The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia.

KEY POINTS: The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end-organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady-state eucapnic hypoxia were measured in a cohort of 82 middle-aged individuals. Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals. It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required. Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor-driven levels of sympathetic nervous system activity and respiratory drive. ABSTRACT: Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor-driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady-state eucapnic hypoxia in middle-aged men and women (n = 82) with continuous positive airway pressure-treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (-35 ± 14% and -42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test-retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady-state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea.

NEW FINDINGS: What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea. ABSTRACT: Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT1 R) blockade. Both AT1 R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h-1 and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O2 tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

Effect of Chronic Intermittent Hypoxia on Angiotensin II Receptors in the Central Nervous System.

Chronic intermittent hypoxia (CIH) increases basal sympathetic nervous system activity, augments chemoreflex-induced sympathoexcitation, and raises blood pressure. All effects are attenuated by systemic or intracerebroventricular administration of angiotensin II type 1 receptor (AT1R) antagonists. This study aimed to quantify the effects of CIH on AT1R- and AT2R-like immunoreactivity in the rostroventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), central regions that are important components of the extended chemoreflex pathway. Eighteen Sprague-Dawley rats were exposed to intermittent hypoxia (FIO2 = 0.10, 1 min at 4-min intervals) for 10 hr/day for 1, 5, 10, or 21 days. After exposure, rats were deeply anesthetized and transcardially perfused with phosphate buffered saline (PBS) followed by 4% paraformaldehyde in PBS. Brains were removed and sectioned coronally into 50 µm slices. Immunohistochemistry was used to quantify AT1R and AT2R in the RVLM and the PVN. In the RVLM, CIH significantly increased the AT1R-like immunoreactivity, but did not alter AT2R immunoreactivity, thereby augmenting the AT1R:AT2R ratio in this nucleus. In the PVN, CIH had no effect on immunoreactivity of either receptor subtype. The current findings provide mechanistic insight into increased basal sympathetic outflow, enhanced chemoreflex sensitivity, and blood pressure elevation observed in rodents exposed to CIH.

Insomnia and Relationship With Immunosuppressant Therapy After Lung Transplantation.

BACKGROUND: Lung transplant recipients are at high risk of developing sleep disorders such as insomnia, but the prevalence and features are currently poorly characterized within this population. Since these disorders are associated with increased morbidity and mortality, it is important to identify them to optimize the care of lung transplant recipients. We sought to evaluate the prevalence of insomnia within our university-based lung transplant clinic and determine whether a relationship exists between insomnia and exposure to immunosuppressant medications following transplantation. METHODS: Participants were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (n = 92) completed the adult sleep history questionnaire, which included the Insomnia Severity Index (ISI) to assess for insomnia (defined as ISI score >10). Cumulative tacrolimus exposure was determined in 73 patients by performing an area under the curve calculation to assess for a potential relationship between tacrolimus exposure and insomnia. RESULTS: The prevalence of insomnia was 40% within this population. Although no difference in time since transplant was found, cumulative mean ± standard error of the mean tacrolimus exposure was significantly higher in patients with insomnia versus those without insomnia (17 190 ± 1673 ng·d/mL vs 12 130 ± 1630 ng·d/mL, respectively; P = .04). Estimated tacrolimus exposure was not greater with increasing frequency of insomnia complaints (analysis of variance P = .54). CONCLUSION: In our population, insomnia is common after lung transplantation, with prevalence greater than the general population. Higher cumulative exposure to tacrolimus may contribute to insomnia in this group. Future research should investigate the relationship between immunosuppressant therapy and development of sleep disorders.

Restless Legs Syndrome Following Lung Transplantation: Prevalence and Relationship With Tacrolimus Exposure.

