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

Abstract

Apnoeas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, which are the primary peripheral chemoreceptors, and is combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apnoeas but they continue beyond the last apnoea and can persist for hours [i.e. ventilatory and sympathetic long-term facilitation (LTF)]. These long-term effects may be adaptive during acute episodic apnoea, although they may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnoea-like stimuli [i.e. acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc)]. This plasticity did not require chronic intermittent hypoxia preconditioning, was dependent on P2X receptors and protein kinase C, and involved heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) receptors. Reactive oxygen species (O ·¯) were involved in initiating plasticity only; no evidence was found for H O involvement. Angiotensin II and 5-HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic-hypercapnic challenges and prevented the induction of sensory LTF 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, although 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 apnoeas.

Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

“…Furthermore, losartan application in superfused CBs effectively prevents the sensory facilitation caused by intermittent hypercapnic hypoxia but does not reverse this effect when applied afterwards (Roy et al . ). This evidence suggests that Ang II surges and AT 1 R activation during intermittent hypoxia activate a cascade of signalling that is subsequently insensitive to acute AT 1 R blockade.…”

Purinergic signalling and TRPV1 receptors are associated with the carotid body plasticity induced by an apnoea‐like stimulus

“…On the other hand, inhibition of protein kinase C (PKC) showed that the phosphorylation mediated by this protein is a key factor in both induction and maintenance of sLTF (Roy et al . ).…”

“…Roy et al . () used the well‐accepted ex‐vivo carotid body – CSN preparation, which keeps the perfusion pressure, temperature and pH in the carotid bifurcation comparable with that in whole animals. They also used an in‐vivo anaesthetized rat preparation to evaluate the role of TRPV1 receptors in sympathetic sLTF.…”

“…Interestingly, Roy et al . () evaluated the role of TRPV1 receptors using in vivo approaches in response to hyperoxia and hypoxia. This set of experiments showed that in their anaesthetized rat preparations the maintenance of carotid body sLTF is dependent on TRPV1 receptors only under normoxic conditions.…”

“…In conclusion, the set of results obtained by Roy et al . () has advanced our knowledge of the plasticity induced by apnoea‐like stimuli due to activation of P2X and TRPV1 receptors in the CSN terminals from naive rats. Given that upregulation of the carotid body activity may lead to cardiovascular dysfunction, the pharmacological control of purinergic signalling and TRPV1 receptors may be a potential therapeutic target in the control of neurogenic hypertension associated with intermittent apnoea.…”