Carotid chemoafferent activity is not necessary for all phrenic long-term facilitation following acute intermittent hypoxia

Abstract

Phrenic long-term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH) or episodic carotid chemoafferent neuron activation. Surprisingly, residual pLTF is expressed in carotid denervated rats. However, since carotid denervation eliminates baroreceptor feedback and causes profound hypotension during hypoxia in anesthetized rats, potential contributions of these uncontrolled factors or residual chemoafferent neuron activity to residual pLTF cannot be ruled out. Since ATP is necessary for hypoxic carotid chemotransduction, we tested the hypothesis that functional peripheral chemoreceptor denervation (with intact baroreceptors) via systemic P2X receptor antagonism blocks hypoxic phrenic responses and AIH-induced pLTF in anesthetized rats. Pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 100 mg/kg i.v.), a non-selective P2X receptor antagonist, was administered to anesthetized, vagotomized, paralyzed and ventilated male Sprague–Dawley rats prior to AIH (3, 5 min episodes of 10% O2; 5 min intervals). Although PPADS strongly attenuated the short-term hypoxic phrenic response (20±4% vs. 113±15% baseline; P < 0.001), pLTF was reduced but not eliminated 60 min post-AIH (25±4% vs. 51±11% baseline; n = 8 and 7, respectively; P < 0.002). Thus, AIH initiates residual pLTF out of proportion to the diminished hypoxic phrenic response and chemoafferent neuron activation. Although the mechanism of residual pLTF following functional chemo-denervation remains unclear, possible mechanisms involving direct effects of hypoxia on the CNS are discussed.

Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS

“…In normal rats, moderate AIH (35–45 mmHg) elicits approximately 60% pLTF at 60 min post-hypoxia (Baker-Herman and Mitchell, 2002; Baker-Herman and Mitchell, 2008; Hoffman et al, 2010; MacFarlane and Mitchell, 2008; Sibigtroth and Mitchell, 2011), although this value decreases in middle-aged (~1year) male rats (Zabka et al, 2001). Here, we investigated AIH-induced pLTF at several ages in MT and age-matched WT littermates (Figures 3A & 3B).…”

Experimental protocols and preparations to study respiratory long term facilitation

“…It was subsequently established that intermittent and not sustained hypoxia was critical for initiating LTF (Baker & Mitchell, 2000), and that the role of this stimulus in the development of LTF was mediated primarily by inspiratory activation mediated by feedback from the carotid bodies (Bach & Mitchell, 1996). These initial findings were challenged subsequently, because carotid body denervated rats exhibited LTF, albeit at a reduced amplitude, indicating that the carotid body was not essential to elicit LTF (Bavis & Mitchell, 2003;Sibigtroth & Mitchell, 2010). Likewise, intermittent hypoxia was shown to be effective in eliciting LTF even when it resulted in the depression of inspiration in post-natal rats (Tadjalli et al, 2007;Tadjalli et al, 2008).…”

Similarities and differences in mechanisms of phrenic and hypoglossal motor facilitation

“…Peripheral chemoreceptor feedback is proposed to be the relevant LTF stimulus since intermittent electrical stimulation of the carotid sinus nerve (without hypoxia) elicits a serotonin-dependent increase in inspiratory burst amplitude in multiple respiratory motor pools (Mateika and Fregosi, 1997, Fregosi and Mitchell, 1994; Millhorn et al, 1980). However, additional direct effects of hypoxia are indicated since a modest phrenic facilitation is elicited in carotid chemoreceptor denervated rats (Bavis and Mitchell, 2003; Sigbigtroth and Mitchell, 2011). …”

“…Similar results have been demonstrated for other metabotropic receptors coupled to Gs proteins, such as 5-HT 7 receptors (Hoffman and Mitchell, 2008; Hoffman et al, 2011; Terada and Mitchell, 2011). Precise interactions between A2A (and/or 5-HT 7 ) and 5-HT 2 receptor pathways may be influenced by the severity of the hypoxic exposure (Terada and Mitchell, 2011) or integrity of sensory inputs (Sigbigtroth and Mitchell, 2011), but this issue has not been completely explored.…”