CONTEXT: Complications following lung transplantation are common and significantly reduce quality of life, and increase morbidity and mortality. Increasing evidence suggests sleep disorders are prevalent following lung transplantation, but factors associated with their development are not known. OBJECTIVES: We sought to evaluate the prevalence of restless legs syndrome (RLS) in a lung transplant population and determine if a relationship exists between RLS and exposure to immunosuppressant medications. DESIGN, SETTING, AND PARTICIPANTS: Subjects were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (N = 81) completed sleep questionnaires, including the four RLS diagnostic criteria, insomnia severity index, and Sheehan disability scale. Cumulative tacrolimus exposure was determined in 62 subjects by calculating an area under the curve (AUC) to assess for a relationship with restless legs syndrome. RESULTS: Prevalence of RLS was 35 percent. Cumulative mean ± SEM tacrolimus exposure was similar in patients with RLS versus those without RLS (17446 ± 1855 ng days/mL vs. 15303 ± 1643 ng days/mL, respectively; p = 0.42). Insomnia severity index scores (12.5 ± 1.0 vs 6.8 ± 0.7, p < 0.0001) and Sheehan disability scores (7.8 ± 1.3 vs 3.6 ± 0.6, p = 0.003) were significantly higher in those with vs those without RLS symptoms, respectively. CONCLUSIONS: Our data confirms increased prevalence of RLS following lung transplantation reported by previous studies. RLS symptoms were not related to estimated tacrolimus exposure. Predictors of RLS following lung transplantation need to be further investigated to better identify and control RLS symptoms and reduce associated insomnia and disability.

Xanthine oxidase inhibition attenuates endothelial dysfunction caused by chronic intermittent hypoxia in rats.

BACKGROUND: Xanthine oxidase is a major source of superoxide in the vascular endothelium. Previous work in humans demonstrated improved conduit artery function following xanthine oxidase inhibition in patients with obstructive sleep apnea. OBJECTIVES: To determine whether impairments in endothelium-dependent vasodilation produced by exposure to chronic intermittent hypoxia are prevented by in vivo treatment with allopurinol, a xanthine oxidase inhibitor. METHODS: Sprague-Dawley rats received allopurinol (65 mg/kg/day) or vehicle via oral gavage. Half of each group was exposed to intermittent hypoxia (FIO(2) = 0.10 for 1 min, 15×/h, 12 h/day) and the other half to normoxia. After 14 days, gracilis arteries were isolated, cannulated with micropipettes, and perfused and superfused with physiological salt solution. Diameters were measured before and after exposure to acetylcholine (10(-6)M) and nitroprusside (10(-4)M). RESULTS: In vehicle-treated rats, intermittent hypoxia impaired acetylcholine-induced vasodilation compared to normoxia (+4 ± 4 vs. +21 ± 6 µm, p = 0.01). Allopurinol attenuated this impairment (+26 ± 6 vs. +34 ± 9 µm for intermittent hypoxia and normoxia groups treated with allopurinol, p = 0.55). In contrast, nitroprusside-induced vasodilation was similar in all rats (p = 0.43). Neither allopurinol nor intermittent hypoxia affected vessel morphometry or systemic markers of oxidative stress. Urinary uric acid concentrations were reduced in allopurinol- versus vehicle-treated rats (p = 0.02). CONCLUSIONS: These data confirm previous findings that exposure to intermittent hypoxia impairs endothelium-dependent vasodilation in skeletal muscle resistance arteries and extend them by demonstrating that this impairment can be prevented with allopurinol. Thus, xanthine oxidase appears to play a key role in mediating intermittent hypoxia-induced vascular dysfunction.

Impaired vascular regulation in patients with obstructive sleep apnea: effects of continuous positive airway pressure treatment.

