Cheryl K. Pickett

Respiration during sleep in normal man.

Respiratory volumes and timing have been measured in 19 healthy adults during wakefulness and sleep. Minute ventilation was significantly less (p less than 0.05) in all stages of sleep than when the subject was awake (7.66 +/- 0.34(SEM) 1/min), the level in rapid-eye-movement (REM) sleep (6.46 +/- 0.29 1/min) being significantly lower than in non-REM sleep (7.18 +/- 0.39 1/min). The breathing pattern during all stages of sleep was significantly more rapid and shallow than during wakefulness, tidal volume in REM sleep being reduced to 73% of the level during wakefulness. Mean inspiratory flow rate (VT/Ti), an index of inspiratory drive, was significantly lower in REM sleep than during wakefulness or non-REM sleep. Thus ventilation falls during sleep, the greatest reduction occurring during REM sleep, when there is a parallel reduction in inspiratory drive. Similar changes in ventilation may contribute to the REM-associated hypoxaemia observed in normal subjects and in patients with chronic obstructive pulmonary disease.

Obstructive Sleep Apnea in Hypothyroidism

To determine the incidence and frequency of sleep apnea in persons with hypothyroidism, 11 consecutive patients with newly diagnosed disease were studied before and during thyroid hormone replacement therapy. Nine patients had episodes of apnea, with the number of episodes per hour of sleep ranging from 17 to 176 (mean, 71.8). Six of the nine patients were obese and had 99.5 episodes per hour compared with 16.3 episodes per hour in the 3 nonobese patients (p less than 0.02). After 3 to 12 months of thyroxine replacement therapy, mean apnea frequency decreased from 71.8 +/- 18.0 (SE) to 12.7 +/- 6.1 episodes per hour, without reduction in body weight. There were fewer changes in sleep stage per hour during treatment (22.1 +/- 4.9) than pretreatment (57.6 +/- 14.5). Carbon dioxide response tests done under non-loaded and flow-resistive loaded conditions before and during thyroxine replacement therapy showed increases in the loaded respiratory effort and ventilation during thyroxine treatment. Sleep apnea episodes are common in persons with untreated hypothyroidism, even with normal lung function. Thyroxine replacement therapy decreases apnea frequency, even without change in body weight.

Spontaneous hypoxaemia and right ventricular hypertrophy in fast growing broiler chickens reared at sea level

1. At 6 weeks of age, the time of most rapid body growth, fast growing broiler chickens showed more right ventricular hypertrophy than slower growing chickens. 2. The degree of right ventricular hypertrophy was directly related to blood haematocrit and indirectly related to arterial oxygen saturation (estimated in the chickens using an ear oximeter designed for man). 3. When oxygen saturation was estimated sequentially from 6 to 17 weeks of age, mean oxygenation improved with age, partly due to the death of the chickens with the worst saturations, but also because of an improvement in oxygenation of the survivors.

Improved arterial oxygenation with feed restriction in rapidly growing broiler chickens

1. Rapidly growing broiler chickens fed ad lib. until 56 days, but feed restricted until 60 days of age, had higher arterial oxygen saturations, lower respiratory frequencies, total ventilations that were not different, and higher tidal volumes compared to those fully fed for 56 days. 2. Arterial oxygen saturation correlated negatively with respiratory frequency, but was not related to total ventilation or tidal volume. 3. Hypoventilation appeared not to be the cause of arterial oxygen desaturation. 4. Arterial oxygen desaturation correlated with the degree of right ventricular hypertrophy.

Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium.

Increased adherence of sickle red blood cells (RBC) to endothelium is implicated as an initiating event of vaso‐occlusion in sickle cell disease. Although much is known about the humoral influences of this interaction, there has been little investigation regarding endothelial contributions. Endothelial derived nitric oxide (NO) inhibits adhesion of platelets and leukocytes to endothelium and decreases expression of VCAM‐1, an endothelial adhesion site implicated in sickle RBC/endothelial adherence. However, whether NO inhibits RBC adherence to endothelium is unexplored. We tested this hypothesis with endothelial monolayers exposed to RBC from normal (Hb AA) and sickle cell (Hb SS) volunteers in a parallel plate flow chamber. To decrease NO production, endothelial monolayers were exposed to 100 μM nitro‐L‐arginine (NLA), an inhibitor of nitric oxide synthase, resulting in an 87% increase in normal RBC adherence (P = 0.002). Because adherence of normal RBC to endothelium was low, the effect of DETA‐NO, an NO donor, was tested after activation of endothelium with TNF‐α increased adherence by 130% (P < 0.001). Subsequent addition of 2 mM DETA‐NO produced a 75% decrease in adherence of normal RBC to endothelium (P = 0.03). At baseline, sickle RBC were significantly more adherent than normal RBC (P < 0.001) and DETA‐NO decreased sickle RBC adherence by 54% (P = 0.04). Thus, NO inhibits both normal and sickle RBC adherence to endothelium. Strategies that enhance NO activity may be therapeutic in sickle cell disease. Am. J. Hematol. 63:200–204, 2000.

