Modulation of the hypoxic ventilatory response by Ca 2+-dependent and Ca 2+-independent protein kinase C in the dorsocaudal brainstem of conscious rats

Abstract

Protein kinase C (PKC) activation in the nucleus tractus solitarii (NTS) is critical for mounting an appropriate hypoxic ventilatory response (HVR). Furthermore, hypoxia elicits translocation of both Ca 2+-dependent and Ca 2+-independent PKC isoforms in the NTS. However, the relative functional contribution of such PKC isoforms in mediating HVR is unclear.To study these issues, chronically instrumented adult Sprague–Dawley rats underwent hypoxic challenges (10% O 2 balance in N 2) following dorsocaudal brainstem microinjections of the selective Ca 2+-dependent PKC inhibitor Gö 6976 (10 mmol in 1 μl). Compared with vehicle, Gö 6976 did not modify normoxic ventilation but maximally attenuated HVR by 38.4±6.7% ( n=9; P<0.01), with similar contributions from tidal volume and respiratory frequency. In seven additional animals, when the non Ca 2+-selective PKC blocker BIM I was concurrently microinjected with Gö 6976, further reductions in peak ventilatory responses to hypoxia occurred ( P<0.04). When BIM V, the inactive analog, was microinjected with Gö 6976, the magnitude of HVR attenuation was unchanged ( n=6; Gö 6976 vs. Gö 6976+BIM V: P=NS). We conclude that in the dorsocaudal brainstem, PKC-mediated components of HVR involve activation of both Ca 2+-dependent and Ca 2+-independent PKC isoforms.