MODULATION OF THE HYPOXIC VENTILATORY RESPONSE BY CA2-DEPENDENT AND CA2+-INDEPENDENT PROTEIN-KINASE-C IN THE DORSOCAUDAL BRAIN-STEM OF CONSCIOUS RATS()

Protein kinase C (PKC) activation in the nucleus tractus solitarii (NT S) is critical for mounting an appropriate hypoxic ventilatory respons e (HVR). Furthermore, hypoxia elicits translocation of both Ca2+-depen dent and Ca2+-independent PKC isoforms in the NTS. However, the relati ve functional contribution of such PKC isoforms in mediating HVR is un clear. To study these issues, chronically instrumented adult Sprague-D awley rats underwent hypoxic challenges (10% O-2 balance in N-2) follo wing dorsocaudal brainstem microinjections of the selective Ca2+-depen dent PKC inhibitor Go 6976 (10 mmol in 1 mu l). Compared with vehicle, Go 6976 did not modify normoxic ventilation but maximally attenuated HVR by 38.4 +/- 6.7% (n = 9; P < 0.01), with similar contributions fro m tidal volume and respiratory frequency. In seven additional animals, when the non Ca2+-selective PKC blocker BIM I was concurrently microi njected with Go 6976, further reductions in peak ventilatory responses to hypoxia occurred (P < 0.04). When BIM V, the inactive analog, was microinjected with Go 6976, the magnitude of HVR attenuation was uncha nged (n = 6; Go 6976 vs. Go 6976 + BIM V: P = NS). We conclude that in the dorsocaudal brainstem, PKC-mediated components of HVR involve act ivation of both Ca2+-dependent and Ca2+-independent PKC isoforms. (C) 1998 Elsevier Science B.V. All rights reserved.