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Biomedical subjects

E C Fletcher

Publications and source records attributed to E C Fletcher.

At least 19 recordsLinked to original sources
PubMed2001

Hypercoagulability in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) has been linked to cardiovascular complications such as stroke and myocardial infarction. Previous studies demonstrate that OSA patients show elevated fibrinogen levels and increased platelet aggregation that are reversed with 1 night of nasal continuous positive airway pressure treatment (NCPAP). Questioning overall coagulability in OSA, we examined whole blood coagulability in 11 chronically NCPAP treated OSA subjects, 22 previously untreated OSA subjects, and in 16 of these after 1 night of NCPAP treatment. PATIENTS AND METHODS: During full polysomnography, subjects from each group had blood drawn prior to bedtime (21:00 h) and upon waking in the morning (07:00 h). RESULTS: Untreated OSA patients had faster P.M. clotting times than chronically treated OSA patients (3.33+/-0.31 versus 6.12+/- 0.66 min, P<0.05 by ANOVA). A.M. values showed similar results (4.31+/- 0.34 min versus 7.08+/-0.52 min, P<0.05 by ANOVA) for the respective groups. One overnight treatment with nasal CPAP did not produce a significant change in A.M. whole blood coagulability (4.35 +/-0.43 to 5.31+/-0.53 min; n=16; P=0.1) in 16 treated subjects. CONCLUSIONS: These data indicate a relationship between obstructive sleep apnea and blood hypercoagulability status that appears to be reversed by chronic NCPAP treatment. These data suggest that NCPAP might protect against the development of cardiovascular complications in OSA patients.

Journal Article↗
PubMed2001

Intermittent hypoxia: cell to system.

This symposium was organized to present research dealing with the effects of intermittent hypoxia on cardiorespiratory systems and cellular mechanisms. The pattern of neural impulse activity has been shown to be critical in the induction of genes in neuronal cells and involves distinct signaling pathways. Mechanisms associated with different patterns of intermittent hypoxia might share similar mechanisms. Chronic intermittent hypoxia selectively augments carotid body sensitivity to hypoxia and causes long-lasting activation of sensory discharge. Intermittent hypoxia also activates hypoxia-inducible factor-1. Reactive oxygen species are critical in altering carotid body function and hypoxia-inducible factor-1 activation caused by intermittent hypoxia. Blockade of serotonin function in the spinal cord prevents long-term facilitation in respiratory motor output elicited by episodic hypoxia and requires de novo protein synthesis. Chronic intermittent hypoxia leads to sustained elevation in arterial blood pressure and is associated with upregulation of catecholaminergic and renin-angiotensin systems and downregulation of nitric oxide synthases.

Animals↗
PubMed2001

Invited review: Physiological consequences of intermittent hypoxia: systemic blood pressure.

One of the major manifestations of obstructive sleep apnea is profound and repeated hypoxia during sleep. Acute hypoxia leads to stimulation of the peripheral chemoreceptors, which in turn increases sympathetic outflow, acutely increasing blood pressure. The chronic effect of these repeated episodic or intermittent periods of hypoxia in humans is difficult to study because chronic cardiovascular changes may take many years to manifest. Rodents have been a tremendous source of information in short- and long-term studies of hypertension and other cardiovascular diseases. Recurrent short cycles of normoxia-hypoxia, when administered to rats for 35 days, allows examination of the chronic cardiovascular response to intermittent hypoxia patterned after the episodic desaturation seen in humans with sleep apnea. The result of this type of intermittent hypoxia in rats is a 10- to 14-mmHg increase in resting (unstimulated) mean blood pressure that lasts for several weeks after cessation of the daily cyclic hypoxia. Carotid body denervation, sympathetic nerve ablation, renal sympathectomy, adrenal medullectomy, and angiotensin II receptor blockade block the blood pressure increase. It appears that adrenergic and renin-angiotensin system overactivity contributes to the early chronic elevated blood pressure in rat intermittent hypoxia and perhaps to human hypertension associated with obstructive sleep apnea.

Animals↗
PubMed2001

Altered vascular reactivity in arterioles of chronic intermittent hypoxic rats.

