Protein kinase C activity in the nucleus tractus solitarii is critically involved in the acute hypoxic ventilatory response, but is not required for intermittent hypoxia-induced phrenic long-term facilitation in adult rats

Protein kinase C (PKC) is a broadly expressed and critically important signalling protein with a wide range of functional roles, including central components of respiratory control. For example, systemic and targeted administration of PKC inhibitors within the nucleus of the solitary tract (nTS) markedly attenuates peak hypoxic ventilatory responses (HVR). Protein kinase C activation in phrenic motor nucleus has also been implicated in some forms of acute respiratory plasticity, such as phrenic long-term facilitation (pLTF), a persistent enhancement of phrenic motor output following acute intermittent hypoxia. To further examine the role of PKC within the nTS, the selective PKC antagonist bisindolylmaleimide I (BIM I) was microinjected in the area corresponding to the nTS via bilateral osmotic pumps in normoxic adult male Sprague-Dawley rats; control animals received bisindolylmaleimide V (BIM V, inactive analogue). In one series of experiments, hypoxic challenges (fractional inspired ) were conducted in unrestrained animals (n = 8 per group). No differences in baseline ventilation emerged; however, peak HVR was attenuated following BIM I (P < 0.01), primarily owing to reductions in respiratory frequency increases (P < 0.01). In a second series of experiments, integrated phrenic nerve activity was recorded in anaesthetized, vagotomized, paralysed and ventilated rats exposed to three 5 min hypoxic episodes separated by 5 min hyperoxia . During baseline conditions, no differences emerged in phrenic nerve output; however, phrenic nerve output measured during the initial hypoxic exposure was significantly attenuated in BIM I-treated rats (P < 0.01). In contrast, both groups of animals displayed significant pLTF (BIM I versus BIM V; n.s.). Thus, we conclude that PKC activation within the nTS is critically involved in the central response to acute hypoxia, but does not appear to play a role in either eliciting or maintaining pLTF.