhibitor, indomethacin, did not modify the coronary vascular effects of PAF. However L-649,923 (a leukotriene antagonist) and MK-886 (a leukotriene synthesis inhibitor) eliminated both the vasodilator and vasoconstrictor effects of PAF. 4 When leukotrienes were administered by bolus injection in the rat perfused heart, LTB4 produced vasodilatation while LTC4 and LTD4 produced vasoconstriction. L-649,923 blocked both the vasodilator and vasoconstrictor effects of the leukotrienes tested. 5 The results suggest that lipoxygenase products are responsible for both the vasodilator and vasoconstrictor actions of PAF in the coronary vasculature of the rat perfused heart while the cyclo-oxygenase products do not play a significant role. The ineffectiveness of PAF antagonists in blocking the vasodilatation produced by PAF is compatible with the concept that there may be multiple PAF receptors.