RATIONALE: Impaired endothelium-dependent vasodilation has been documented in patients with sleep apnea. This impairment may result in blood flow dysregulation during apnea-induced fluctuations in arterial blood gases. OBJECTIVES: To test the hypothesis that hypoxic and hypercapnic vasodilation in the forearm and cerebral circulation are impaired in patients with sleep apnea. METHODS: We exposed 20 patients with moderate to severe sleep apnea and 20 control subjects, to isocapnic hypoxia and hyperoxic hypercapnia. A subset of 14 patients was restudied after treatment with continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS: Cerebral flow velocity (transcranial Doppler), forearm blood flow (venous occlusion plethysmography), arterial pressure (automated sphygmomanometry), oxygen saturation (pulse oximetry), ventilation (pneumotachograph), and end-tidal oxygen and carbon dioxide tensions (expired gas analysis) were measured during three levels of hypoxia and two levels of hypercapnia. Cerebral vasodilator responses to hypoxia (-0.65 +/- 0.44 vs. -1.02 +/- 0.72 [mean +/- SD] units/% saturation; P = 0.03) and hypercapnia (2.01 +/- 0.88 vs. 2.57 +/- 0.89 units/mm Hg; P = 0.03) were smaller in patients versus control subjects. Hypoxic vasodilation in the forearm was also attenuated (-0.05 +/- 0.09 vs. -0.10 +/- 0.09 unit/% saturation; P = 0.04). Hypercapnia did not elicit forearm vasodilation in either group. Twelve weeks of continuous positive airway pressure treatment enhanced hypoxic vasodilation in the cerebral circulation (-0.83 +/- 0.32 vs. -0.46 +/- 0.29 units/% saturation; P = 0.01) and forearm (-0.19 +/- 0.15 vs. -0.02 +/- 0.08 units/% saturation; P = 0.003), and hypercapnic vasodilation in the brain showed a trend toward improvement (2.24 +/- 0.78 vs. 1.76 +/- 0.64 units/mm Hg; P = 0.06). CONCLUSIONS: Vasodilator responses to chemical stimuli in the cerebral circulation and the forearm are impaired in many patients with obstructive sleep apnea. Some of these impairments can be improved with continuous positive airway pressure.

Pharmacologic approaches for the management of symptoms and cardiovascular consequences of obstructive sleep apnea in adults.

INTRODUCTION: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, arousals from sleep, and daytime sleepiness. Accumulating evidence indicates that hypoxemia and sleep disruption contribute to the development of cardiovascular abnormalities in OSA. OSA is effectively treated with continuous positive airway pressure (CPAP) therapy that splints open the airway during sleep. Studies have shown that CPAP therapy improves daytime sleepiness and attenuates cardiovascular abnormalities in patients with OSA. However, not all patients with OSA tolerate or adhere to CPAP therapy. Even patients who regularly use CPAP therapy may have a few hours each night exposed to the negative effects of untreated OSA. As a result, complementary pharmacologic therapies that can be used with CPAP therapy have the potential to reduce symptoms and consequences of OSA. DISCUSSION: The wake-promoting medications modafinil and armodafinil effectively improve residual sleepiness in patients treated with CPAP therapy. Although results are equivocal so far, modafinil and armodafinil may also improve quality of life and global clinical condition in patients with OSA and residual sleepiness treated with CPAP therapy. Pharmacologic therapies also have the potential to be used with CPAP therapy to minimize cardiovascular perturbations and risk of cardiovascular disease. Preliminary studies suggest that inhibition of the enzyme xanthine oxidase and inhibition of sympathetic nervous system overactivity may have therapeutic potential to reduce cardiovascular harm in patients with OSA. CONCLUSION: Future studies of pharmacologic therapies to reduce symptoms and cardiovascular consequences of OSA should be increasingly performed as our understanding of the mechanisms mediating the adverse effects of OSA continues to evolve.

Effect of annual influenza immunization on antibody response in lung transplant patients.

