Time-dependent hypoxic ventilatory responses in rats: effects of ketanserin and 5-carboxamidotryptamine

We hypothesized that the 5-hydroxytryptamine (5-HT) active drugs ketanserin and 5-carboxamidotryptamine (5-CT) would modulate time-dependent hypoxic phrenic and hypoglossal responses, including1) short-term hypoxic response,2) posthypoxia frequency decline (PHFD), and 3) long-term facilitation (LTF) of respiratory motor output. Phrenic and hypoglossal nerve activities were recorded in urethan-anesthetized, paralyzed, vagotomized, and artificially ventilated rats pretreated either with ketanserin (5-HT_2A/C antagonist; 2 mg/kg iv), 5-CT (5-HT_1A/B agonist; 10 μg/kg iv), or saline (sham). Rats were exposed to three 5-min episodes of hypoxia [fractional inspired O₂($F{I}_{O_2}$ ) = 0.11], separated by 5 min of hyperoxia ($F{I}_{O_2}$ = 0.5). During hypoxia, ketanserin augmented phrenic but not hypoglossal burst amplitude; 5-CT had no effect. Both drugs accentuated PHFD. Ketanserin blocked phrenic LTF; hypoglossal LTF was not apparent, even in sham-treated rats. 5-CT reversed LTF, resulting in a long-lasting depression of phrenic burst frequency and amplitude without effect on hypoglossal burst amplitude. The data suggest that1) 5-HT_2A/C receptor activation modulates the short-term hypoxic phrenic response and PHFD and is necessary for LTF; and 2) 5-CT may affect time-dependent hypoxic ventilatory responses by reducing serotonin release via 5-HT_1A/Bautoreceptor activation.