Serotonin 5-HT3-receptor antagonist GR 38032F suppresses sleep apneas in rats.

The effects of administration of GR38032F, a 5-HT3 receptor antagonist, on spontaneous sleep apneas were studied in adult Sprague-Dawley rats by monitoring sleep, respiration and blood pressure for 6 hours. Intraperitoneal injection of GR38032F (1 mg/kg) suppressed spontaneous central apneas during non-rapid-eye-movement (NREM) and especially during rapid-eye-movement (REM) sleep. This effect was associated with increased respiratory drive but did not cause cardiovascular changes at the dose tested. The suppressive action of GR38032F on spontaneous sleep apneas is analogous to findings in anesthetized rats in which 5-HT and 2-methyl-5-HT provoked central apneas that were antagonized by GR38032 (Yoshioka et al, JPET 1992; 260:917-924). Our data implicate 5-HT3 receptor systems in determining sleep-related respiratory drive and apnea expression in rats, effects which are most probably mediated by vagal afferents.

Diazepam suppresses sleep apneas in rats.

To test the respiratory effects of benzodiazepines in an established animal model of central apnea, we administered nonhypnotic and hypnotic doses of diazepam to nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded following intraperitoneal injection of: (1) saline; (2) 0.05 mg/kg diazepam; or (3) 5 mg/kg diazepam. Normalized inspiratory minute ventilation increased significantly during wakefulness and non-rapid eye movement (non-REM) sleep following each dose of diazepam (p < 0.003 in each case) and following the highest dose during rapid eye movement (REM) sleep (p = 0.01). In accord with this respiratory stimulation, non-REM-related spontaneous and post-sigh apnea expression decreased following each dose of diazepam (p = 0.006 to 0.04), but REM-related apnea expression was unaffected despite significant respiratory stimulation. The durations of non-REM and REM sleep were unaffected by the low dose, but following 5 mg/kg of diazepam non-REM sleep was increased (p = 0.03) and REM sleep was decreased (p = 0.009). We conclude that both hypnotic and non-hypnotic doses of benzodiazepines may be associated with suppression of sleep-related central apnea. We further conclude that non-REM and REM-related apneas arise from at least partially distinct mechanisms.

Cardiopulmonary interactions following REM sleep deprivation in Sprague-Dawley rats.

We characterized the effects of 48 h of rapid-eye-movement (REM) sleep deprivation on cardiovascular and respiratory variables and on sleep-related cardiopulmonary interactions in adult male Sprague-Dawley rats. Rats were instrumented for monitoring EEG, EMG, and aortic blood pressure. Respiratory rate and minute ventilation were measured by unrestrained single-chamber plethysmography. By using radiotelemetry to monitor blood pressure we clearly demonstrated progressive decreases in mean blood pressure with transitions from wakefulness to non-rapid-eye-movement and REM sleep which were unaffected by REM sleep deprivation. Mirror-image state-dependent increases in heart period suggest that baroreflexes were augmented during sleep with respect to wakefulness. REM sleep deprivation was also associated with lower blood pressure and longer heart period over all sleep/wake states, although this achieved statistical significance only during REM sleep and only during the first hour of recovery sleep. These cardiovascular changes coupled with the observed decreases in respiratory rate and minute ventilation suggest a further augmentation of baroreflexes following REM sleep deprivation.

Cardiopulmonary control in sleeping Sprague-Dawley rats treated with hydralazine.

To test the hypothesis that hydralazine can suppress spontaneous sleep-related central apnea, respiratory pattern, blood pressure, and heart period were monitored in Sprague-Dawley rats. In random order and on separate days, rats were recorded after intraperitoneal injection of 1) saline or 2) 2 mg/kg hydralazine. Normalized minute ventilation (NVI) declined significantly with transitions from wake to non-rapid-eye-movement (NREM) sleep (-5.1%; P = 0.01) and rapid-eye-movement (REM) sleep (-4.2%; P = 0.022). Hydralazine stimulated respiration (NVI increased by 21%; P < 0.03) and eliminated the effect of state on NVI. Blood pressure decreased by 17% after hydralazine, and the correlation between fluctuations in mean blood pressure and NVI changed from strongly positive during control recordings to weakly negative after hydralazine (P < 0.0001 for each). Postsigh and spontaneous apneas were reduced during NREM and REM sleep after hydralazine (P < 0.05 for each). This suppression was strongly correlated with the reduction in blood pressure and with the degree of respiratory stimulation. We conclude that mild hydralazine-induced hypotension leads to respiratory stimulation and apnea suppression.

Protoveratrines A and B increase sleep apnea index in Sprague-Dawley rats.

The action of protovertarines A and B, which stimulate carotid sinus baroreceptors and vagal sensory endings in the heart as well as pulmonary bed, were assessed on spontaneous and postsigh central sleep apneas in freely moving Sprague-Dawley rats. During the 6-h recording period, animals were simultaneously monitored for sleep by using electroencephalogram and electromyogram recordings, for respiration by single-chamber plethysmography, and for blood pressure and heart period by using radiotelemetry. After administration of 0.2, 0.5, or 1 mg/kg sc of protoveratrines, cardiopulmonary changes lasting at least 6 h were observed in all three behavioral states [heart period increased up to 23% in wakefulness, 21% in non-rapid-eye-movement (non-REM) sleep, and 20% in REM sleep; P < 0.005 for each]. At the same time, there was a substantial increase in the number of spontaneous (375% increase; P = 0.04) and postsigh (268% increase, P = 0.0002) apneas. Minute ventilation decreased by up to 24% in wakefulness, 25% in non-REM, and 35% in REM sleep (P < 0.05 for each). We conclude that pharmacological stimulation of baroreflexes promotes apnea expression in the sleeping rat.

Hydralazine reduces elevated sleep apnea index in spontaneously hypertensive (SHR) rats to equivalence with normotensive Wistar-Kyoto rats.

The effects of lowering blood pressure (BP) by hydralazine (HY) (2 mg/kg) on spontaneous (SA) and post-sigh (PSA) sleep apneas have been studied in spontaneously hypertensive (SHR) rats by monitoring their respiration and sleep by the EEG for 6 hours. Normotensive Wistar-Kyoto (WKY) rats, from which the SHR rat strain was derived, were used as an appropriate control. The SHR rats had more SA (p < 0.02) and PSA (p < 0.0001) apneas/hour than WKY rats during nonrapid eye movement sleep and their mean BP was higher by 40 mm Hg (p < 0.0001) than WKY rats. Administration of HY to SHR rats equalized their BP with the arterial pressure of WKY rats and reduced the SA and the PSA apneas/hour to equivalence with WKY normotensive rats. These results demonstrate that even in the context of lifelong hypertension, acute normalization of BP significantly reduces sleep apneas in rats. They further suggest that improved management of BP may be clinical benefit to patients with apnea who have long-standing hypertension.