BACKGROUND: Influenza viral infections cause significant morbidity and mortality each season. Lung transplant patients may be at higher risk because of their underlying pathophysiology. Although annual immunization is the standard of care, its efficacy remains largely unproven. Previous studies showed poor antibody response to influenza vaccine in lung transplant patients, but no data on the antibody response in consecutive seasons have been published. METHODS: We studied antibody responses to influenza vaccine in 122 subjects: 66 lung transplant recipients, 28 control subjects, and 28 patients awaiting lung transplantation. We compared antibody response rates to individual viruses contained in influenza vaccines in consecutive years within the 3 groups. Serum antibody concentrations were measured at baseline and 2 to 4 weeks after vaccination by using the hemagglutination inhibition assay. Log-transformed antibody concentrations and incidence of serconversion and seroprotection were calculated. RESULTS: Median log-transformed antibody responses were similar in consecutive seasons in lung transplant subjects. Incidences of seroprotection and seroconversion did not differ between consecutive seasons in lung transplant recipients. CONCLUSIONS: Antibody responses were similar in consecutively measured years in lung transplant subjects. Annual influenza vaccination in lung transplant subjects produces similar immune responses in 2 consecutive years, indicating that these patients are not at significantly increased risk of vaccine failure.

Lipopolysaccharide increases cell surface P-glycoprotein that exhibits diminished activity in intestinal epithelial cells.

Increasingly, it is recognized that commensal microflora regulate epithelial cell processes through the dynamic interaction of pathogen-associated molecular patterns and host pattern recognition receptors such as Toll-like receptor 4 (TLR4). We therefore investigated the effects of bacterial lipopolysaccharide (LPS) on intestinal P-glycoprotein (P-gp) expression and function. Human SW480 (P-gp+/TLR4+) and Caco-2 (P-gp+/TLR4-) cells were treated with medium control or LPS (100 ng/ml) for 24 h prior to study. P-gp function was assessed by measuring the intracellular concentration of rhodamine 123 (Rh123). To confirm P-gp-specific effects, breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 2 (MRP-2/ABCC2) were also analyzed. Treatment of SW480 cells with LPS led to diminished P-gp activity, which could be prevented with polymyxin B (control: 207+/-16 versus LPS: 402+/-22 versus LPS+polymyxin B: 238+/-26 pmoles Rh123/mg protein, p<0.05 control versus LPS). These effects could be blocked by using polymyxin B and were not seen in the P-gp+/TLR4--Caco-2 cell line (control: 771+/-28 versus LPS: 775+/-59 pmoles Rh123/mg protein). Total cellular levels of P-gp did not change in LPS-treated SW480 cells; however, a significant increase in cell surface P-gp was detected. No change in activity, total protein, or apically located MRP-2 was detected following LPS treatment. Sequence analysis confirmed wild-type status of SW480 cells. These data suggest that activation of TLR4 in intestinal epithelial cells leads to an increase in plasma membrane P-gp that demonstrates a diminished capacity to transport substrate.

Humoral immune responses to influenza vaccination in patients with obstructive sleep apnea.

STUDY OBJECTIVE: To compare humoral immune responses to influenza vaccination in subjects with obstructive sleep apnea (OSA) and in healthy volunteers (control subjects). DESIGN: Prospective, controlled, parallel-design study. SETTING: Sleep disorders center at a university hospital. SUBJECTS: Fourteen untreated subjects with moderate-to-severe OSA (apnea hypopnea index > 15 events/hr) and 17 healthy volunteers (control subjects). INTERVENTION: All subjects were given the influenza vaccine for the years 2004-2005 or 2005-2006. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained before and 2-4 weeks after vaccination to measure serum antibody titers for the A/New Caledonia/20/99 (H1N1)-like and B/Shanghai/361/2002-like viral strains by using the hemagglutination inhibition assay. Seroconversion was defined as an increase in the antibody titer by more than 4-fold, whereas seroprotection was defined as an antibody titer greater than 40 hemagglutination units. The mean +/- standard error of the mean apnea hypopnea index, calculated as the number of abnormal respiratory events divided by the number of hours of total sleep time, was 56 +/- 12 events/hour in the OSA group and 1.0 +/- 0.4 oxygen desaturations/hour in the control group (p<0.05). However, no significant differences were observed in changes in antibody concentration, frequencies of seroconversion, or rates of seroprotection between subjects with OSA and control subjects. Polysomnographic measures of OSA were not correlated with immune responses. CONCLUSION: Although pathophysiologic characteristics of OSA may influence immune responses, moderate-to-severe OSA did not impair humoral responses to the influenza vaccine in these subjects.

Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats.

We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for V̇co2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the V̇e/V̇co2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation.

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia.

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

Systemic and local adrenergic regulation of muscle glucose utilization during hypoglycemia in healthy subjects.

Adrenergic responses are crucial for hypoglycemic recovery. Epinephrine increases glucose production, lipolysis, and peripheral insulin resistance as well as blood flow and glucose delivery. Sympathetic activation causes vasoconstriction and reduces glucose delivery. To determine the effects of alpha- and beta-adrenergic activity on muscle glucose uptake during hypoglycemia, we studied forearm blood flow (FBF) (plethysmography), arteriovenous glucose difference (AV-diff), and forearm glucose uptake (FGU) during insulin infusion with 60 min of euglycemia followed by 60 min of hypoglycemia. Twelve healthy subjects (27 plus minus 5 years of age) were randomized to intravenous propranolol (IV PROP, 80 microg/min), intravenous phentolamine (IV PHEN, 500 microg/min), intra-arterial propranolol (IA PROP, 25 microg/min), intra-arterial phentolamine (IA PHEN, 12 microg/min per 100 ml forearm tissue), and saline (SAL). FBF increased during hypoglycemia with SAL (P < 0.001) but not with IA or IV PROP. FGU (P = 0.015) and AV-diff (P = 0.099) fell during hypoglycemia with IA PROP but not with IV PROP. FBF increased during hypoglycemia with IA and IV PHEN (P < 0.005). AV-diff fell during hypoglycemia with IA and IV PHEN (P < 0.01), but FGU was unchanged. Blood pressure fell (P < 0.001), and adrenergic and neuroglycopenic symptoms increased with IV PHEN (P < 0.01). Thus, systemic but not local propranolol prevents a decrease in forearm glucose extraction during hypoglycemia, suggesting that epinephrine increases peripheral muscular insulin resistance through systemic effects. alpha-Adrenergic activation inhibits vasodilation and helps maintain brain glucose delivery.

Impaired skeletal muscle and skin microcirculatory function in human obesity.

BACKGROUND: Obesity is associated with exaggerated blood pressure and systemic vascular resistance responses to mental stress. OBJECTIVE: To test the hypothesis that skin and muscle microvascular dilatation in response to mental stress is blunted in obesity. DESIGN AND METHODS: Blood pressure, heart rate and forearm and skin blood flow responses to mental stress were compared in 23 obese and 23 age- and sex-matched lean normotensive individuals. RESULTS: Blood pressure was almost identical in both obese (mean 94 +/- 1 mmHg) and lean (93 +/- 2 mmHg) individuals. The increase in blood pressure during mental stress was similar in obese and lean individuals (2.0 +/- 0.9% compared with 3.1 +/- 4.0%; P = 0.8). Forearm vascular resistance decreased during mental stress in both groups, but this decrease was significantly blunted in obese individuals compared with controls (decreases of 14 +/- 4% and 26 +/- 3%; P < 0.01). Skin microcirculatory dilatation was also significantly blunted in obese individuals compared with controls (decreases of 5 +/- 2 and 17 +/- 4%; P = 0.02). CONCLUSIONS: Normotensive obese individuals exhibit markedly impaired muscle and skin microcirculatory responses to mental stress. The increased propensity of obese individuals to develop hypertension under conditions of chronic psychosocial stress may underlie obesity-related hypertension and cardiovascular disease.

Quantifying hypoxia-induced chemoreceptor sensitivity in the awake rodent.

