1 The mechanisms of action of platelet activating factor (PAF) in the bronchial and cardiovascular systems have not yet been fully elucidated. In order to characterize better and to ascertain whether the effects of PAF in both these systems may be ascribed to the same mechanisms, we examined the actions of PAF in the heart-lung preparation of guinea-pig (HLP). The role of platelets and of cyclo-oxygenase metabolites was investigated. 2 In HLPs perfused with autologous blood, bolus injections of PAF (4-32 ng) produced major effects at the pulmonary vascular and bronchial levels. Both dose-related pulmonary vascular hypertension and bronchoconstriction produced by PAF were diminished to the same extent (46% and, respectively, 47%) when HLPs were perfused with a medium consisting of homologous red blood cells suspended in physiological solution containing 3.5% dextran (RBC). This suggests that the effects of PAF partially depend on the presence of formed elements.3 When indomethacin (30 pM) was added to the perfusing blood, the dose-response curve for the pulmonary hypertensive responses produced by PAF was strongly reduced (90%) in comparison to control preparations, whereas the bronchoconstrictor effects of PAF were only partially diminished (23%). These data constitute direct evidence that products of the cyclo-oxygenase pathway exert a major role in the vascular, rather than in the bronchial actions of PAF. 4 In HLPs perfused with RBC containing indomethacin (30 gLM), the pulmonary vascular hypertensive responses produced by PAF were almost completely abolished, thus indicating that cyclo-oxygenase products from tissues are involved in these effects. Conversely, PAF administration continued to cause dose-related bronchoconstrictor responses that were reduced only partially in comparison with HLPs perfused with RBC in the absence of the cyclo-oxygenase inhibitor. This implies that PAF also has direct action on the bronchoconstriction evoked. 5At the cardiac level, administration of PAF in HLPs perfused with blood caused a dose-related increase in right atrial pressure accompanied by a decrease in left atrial pressure and cardiac output, which were completely suppressed or attenuated by the absence of formed elements and the addition of indomethacin. This suggests that the progressive heart impairment is secondary to the severe pulmonary hypertension induced by PAF. 6 The results of this study performed in the heart-lung preparation of the guinea-pig, which made it possible to simultaneously record cardiovascular and bronchial parameters, indicate that various components are involved in the responses produced by PAF. It is suggested that different mechanisms depending on the relative contribution of these components may account for the PAF-induced effects at the pulmonary vascular and airway levels.

1 We investigated the potentiating e ect of low concentrations of neuropeptide Y (NPY) on the vasoconstriction induced by transmural nerve stimulation (TNS) and noradrenaline (NA) in human saphenous veins. The e ects of (i) endothelium removal; (ii) the addition of the NO pathway precursor L-arginine; (iii) the ET A /ET B endothelin receptor antagonist Ro 47-0203; (iv) the cyclo-oxygenase inhibitor, indomethacin; (v) the selective thromboxane A 2 (TxA 2 ) receptor antagonists Bay u3405 and ifetroban, and (vi) the TxA 2 synthase inhibitor, UK 38485, were studied in order to gain information about the mechanisms of NPY-induced potentiation. 2 Contractile response curves for TNS (0.5 ± 8 Hz) and for exogenously administered NA (0.1 ± 3 mM) were obtained in superfused saphenous vein rings. The contractions induced by both TNS and NA at all tested frequencies and concentrations, respectively, were signi®cantly potentiated by 50 nM NPY in endothelium intact veins. Conversely, in endothelium-denuded vessel rings the contractile-response curves to TNS and NA overlapped both in the absence and presence of NPY, thus suggesting that a release of vasoactive substances from endothelial cells could account for the noradrenergic NPY-induced potentiation.3 In vessels with intact endothelium, the potentiating action of NPY on TNS and NA was una ected by the presence of high concentrations of the NO precursor L-arginine (3 ± 10 mM) or the non-selective ET A /ET B endothelin receptor antagonist, Ro 47-0203 (10 mM). These data indicate that the NPY-induced e ect does not involve either the endothelium-derived vasodilator nitric oxide or the vasoconstrictor endothelin. Conversely, in the presence of the cyclo-oxygenase inhibitor, indomethacin (30 mM), NPY failed to potentiate the vasoconstrictions produced by either nerve stimulation or by exogenous NA, thus providing evidence that arachidonic acid metabolites through the cyclo-oxygenase pathway are mainly responsible for the potentiation evoked by NPY. 4 When the TxA 2 receptor antagonists, Bay u 3405 (1 mM) and ifetroban (1 mM) were added to the superfusing medium, NPY did not alter either the frequency-or the concentration-response curves for either TNS or NA. Accordingly, both TNS-and NA-induced contractions were not potentiated by NPY in the presence of the TxA 2 synthase inhibitor, UK 38485 (10 mM). This clearly demonstrates the pivotal role of TxA 2 in NPY-induced potentiation. 5 In superfused vein rings with endothelium, a subthreshold concentration (0.2 nM) of the TxA 2 mimetic U 46619 potentiated both TNS-and NA-induced vasoconstrictions. This potentiation was higher at low stimulation frequencies and low NA concentrations, and resembled that produced by NPY. 6 Our results indicate that in the human saphenous vein NPY potentiates the contractions produced by sympathetic nerve stimulation acting at the postjunctional level, primarily on endothelial cells. In particular, the NPY-induced release of a cyclo-oxygenase metabolite, namely TxA 2 , may have a synergistic e ect on t...

1 The specific type(s) of voltage-sensitive calcium channels (VSCCs) involved in sympathetic neurotransmission have not yet been characterized in human vascular tissues. We therefore examined the functional role of the N-and L-type VSCCs in human saphenous veins. 2 Contractile response curves for transmural nerve stimulation (TNS) and for exogenously administered noradrenaline (NA) were obtained in superfused saphenous vein rings. The contractions induced by TNS, but not by NA, were inhibited by 1 jLM tetrodotoxin and by 10 ItM guanethidine. Both responses were substantially reduced by 1 jtM phentolamine, indicating that the contractions evoked by TNS were mediated by endogenous NA released from noradrenergic nerves.3 In the presence of 2 gM w-conotoxin GVIA (omega Conus Geographus toxin, fraction VI A; w-CgTx), a polypeptide with specific inhibitory activity on N-and L-type calcium channels, the neurally evoked contractions were almost completely abolished. In contrast, the responses induced by exogenous NA were not affected by the neurotoxin, thus providing evidence of the exclusive presynaptic action of w-CgTx.4 In the presence of the calcium antagonist verapamil (10 gM), which selectively blocks L-type VSCCs, the contractions induced by both TNS and NA were diminished to the same extent, suggesting that the organic calcium blocker is active only at the postjunctional level. 5 It is concluded that N-type calcium channels are the main pathway of calcium entry controlling the functional responses induced by activating sympathetic nerves; the role of L-type channels appears to be limited to the postjunctional level, modulating smooth muscle contractions.

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