Am. J. Respir. Crit. Care Med., Volume 159, Number 3, March 1999, 968-973

Protein Kinase C Modulates Ventilatory Patterning in the Developing Rat

HARI P. R. BANDLA, NARONG SIMAKAJORNBOON, GAVIN R. GRAFF, and DAVID GOZAL

Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Departments of Pediatrics and Physiology, and Inter-Departmental Neuroscience and Cellular and Molecular Biology Programs, Tulane University School of Medicine, New Orleans, Louisiana

Protein kinase C (PKC) mediates important components of signal transduction pathways underlying neuronal excitability and modulates respiratory timing mechanisms in adult rats. To determine ventilatory effects of systemic PKC inhibition during development, whole-body plethysmographic recordings were conducted in 2-3-d (n = 11), 5-6-d (n = 19), 10-12-d (n = 14), and 20-21-d-old (n = 14) rat pups after treatment with vehicle and Ro 32-0432 (100 mg/kg, intraperitoneally). Ro 32-0432 decreased minute ventilation ( E) by 51.0 ± 5.5% (mean ± SEM) in youngest pups (p < 0.01) but only 19.1 ± 6.8% in 20-21-d-old pups (p < 0.01). E decreases were always due to frequency reductions with tidal volume (VT) remaining unaffected. Respiratory rate decreases primarily resulted from marked expiratory time (TE) prolongations being more pronounced in 2-3-d-old (115.5 ± 28.9%) compared with 20-21-d old (36.6 ± 10.9%; p < 0.002 analysis of variance [ANOVA] ). Expression of the PKC isoforms , , , , , and µ was further examined in brainstem and cortex by immunoblotting and revealed different patterns with postnatal age and location. We conclude that endogenous PKC inhibition elicits age-dependent ventilatory reductions which primarily affect timing mechanisms rather than changes in volume drive. This effect on ventilation abates with increasing postnatal age suggesting that the neural substrate mediating overall respiratory output may be more critically dependent on PKC activity in the immature animal.

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