We evaluated several methods for characterizing hypoxic chemosensitivity in the conscious rat. Adult Sprague-Dawley rats (n = 30) were exposed to normobaric hypoxia [inspired oxygen fraction (Fio2) 0.15, 0.12, and 0.09]. We measured ventilation (V̇e; barometric plethysmography), arterial oxygen saturation (SpO2; pulse oximeter), and oxygen consumption and carbon dioxide production (V̇o2 and V̇co2; analysis of expired air). Linear regression analysis was used to define stimulus-response relationships. Testing was performed on 2 days to assess day-to-day reproducibility. Exposure to graded, steady-state hypoxia caused progressive reductions in SpO2 that were, for any given Fio2, quite variable (SpO2 range, 20-30%) among individuals. Hypoxia produced progressive increases in V̇e caused by increases in both tidal volume (VT) and breathing frequency. Hypoxia also increased the VT:inspiratory time (Ti) ratio, an indicator of central respiratory "drive." Hypoxia caused consistent, progressive declines in V̇o2, V̇co2, and core temperature (>20% at the lowest SpO2). We propose that optimal quantification of carotid chemoreceptor hypoxic sensitivity in the unanesthetized rodent should employ SpO2 [a surrogate for arterial Po2 (PaO2 )] as the stimulus variable and the ventilatory equivalent for V̇co2 (V̇e/V̇co2) and/or mean inspiratory flow rate (VT/Ti) normalized for V̇co2 as the response variables. Both metrics take into account not only the important influence of a falling metabolic rate, but also SpO2, which represents the hypoxic stimulus at the carotid body. Because of the somewhat curvilinear nature of these responses, exposure to multiple levels of graded hypoxia provides the most complete characterization of hypoxic chemosensitivity.

Sildenafil increases sympathetically mediated vascular tone in humans.

BACKGROUND: Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. METHODS: We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. RESULTS: Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). CONCLUSIONS: Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

Pharmacy students' retention of knowledge and skills following training in automated external defibrillator use.

OBJECTIVES: To assess pharmacy students' retention of knowledge about appropriate automated external defibrillator use and counseling points following didactic training and simulated experience. DESIGN: Following a lecture on sudden cardiac arrest and automated external defibrillator use, second-year doctor of pharmacy (PharmD) students were assessed on their ability to perform basic life support and deliver a shock at baseline, 3 weeks, and 4 months. Students completed a questionnaire to evaluate recall of counseling points for laypeople/the public. ASSESSMENT: Mean time to shock delivery at baseline was 74 ± 25 seconds, which improved significantly at 3 weeks (50 ± 17 seconds, p < 0.001) and was maintained at 4 months (47 ± 18 seconds, p < 0.001). Recall of all signs and symptoms of sudden cardiac arrest and automated external defibrillator counseling points was diminished after 4 months. CONCLUSION: Pharmacy students can use automated external defibrillators to quickly deliver a shock and are able to retain this ability after 4 months. Refresher training/courses will be required to improve students' retention of automated external defibrillator counseling points to ensure their ability to deliver appropriate patient education.

Sleep-disordered breathing and obesity: pathophysiology, complications, and treatment.

Sleep-disordered breathing (SDB) is a medical condition that has increasingly recognized adverse health effects. Obesity is the primary risk factor for the development of SDB and contributes to cardiovascular and metabolic abnormalities in this population. However, accumulating evidence suggests that SDB may be related to the development of these abnormalities independent of obesity. Periodic apneas and hypopneas during sleep result in intermittent hypoxemia, arousals, and sleep disturbances. These pathophysiologic characteristics of SDB are likely mechanisms underlying cardiovascular and metabolic abnormalities including hypertension and other cardiovascular diseases, altered adipokines, inflammatory cytokines, insulin resistance, and glucose intolerance. Treatment of SDB with continuous positive airway pressure reverses some but not all of these abnormalities; however, studies to date have demonstrated inconsistent findings. Weight loss strategies, including diet, exercise, medications, and bariatric surgery, have been evaluated as a treatment strategy for SDB. In preliminary studies, dietary intervention and exercise reduced severity of SDB. One study demonstrated improvements in SDB severity using the weight-reducing medication sibutramine. In morbidly obese subjects, bariatric surgery effectively induces weight loss and improvement in SDB severity and symptoms, but long-term benefits remain uncertain. Large randomized trials are required to determine the utility of these strategies as long-term approaches to improving SDB and reducing associated complications.