Recurrent episodic hypoxia (EH) is a feature of sleep apnea that may be responsible for some chronic cardiovascular sequelae such as systemic hypertension. Chronic EH (8 h/day for 35 days) causes elevation of diurnal resting (unstimulated) mean arterial blood pressure (MAP) in the rat. We used in vivo video microscopy to examine arteriolar reactivity in the cremaster muscle of male Sprague-Dawley rats subjected to 35 days of EH. Cremaster muscles of EH (n = 6) and control (n = 6) rats were exposed to varying doses of norepinephrine (NE) (10(-10) to 10(-5) M), ACh (10(-9) to 10(-5) M), and endothelin-1 (10(-12) to 10(-8) M). In a separate experiment, EH (n = 5) and control (n = 6) rats were given one dose of a nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-5) M). We also examined endothelial NOS mRNA from the kidneys of EH-stimulated and control (unstimulated) rats. Telemetry-monitored EH rats showed a 16-mmHg increase in MAP over 35 days, whereas control rats showed no change. The response to NE and endothelin-1 were similar for EH and control rats. ACh vasodilatation of arterioles in EH rats was significantly attenuated compared with that of controls. The degree of vasoconstriction in response to blockade of the nitric oxide system by L-NAME was significantly less (83% of baseline diameter with L-NAME) for arterioles of EH rats compared with that for controls (61% of baseline diameter), implying lower basal resting nitric oxide release in the EH rats. Whole kidney mRNA endothelial NOS levels were not different between groups. These data support the hypothesis that chronic elevation of blood pressure associated with EH involves increased peripheral resistance from decreased basal release or production of nitric oxide after 35 days of EH.

Acetylcholine↗
PubMed2000

Cardiovascular effects of continuous positive airway pressure in obstructive sleep apnea.

The cardiovascular sequelae best shown to be associated with OSA are systemic hypertension and acute vascular events. The cardiovascular sequelae, including acute myocardial infarction or nocturnal angina may be contributed to by arterial vasospasm or clot formation in the area of an atheroma. Thus far there are no data showing that treatment of OSA eliminates vascular sequelae, but much evidence shows that chronic CPAP therapy may lower elevated blood pressure in some patients. However, for a variety of reasons mentioned above, CPAP does not correct hypertension in all OSA patients.

Acute Disease↗
PubMed2000

Unattended home diagnosis and treatment of obstructive sleep apnea without polysomnography.

OBJECTIVE: To test the effectiveness of unattended home monitoring along with automatic titrating continuous positive airway pressure (auto-CPAP) as an acceptable method for diagnosing and prescribing proper CPAP pressure for treatment of patients presenting with classic symptoms of obstructive sleep apnea (OSA). DESIGN: Nonrandomized, prospective case study of 63 patients with a presumptive diagnosis of OSA. SETTING: University hospital and veterans affairs medical center ambulatory sleep disorders clinics. PARTICIPANTS: Fifty-eight men and 5 women were recruited for symptoms of excessive daytime sleepiness, heavy snoring, and witnessed apnea. INTERVENTION: Subjects with 10 or more respiratory events per hour were titrated by automatic, unattended home monitoring to an optimal CPAP pressure. MAIN OUTCOME MEASURES: Number of subjects able to be diagnosed by unattended home monitoring, titrated to optimal CPAP pressure, accepted an auto-CPAP machine for home use, and symptoms improved. RESULTS: Fifty-four (86%) of 63 patients completed sufficient diagnostic studies, and in 45 (83%) of these, a diagnosis of OSA was established. Nine subjects were unable to adjust to the nasal mask for an adequate diagnostic recording, and 9 had fewer than 10 respiratory events per hour. Ten subjects with OSA could not complete a titration study. Thirty-five of the subjects diagnosed with OSA accepted the auto-CPAP machine into their home, while 30 used it for therapy longer than 3 weeks. The estimated cost of performing in-home studies was less than one fourth of the estimated cost for in-laboratory polysomnographic examinations had they been performed. CONCLUSION: Unattended monitoring plus auto-CPAP allows cost-effective diagnosis and CPAP titration of most patients with OSA with straightforward symptoms.

Diagnosis, Differential↗
PubMed2000

Effect of episodic hypoxia on sympathetic activity and blood pressure.