Decreased carotid body hypoxic sensitivity in chronic hypoxia: role of dopamine

Previously we showed that prolonged exposure to severe hypoxia produces decreased peripheral chemoreceptor responsiveness to hypoxia and attenuates central nervous system (CNS) chemosensory translation, which together may contribute to the decreased hypoxic ventilatory response (HVR) in chronic hypoxia. In this study, we sought to determine whether the central or peripheral activity of endogenous dopamine modulates this decreased HVR. We examined the effects of peripheral and central dopamine receptor blockade on HVR and carotid sinus nerve (CNS) response to hypoxia in controls and in cats exposed to a simulated altitude of 5500 m for 3 weeks. Domperidone increased CSN response to hypoxia in hypoxic cats to levels similar to those observed in controls. HVR was also augmented by domperidone in hypoxic cats, but remained below that of controls. As a result, the CNS chemosensory translation remained reduced in hypoxic animals. We further treated animals with haloperidol. However, this combined treatment with domperidone and haloperidol led to no further increase in CSN or ventilatory responses to hypoxia, or in CNS chemosensory translation in hypoxic cats. Thus, decreased HVR in hypoxic cats is mediated both by depression of hypoxic sensitivity of the carotid body, which is largely dopaminergic, and by decreased CNS chemosensory translation which must involve non-dopaminergic mechanisms.

Possible Gender Differences in the Effect of Exercise on Hypoxic Ventilatory Response

Gender differences in resting ventilation and hypoxic ventilatory response (HVR) have been reported. Ventilation and HVR are closely related to changes in metabolic rate in men. However, it is unclear whether there is a comparable relationship between metabolic rate and ventilation or HVR in women. We studied 13 men and 12 women to determine whether exercise-induced increases in metabolic rate influenced ventilation, HVR, and hypercapnic ventilatory response (HCVR) differently in men and women. Minute ventilation per unit metabolic rate was higher (lower end-tidal PCO2) in women than men during rest and mild exercise. Resting HVR values were similar in men and women. With mild, exercise-induced increases in O2 consumption (24 +/- 4% in men and 27 +/- 2% in women, p = NS), HVR increased in men (p less than 0.05) but not in women. Moderate exercise-induced increases in O2 consumption (313 +/- 13% in men and 330 +/- 13% in women, p = NS), raised hypoxic responses in both sexes. HCVR values were similar in men and women at rest and during mild exercise. Moderate exercise increased HCVR equally in the sexes. Thus the higher resting ventilation and lesser change in HVR during mild exercise suggested that women were less sensitive to mild metabolic rate stimulation than men.

Combined effects of female hormones and exercise on hypoxic ventilatory response

Mild elevations in metabolic rate may influence hypoxic ventilatory response (HVR) differently in men and women. The possible involvement of the female hormones in accounting for this gender difference is supported by observations that mild exercise raised HVR in ovariectomized women treated with estrogen and progestin but not in the same women treated with placebo (Regensteiner et al., 1989). We compared the effects of mild exercise on HVR in 12 women in the follicular phase vs the luteal phase of the menstrual cycle and during MPA (medroxyprogesterone acetate, 20 mg tid) vs placebo treatment. End-tidal PCO2 fell in the luteal compared to the follicular phase and in the follicular MPA compared to the follicular placebo condition. Resting HVR was similar in subjects in the follicular versus the luteal phases of the menstrual cycle and in MPA-treated vs placebo-treated subjects at either the existing (eucapnia) or follicular placebo (normocapnia) end-tidal PCO2. Mild exercise increased expired ventilation but not HVR in placebo-treated subjects in the follicular or luteal placebo conditions. In MPA-treated subjects, exercise raised HVR in the luteal phase (P less than 0.05) and tended to increase HVR in the follicular phase (P = 0.08). The increase in HVR with exercise was greater in MPA-treated subjects than in women given placebo (delta rest to exercise = 26% vs 9%, P less than 0.05). We concluded that elevations in progestin levels achieved by administering progestin in the luteal phase of the menstrual cycle potentiated the effect of metabolic rate on HVR.

Short‐Term Effects of Estrogen and Progestin on Blood Pressure of Normotensive Postmenopausal Women

Blood pressure rises in women with increasing age, possibly related to the decrease in production of female hormones that accompanies menopause. Although estrogen or progestin administration alone consistently does not lower blood pressure in postmenopausal women, possible interactions of these two hormones in affecting blood pressure are not well understood. We studied 12 surgically postmenopausal, normotensive women, aged 51 ±2 years (SEM). Treatment for each subject consisted of 1 week each of placebo, estrogen (conjugated equine estrogens, 2.5 mg/day), progestin (medroxyprogesterone acetate, 60 mg/day), and combined estrogen and progestin, given in varied order. At the end of each week, auscultatory blood pressures were measured while patients were seated. Neither estrogen nor progestin alone either increased or decreased blood pressure significantly, whereas combined estrogen and progestin lowered systolic, diastolic, and mean blood pressures 6 to 7 mm Hg (P <.05). Treatment order was unrelated to the change in blood pressure values. The authors suggest that administering progestin with estrogen may be more effective in lowering blood pressure than either hormone alone in postmenopausal women.