Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor dependent sensory long-term facilitation in naïve carotid bodies

Abstract

Apneas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, the primary peripheral chemoreceptors, and combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apneas but they continue beyond the last apnea and can persist for hours (i.e. ventilatory and sympathetic LTF). These long-term effects may be adaptive during acute episodic apnea, but may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnea-like stimuli i.e. acute intermittent hypoxia with concurrent hypercapnia (AIH-Hc). This plasticity did not require chronic intermittent hypoxia (CIH) preconditioning, was dependent on P2X receptors and PKC, and involved heat-sensitive TRPV1 receptors. ROS (O₂·⁻) were involved in initiating plasticity only; no evidence was found for H₂O₂ involvement. Angiotensin II and 5HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic-hypercapnic challenges and prevented induction of sLTF but, if applied after AIH-Hc, failed to reduce plasticity-associated activity. Conversely, TRPV1 receptor antagonism had no effect on responses to individual hypoxic-hypercapnic challenges but reduced plasticity-associated activity by ∼50%. Further, TRPV1 receptor antagonism in vivo reduced sympathetic LTF caused by AIH-Hc, but only if the CBs were functional. These data demonstrate a new mechanism of CB plasticity and suggest P2X-TRPV1 dependent sensory LTF as a novel target for pharmacological intervention in some forms of neurogenic hypertension associated with recurrent apneas.

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