REACTIVE OXYGEN RADICALS AND GASEOUS TRANSMITTERS IN THE CAROTID BODY ACTIVATION BY INTERMITTENT HYPOXIA

Sleep apnea is a prevalent respiratory disease characterized by periodic cessation of breathing during sleep causing intermittent hypoxia (IH). Sleep apnea patients and rodents exposed to IH exhibit elevated sympathetic nerve activity and hypertension. A heightened carotid body (CB) chemo reflex has been implicated in causing autonomic abnormalities in IH treated rodents and in sleep apnea patients. The purpose of this article is to review the emerging evidence showing that interactions between reactive oxygen species (ROS) and gaseous transmitters as a mechanism causing hyperactive CB by IH. Rodents treated with IH exhibit markedly elevated ROS in the CB, which is due to transcriptional upregulation of pro-oxidant enzymes by hypoxia-inducible factor (HIF)-1, and insufficient transcriptional regulation of anti-oxidant enzymes by HIF-2. ROS, in turn, increases cystathionine-γ-lyase (CSE)-dependent H(2)S production in the CB. Blockade of H(2)S synthesis prevents IH-evoked CB activation. However, the effects of ROS on H(2)S production is not due to direct effects on CSE enzyme activity, rather due to inactivation of heme oxygenase-2 (HO-2), a carbon monoxide (CO) producing enzyme. CO inhibits H(2)S production through inactivation of CSE by PKG-dependent phosphorylation. During IH, reduced CO production resulting from inactivation of HO-2 by ROS releases the inhibition of CO on CSE thereby increases H(2)S. Inhibiting H(2)S synthesis prevented IH-evoked sympathetic activation and hypertension.