CARDIORESPIRATORY RESPONSES TO SYSTEMIC ADMINISTRATION OF A PROTEIN-KINASE-C INHIBITOR IN CONSCIOUS RATS

Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains unde fined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg ip) were assessed by whole body plethysmography during normoxia, hypoxia (10% O-2), and hyperoxia (100% O-2) in unres trained Sprague-Dawley rats. A sustained expiratory time increase occu rred within 8-10 min of injection in room air [mean 44.8 +/- 5.2 (SE) %], was similar to expiratory time prolongations after Ro-32-0432 admi nistration during 100% O-2 (45.5 +/- 8.1%; not significant), and was a ssociated with mild minute ventilation ((V) over dot E) decreases. Hyp ercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32 -0432. During 10% Oa, (V) over dot E increased from 122.6 +/- 15.6 to 195.7 +/- 10.1 ml/min in vehicle-treated rats (P < 0.001). In contrast , marked attenuation of (V) over dot E hypoxic responses occurred afte r Ro-32-0432 [86.2 +/- 6.2 ml/min in room air to 104.1 +/- 7.1 ml/min in 10% O-2; pre- vs. post-Ro32-0432, P < 0.001(analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abo lished in the particulate subcellular fraction of brain tissue after R o-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilato ry reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in s ignal transduction pathways within brain regions underlying respirator y control.