Phrenic long-term facilitation following acute intermittent hypercapnic-hypoxia in rats

Phrenic long-term facilitation (pLTF) is a form of respiratory motor plasticity, expressed as a lasting increase in phrenic nerve activity following acute intermittent hypoxia (AIH). Whereas AIH also elicits ventilatory LTF (vLTF) in unanesthetized rats, concurrent hypercapnia (elevated background or episodic hypercapnia) is required for vLTF in humans. One major difference between rodent and human studies is the diurnal phase (nocturnal rats vs. diurnal humans). Diurnal phase regulates pLTF magnitude and mechanism; 15, 1-min hypoxic episodes elicit more robust pLTF in the rest (∼130%) versus active phase (∼30%) in rats. Thus, we assessed differences in pLTF elicited by acute intermittent hypercapnic-hypoxia (AIHH) versus AIH in mid-rest versus mid-active phase rats. In anesthetized, paralyzed, vagotomized, and ventilated male Sprague-Dawley rats (n = 7 per group), pLTF was assessed following moderate AIH (arterial Po₂ range 35-49 mmHg; 15, 1-min episodes) or AIHH (arterial Pco₂ range 46-50 mmHg) in the mid-rest (noon) and mid-active phases (midnight). In contrast to expectations, mid-rest phase pLTF 90-min post-AIHH (64 ± 45%) was less than that elicited by AIH (132 ± 93%; P < 0.001). As reported previously, AIH-induced pLTF was lower in mid-active (46 ± 47%; P = 0.050) versus mid-rest rats; however, AIHH-induced pLTF was not significantly different in mid-rest versus mid-active phase rats (37 ± 28%; P = 0.20), and there was no longer a significant difference between AIH versus AIHH in the active phase (P = 0.650). Thus, adding hypercapnia to an AIH protocol suppresses pLTF in anesthetized rats exclusively in the mid-rest, but not mid-active phase of the diurnal cycle. Possible mechanisms for hypercapnia and time-of-day effects are discussed.NEW & NOTEWORTHY Diurnal variations in acute intermittent hypoxia (AIH)-induced respiratory plasticity were evident in young, male rats, with robust phrenic long-term facilitation (pLTF) during their mid-rest phase and reduced pLTF during the mid-active phase. Surprisingly, adding hypercapnia (AIHH) suppressed pLTF during the mid-rest phase, with minimal impact during the mid-active phase. These results contrast with diurnal humans, where hypercapnia is necessary for ventilatory LTF, revealing species and time-of-day-dependent mechanisms that shape AIH efficacy.