One of the major manifestations of obstructive sleep apnea (OSA) is profound and repeated (episodic) hypoxia during sleep. Acute hypoxia leads to stimulation of the peripheral chemoreceptors, which in turn directly increase sympathetic outflow. It is believed that this increase in sympathetic outflow is directly responsible, at least in part, for the acute blood pressure (BP) changes seen in OSA. It is difficult however, to study the chronic effects of repeated episodic hypoxia (EH) in humans since the chronic cardiovascular changes may take many years to manifest. For this reason, we developed a method of providing recurrent short periods of hypoxia (resembling the episodic desaturation in humans with OSA) to rats for 35 days, stimulating the chemoreceptors and the sympathetic nervous system, allowing examination of the chronic cardiovascular response to EH. The result of EH in rats is a 10-14 mmHg increase in resting (unstimulated) mean BP that lasts for several weeks after cessation of the daily EH. This BP increase is blocked by carotid body denervation, sympathetic nerve ablation, renal sympathectomy, adrenal medullectomy, and the angiotensin-1 receptor blocker losartan. Thus, it appears that adrenergic and renin-angiotensin system over-activity contribute to the early chronic elevated BP in EH and perhaps in human hypertension associated with OSA.

Animals↗
PubMed1999

Acute and chronic blood pressure response to recurrent acoustic arousal in rats.

Repetitive episodic hypoxia every 30 sec administered chronically to Sprague-Dawley (SD) rats has been shown by previous studies to cause a sustained increase in daytime blood pressure (BP). Acoustic arousal in humans during wake or sleep produces an acute BP rise. The question then arises as to whether chronic episodic acoustic arousal applied with the same frequency and duration as episodic hypoxia induces elevated BP. We exposed 14-week-old (N = 10) SD rats in individual cages to recurrent buzzer noise (500 Hz, 100 dB) 6 out of every 30 sec, 7 h/day for 35 days. Ten other rats were placed in similar cages daily but not exposed to noise, to provide a sham condition. An infrared beam with a detector was positioned at the end of each cage. This allowed us to quantify motion by registering the number of times the rat broke the beam per 7 h period. Mean intraarterial BP was measured in unrestrained conscious animals at baseline and at the end of 35 days of their respective conditions. Acute episodic acoustic stimulation caused an immediate response in BP and heart rate. Habituation occurred in that the movement response to 120 noises per hour was 75% in hour one and 20% in hours two through seven on day one. The movement response was further reduced by day 35 but remained significantly higher than in animals not stimulated by noise. The cardiovascular response to noise also showed signs of habituation. Chronic noise stimulation produced no sustained increases in BP after 35 days of exposure.

Acoustic Stimulation↗
PubMed1999

Renin activity and blood pressure in response to chronic episodic hypoxia.

Previous studies in several strains of rats have demonstrated that 35 days of recurrent episodic hypoxia (EH) (7 hours per day), with a fractional concentration of inspired oxygen that produces desaturation equivalent to the recurrent hypoxemia of sleep apnea, results in an 8 to 13 mm Hg persistent increase in diurnal systemic blood pressure (BP). Carotid chemoreceptors and the sympathetic nervous system have been shown to be necessary for development of this BP increase. Both renal artery denervation and adrenal demedullation block the BP response to chronic EH. The present study was undertaken to define further the role of the kidneys and the renin-angiotensin system in this BP increase. Separate groups of male Sprague-Dawley rats had either (1) bilateral renal artery denervation with EH, (2) sham surgery with EH, (3) sham surgery with sham EH (compressed air), (4) EH with losartan, (5) unhandled with losartan, or (6) unhandled. The experimental period lasted 35 days. Both renal-artery denervated and losartan-treated animals showed no BP change or a lowering of BP in response to EH, whereas the sham-operated EH animals showed a progressive, sustained increase in resting room air BP. BP remained at basal levels or fell in unhandled and unhandled losartan-treated animals. Plasma renin activity was elevated 4-fold versus basal levels in EH animals with renal nerves intact but remained at baseline levels in denervated animals. At the end of the experiment, renal tissue catecholamines confirmed renal denervation in those animals. In conclusion, EH causes a progressive increase in BP, mediated in part through renal sympathetic nerve activity that acts to increase renin-angiotensin system activity through angiotensin II type 1 receptors.

Adrenal Medulla↗
PubMed1999

Pulmonary rapidly adapting receptor stimulation does not increase airway resistance in anesthetized rabbits.

