Modulation of hypoxic ventilatory response by systemic platelet-activatingfactor receptor antagonist in the rat

Platelet activating factor (PAF) has recently emerged as an important modul ator of neuronal excitability by enhancing synaptic glutamate release. Sinc e PAF receptors (PAFR) are ubiquitously distributed in the brain, we hypoth esized that PAF may play a role in respiratory control. To examine this iss ue, hypoxic (10% O-2, for 15 min, n=14) and hypercapnic (5% CO2, for 30 min , n=6) challenges were performed in chronically-instrumented, unrestrained adult rats following administration of the pre-synaptic PAFR antagonist BN5 2021 (i.p. 20 mg/kg in 0.5 ml) or vehicle (Veh). In normoxia, BN52021 elici ted VT decreases and corresponding f increases such that minute ventilation ((V) over dot E)was unaffected. During hypercapnia, peak (V) over dot E in creased similarly after both treatments (103 +/- 18% in BN52021 vs. 94 +/- 19% in Veh, p-NS). In contrast, significant reductions in the peak hypoxic VE response occurred after BN52021 (42 +/- 10% vs. 104 +/- 18% in Veh, P < 0.002). BN52021 increased normoxic arterial blood pressure and decreased he art rate. However, hypoxia-induced chronotropic responses were attenuated a nd depressor responses were enhanced by BN52021. We further examined protei n kinase C (PKC) translocation patterns during acute hypoxia after systemic BN52021 administration. Activation of PKC beta and delta was blocked by BN 52021, PKC gamma was attenuated, with no effects on PKC alpha, epsilon, the ta, iota, mu, and zeta. We conclude that systemic administration of a PAFR antagonist attenuates cardioventilatory recruitment to hypoxia and selectiv ely attenuates activation of PKC in the rat brainstem. We speculate that en hanced regional PAF production and release during hypoxic conditions may co ntribute important excitatory inputs and signal transduction pathways withi n neuronal structures underlying cardiovascular and respiratory control. (C ) 1998 Elsevier Science B.V. All rights reserved.