Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O(2) fraction (FI(O(2))) = 0.10], chronic hypercapnia (inspiratory CO(2) fraction = 0.10), hypoxia-hypercapnia (FI(O(2)) = 0.10, inspiratory CO(2) fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone (P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk (P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 +/- 1.8 mmHg) was significantly (P < 0.01, ANOVA) elevated compared with control conditions (12.1 +/- 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 +/- 0.9 mmHg) or hypercapnia (11.8 +/- 1.3 mmHg). HPV (FI(O(2)) = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control (P < 0.05, ANOVA). Addition of N(omega)-nitro-L-arginine methyl ester (10(-4) M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.

Previous animal studies support the presence of an upper airway reflex mechanism that when blocked by topical anesthesia of the upper airway results in upper airway occlusion. We sought a similar reflex mechanism in humans. Nine normal male volunteers 20 to 28 yr of age underwent 3 successive overnight sleep studies: a control study (C); a study in which selective topical oropharyngeal anesthesia (OPA) was achieved prior to sleep using a 10% lidocaine spray and 0.25% bupivocaine solution; a study in which selective nasal anesthesia (NA) was achieved prior to sleep using a mixture of 2% lidocaine and 0.25% bupivocaine solutions instilled into the nose while the nasal airway was positioned as the most dependent part of the upper airway. Total sleep times were similar during the 3 study nights as were the amounts of slow-wave and rapid-eye-movement (REM) sleep. Obstructive apneas and hypopneas (OAH) differed significantly between the 3 study nights [13(3.8), mean (SEM), during OPA as compared to 3(1.8) during C and 7(2.5) during NA; p less than 0.01 by ANOVA] and were most frequent during REM sleep. Total apneas and hypopneas also differed significantly between the 3 study nights [19(3.9) during OPA as compared to 8(2.1) during C and 14(3.9) during NA; p less than 0.01 by ANOVA]. Movement arousals terminating periods of abnormal respiration also differed significantly [21(6.1) during OPA as compared to 12(3.6) during C and 14(4.6) during NA; p less than 0.05 by ANOVA]. No subject, however, developed clinically significant sleep apnea or significant oxygen desaturation during sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Obstruction of the upper airway (UA) due to collapse of the pharynx is a common event during sleep. When the pharynx narrows, inspiratory efforts generate less airflow, but produce large negative pressures across the wall of the extra-thoracic airway below the site of obstruction. Upper airway negative pressure (UANP) distorts mechanoreceptors in the airway wall, inducing reflex responses including an increase in UA muscle activity and an inhibition of motor drive to the diaphragm (Mathew et al. 1982a,b;Amis et al. 1999). Activation of UA muscles serves to dilate and stabilize the UA while a reduction in diaphragm activity limits the collapsing inspiratory negative transmural pressure to which the UA is subjected. These reflex changes protect and maintain UA patency (Sant'Ambrogio et al. 1995).While the rat is widely used as an experimental animal particularly for neurophysiological and neuropharmacological studies, the reflex responses to upper airway negative pressure have only been briefly explored in this species. Zhang & Bruce (1998) reported that genioglossus muscle activity is excited by UANP but this study did not confirm that the response was reflex in nature by determining the afferent pathway(s). A number of studies performed in other species have found that the superior laryngeal nerve (SLN) is the major afferent pathway mediating the reflex response to UANP (Mathew et al. 1982c;Mathew, 1984;Hwang et al. 1984a). However, other UA afferents, including the glossopharyngeal and trigeminal nerves, have been shown in different studies to contribute to, modify, or even play a dominant role in mediating the response to negative pressure (Mathew et al. 1982c;Hwang et al. 1984a;Horner et al. 1991;Curran et al. 1997). We conducted this study to examine in detail the respiratory responses to UANP in the anaesthetized rat and the role of the SLN as an afferent pathway for these responses.Reflex respiratory response to changes in upper airway pressure in the anaesthetized rat 1. We examined the upper airway (UA) motor response to upper airway negative pressure (UANP) in the rat. We hypothesized that this response is mediated by superior laryngeal nerve (SLN) afferents and is not confined to airway dilator muscles but also involves an increase in motor drive to tongue retractor and pharyngeal constrictor muscles, reflecting a role for these muscles in stabilizing the UA.2. Experiments were performed in 49 chloralose-anaesthetized, tracheostomized rats. Subatmospheric pressure in the range 0 to _30 cmH 2 O was applied to the isolated UA. Motor activity was recorded in separate experiments from the main trunk of the hypoglossal nerve (XII, n = 8), the pharyngeal branch of the glossopharyngeal nerve (n = 8), the medial and lateral branches of the XII (n = 8) and the pharyngeal branch of the vagus (n = 8). Afferent activity was recorded from the whole SLN in six experiments.3. All UA motor outflows exhibited phasic inspiratory activity and this was significantly (P < 0.05) increased by UANP. Tonic end-expiratory acti...