In open-chest artificially ventilated rabbits, removal followed by replacement of positive end-expiratory pressure (PEEP maneuver) favors stimulation of airway rapidly adapting receptors (RARs). The purpose of the present study was to determine whether activation of RARs can cause bronchoconstriction. We measured airway pressure, airflow, and tidal volume, and calculated dynamic lung compliance and total lung resistance. PEEP maneuver increased airway pressure swings (16.4 +/- 4% above control; p = 0.0016) and decreased compliance (to 84.8 +/- 2.8% of control; p = 0.0002) without changing resistance (108.0 +/- 4.4% of control; p = 0.85). On the other hand, the resistance increased greatly (93 +/- 13%, p < 0.01) after intravenous injection of acetylcholine or electrical stimulation of vagal efferents, indicating that our system could detect increases in the resistance. In a separate group, we stimulated RARs by stroking the trachea with a cotton tip (tickling), tickling produced cough, manifested by increased pressure and flow without resistance changing. These changes were abolished after paralysis with succinylcholine. Because we did not detect an increase in airflow resistance during activation of RARs by the PEEP maneuver and tickling, we conclude that increase in resistance may not be an important reflex component of airway RARs.

Acetylcholine↗
PubMed1999

Pulmonary edema develops after recurrent obstructive apneas.

There are anecdotal reports of pulmonary edema after a night of recurrent obstructive apneas (OAs) in humans, but no data on lung water, gas exchange, filling pressure, or cardiac output (Q) exist in these patients. By clamping the endotracheal tube of eight intubated, anesthesized dogs, we created repetitive OAs of 45-s duration at 30-s intervals, for 8 h. Five additional dogs without apneas, but identically instrumented, were studied simultaneously, serving as nonapneic controls. Sa (O(2)) was measured by intraarterial catheter, pulmonary capillary wedge pressure (Pcw), continuous cardiac output (Q), and mixed venous oxygen saturation (Sv(O(2))) were measured by flotation catheter. Basal and hourly hemodynamics and blood gases (arterial and venous) under steady state respiration were measured. Venous admixture (Q S/Q T) was calculated by standard equations. Pa(O(2)) from the beginning to the end of the experiment fell from 89.6 to 82.8 mm Hg in apneic animals and from 92.2 to 85.5 mm Hg in controls. The Q S/Q T increased in both groups but more so in the apnea group (3.3 to 19.4%) than in nonapneic controls (3.1 to 7.9%). Neither Q nor Pcw changed significantly in either group. Lung wet/dry weight was 5.40 +/- 0.93 in apneic animals and 5.00 +/- 0.67 in controls. Light microscopy showed gross alveolar fluid in three apneic dogs, and electron microscopy showed interstitial fluid in two additional apneic dogs. One of the lung edema dogs expired of acute heart failure in the seventh hour of the experiment. Worsening of gas exchange and histology suggest that lung edema can result from recurrent OAs.

Animals↗
PubMed1999

Hydrogen peroxide in the lung parenchyma stimulates vagally mediated phrenic activity.

STUDY OBJECTIVE: To elucidate the mechanism of hyperpnea and tachypnea, which are the common findings in cardiopulmonary patients. RATIONALE: Recently, it was found that activating pulmonary afferents by directly injecting hypertonic saline solution into the lung periphery causes a vagally mediated neural hyperpnea and tachypnea, ie, the excitatory lung reflex. Since reactive oxygen species are released during a variety of pulmonary diseases, we examined whether hydrogen peroxide (H(2)O(2)), a common mediator in cardiopulmonary diseases, can initiate the same excitatory lung reflex. MEASUREMENTS AND RESULTS: We recorded phrenic efferent activity in anesthetized, open chest, artificially ventilated rabbits as an index of respiratory drive and examined the respiratory responses to injections of H(2)O(2) (10 micromol in 0.1 mL). The responses were compared with those to hypertonic saline solution (8.1%, 0.1 mL). H(2)O(2) and hypertonic saline solution increased both the rate (mean [+/- SEM], 43 +/- 8% and 61 +/- 10%, respectively; n = 30; p = 0.001) and the amplitude of phrenic bursts (12 +/- 2% and 20 +/- 4%, respectively; n = 30; p = 0.033). These responses were abolished by bilateral vagotomy. CONCLUSION: H(2)O(2) can initiate the excitatory lung reflex. Therefore, mediator(s) released in pulmonary diseases could be one of the mechanisms causing hyperpnea and tachypnea.

Animals↗