The Effect of Systemic Protein Kinase C (PKC) Inhibition on Hypoxic Ventilatory Response Modulation is Developmentally Regulated in the Rat. ♦ 1934

Abstract

In the adult rat, PKC activity mediates important excitatory components of hypoxic chemotransduction (Gozal et al, J. Appl. Physiol. 1998). Thirty min hypoxic challenges with 10% O2 were performed before and after systemic PKC inhibition with Ro 32-0432 (i.p. 100 mg/kg). Ventilatory responses were assessed using whole-body plethysmography in 2-3 d (n=11), 5-6 d (n=19), 10-12 d (n=14), and 20 d (n=14) rat pups. After vehicle, age-dependent increases in peak VE occurred and were 33.3±8.7 [SE], 41.1±11.0, 60.4±9.0, and 94.7±10.0% of baseline room air values prior to hypoxia respectively (p<0.001). After Ro 32-0432 treatment, although normoxic VE was reduced by Ro 32-0432, peak VE increases with hypoxia were not affected in younger animals (55.1±9.7%, p-NS). However, with increasing post-natal age, progressive attenuation of peak VE hypoxic responses occurred (27.2±11.8% in 5-6 d, 15.8±6.8% in 10-12 d, and 13.7±8.8% in 20 d; p < 0.001). The VE decrease at 30 min hypoxia was less prominent in older animals after vehicle (p<0.02). In contrast, after Ro 32-0432, the ventilatory decrease during late hypoxia was enhanced as post-natal age increased (p < 0.05). Western blots of protein equivalents of lysates from the dorsal brainstem revealed increased expression of PKC isoforms b, g, and d with age. We conclude that PKC-mediated contributions to the early and late hypoxic ventilatory responses exhibit age-dependent behavior which parallels PKC expression in the dorsal brainstem. We speculate that PKC ontogeny may account, at least in part, for the characteristic evolution of hypoxic ventilatory responses in many mammalian species.