SUMMARY1. The effects of electrical stimulation of sympathetic nerves on sinus nerve chemosensory activity and carotid body blood flow were investigated in anaesthetized cats.2. Two categories, designated as types I and II, of excitatory responses of chemosensory discharges to sympathetic stimulation were distinguished. Type I responses displayed elevations in impulse frequencies which were usually maximal in the initial 10-20 see of stimulation, resisted a-adrenoceptor antagonism induced by phentolamine or phenoxybenzamine and were enhanced after administration ofthe dopamine antagonist, haloperidol. Type II responses showed increases in impulse frequencies which became more pronounced as stimulation progressed. These responses were susceptible to a-adrenoceptor blockade, were unaffected by haloperidol administration and were usually recorded during systemic hypotension.3. Inhibitory changes due to activation ofsympathetic fibres were recorded in 10O of chemosensory preparations. These effects were usually either abolished or replaced by type I excitatory responses after haloperidol administration.4. Sympathetic stimulation caused reductions of carotid body blood flow during both natural and artificial perfusion of the organ. This effect was abolished or considerably attenuated by x-adrenoceptor antagonism and was unaffected by haloperidol administration.5. Possible mechanisms which could account for the influences of sympathetic stimulation on chemoreceptor activity and carotid body blood flow are discussed. It is concluded that inhibitory and type I excitatory responses probably arise from activation of sympathetic fibres with non-vascular terminations within the carotid body. Type II excitatory responses are most likely due to blood flow changes.

Previous studies support the presence of an upper airway reflex mechanism that contributes to the maintenance of upper airway patency during sleep. We investigated the possibility that interference with this reflex mechanism contributes to the development of obstructive sleep apnea. Eight otherwise asymptomatic snorers (seven male and one female), age 39 +/- 5.3 yr (mean +/- SEM), underwent overnight sleep studies on three successive nights. An acclimatization night was followed by two study nights randomly assigned to control (C) and oropharyngeal anesthesia (OPA). On the OPA night topical anesthesia was induced using 10% lidocaine spray and 0.25% bupivacaine gargle. A saline placebo was used on night C. All subjects slept well on both study nights (mean sleep duration was 6.2 h on both study nights), and sleep stage distribution was similar on both nights. Obstructive apneas and hypopneas (OAH) rose from 114 +/- 43 during C to 170 +/- 49 during OPA (p less than 0.02). Central apneas and hypopneas (CAH) were unchanged between the two nights (8 +/- 4.9 versus 7 +/- 3). The duration of OAH was similar on both study nights (20 +/- 1.9 s during C versus 20 +/- 1.5 s during OPA). The frequency of movement arousals terminating OAH tended to be higher during OPA (7 +/- 2.9/h) than during C (3 +/- 0.7); P = NS. The frequency of oxyhemoglobin desaturations was also higher during OPA (5 +/- 2.1/h) than during C (3 +/- 1.4), p less than 0.07.(ABSTRACT TRUNCATED AT 250 WORDS)