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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.
Assuntos
Hiperóxia , Idoso , Pressão Sanguínea , Células Quimiorreceptoras , Feminino , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sistema Nervoso SimpáticoRESUMO
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.
Assuntos
Alopurinol/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Apneia Obstrutiva do Sono/tratamento farmacológico , Adulto , Idoso , Alopurinol/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipóxia/fisiopatologia , Losartan/farmacologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
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.
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Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae.
Assuntos
Síndromes da Apneia do Sono/fisiopatologia , Animais , Sistema Cardiovascular/fisiopatologia , Cognição/fisiologia , Modelos Animais de Doenças , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Resistência à Insulina/fisiologia , Sistema Nervoso/fisiopatologia , Sistema Respiratório/fisiopatologia , Síndromes da Apneia do Sono/históriaRESUMO
We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost.
Assuntos
Hipóxia/metabolismo , Oxigênio/metabolismo , Aclimatação , Adaptação Fisiológica , Altitude , Animais , Exercício Físico , Humanos , Hipóxia/fisiopatologia , Resistência Física , Sono , Fatores de Tempo , VigíliaRESUMO
Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma.
Assuntos
Remodelação das Vias Aéreas/imunologia , Alérgenos/imunologia , Hipóxia/metabolismo , Ovalbumina/imunologia , Pneumonia/imunologia , Animais , Asma/metabolismo , Doença Crônica , Colágeno/imunologia , Modelos Animais de Doenças , Hipóxia/imunologia , Masculino , Pneumonia/patologia , RatosRESUMO
α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n = 14, 35 ± 3 years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n = 16, 31 ± 3 years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). α-Adrenergic agonists (phenylephrine and clonidine) and an antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Resting MSNA was â¼35% higher in adults with MetSyn (P < 0.05), but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in adults with MetSyn (P < 0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (P > 0.05). Interestingly, exercise-mediated vasodilatation was greater in MetSyn (P < 0.05). Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity hand-grip exercise when compared with age-matched healthy control subjects. These results suggest that adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity.
Assuntos
Exercício Físico , Síndrome Metabólica/fisiopatologia , Contração Muscular , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Sistema Nervoso Simpático/fisiopatologia , Vasoconstrição , Adaptação Fisiológica , Agonistas alfa-Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos alfa/administração & dosagem , Adulto , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Feminino , Força da Mão , Humanos , Infusões Intra-Arteriais , Fluxometria por Laser-Doppler , Masculino , Síndrome Metabólica/diagnóstico , Fluxo Sanguíneo Regional , Fatores de Tempo , Extremidade Superior , Vasoconstrição/efeitos dos fármacos , VasodilataçãoRESUMO
In patients with hypertension, volitional slowing of the respiratory rate has been purported to reduce arterial pressure via withdrawal of sympathetic tone. We examined the effects of paced breathing at 7, 14, and 21 breaths/min, with reciprocal changes in tidal volume, on muscle sympathetic nerve activity, forearm blood flow, forearm vascular conductance, and blood pressure in 21 men and women, 8 of whom had modest elevations in systemic arterial pressure. These alterations in breathing frequency and volume did not affect steady-state levels of sympathetic activity, blood flow, vascular conductance, or blood pressure (all P > 0.05), even though they had the expected effect on sympathetic activity within breaths (i.e., increased modulation during low-frequency/high-tidal volume breathing) (P < 0.001). These findings were consistent across subjects with widely varied baseline levels of sympathetic activity (4-fold), mean arterial pressure (78-110 mmHg), and vascular conductance (15-fold), and those who became hypocapnic during paced breathing vs. those who maintained normocapnia. These findings challenge the notion that slow, deep breathing lowers arterial pressure by suppressing steady-state sympathetic outflow.
Assuntos
Fluxo Sanguíneo Regional , Taxa Respiratória , Sistema Nervoso Simpático/fisiologia , Adulto , Pressão Sanguínea , Feminino , Antebraço/irrigação sanguínea , Antebraço/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Volume de Ventilação PulmonarRESUMO
The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.
RESUMO
Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and α-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) as animal models exhibit increased sympathetic activity and α-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased α-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost. We measured MSNA (microneurography of the peroneal nerve) and forearm blood flow (FBF, Doppler ultrasound) in 16 healthy control subjects (31 ± 3 years) and 14 adults with MetSyn (35 ± 3 years; P > 0.05) during local administration of α-adrenergic agonists (phenylephrine (PE), α(1); clonidine (CL), α(2)). MSNA was greater in MetSyn subjects than in healthy controls (P < 0.05). A group difference in vasoconstriction to PE was not detected (P = 0.08). The level of α(1)-mediated vasoconstriction was inversely related to MSNA in control subjects (r = 0.5, P = 0.04); this balance between MSNA and α(1) responsiveness was lost in adults with MetSyn. MetSyn subjects exhibited greater vasoconstriction to CL infusion as compared with healthy controls (P < 0.01). A relationship between MSNA and α(2)-mediated vasoconstriction was not detected in either group. In summary, altered neurovascular control in human MetSyn is receptor specific. The observed uncoupling between MSNA and α(1)-adrenergic responsiveness and increased α(2) vasoconstriction may lead to reduced FBF, altered flow distribution, and/or severe hypertension with the progression toward diabetes and cardiovascular disease.
Assuntos
Síndrome Metabólica/fisiopatologia , Músculo Esquelético/irrigação sanguínea , Receptores Adrenérgicos alfa/fisiologia , Adolescente , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Clonidina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Nervo Fibular/fisiologia , Fenilefrina/farmacologia , Fluxo Sanguíneo Regional , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologia , Adulto JovemRESUMO
The perylenequinones are a novel class of natural products characterized by pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light-activated biological activity, targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this class of compound, as well as several related phenanthroperylenequinones, are reviewed. Natural product modifications that improve biological profiles, and avenues for the total synthesis of analogs, which are not available from the natural product series, are outlined. An overview of structure/function relationships is provided.
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The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.
Assuntos
Antifúngicos/farmacologia , Inibidores de Calcineurina , Candida albicans/efeitos dos fármacos , Fluconazol/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinolinas/farmacologia , Antifúngicos/química , Calcineurina/metabolismo , Candida albicans/crescimento & desenvolvimento , Candida albicans/isolamento & purificação , Relação Dose-Resposta a Droga , Fluconazol/química , Proteínas de Choque Térmico HSP90/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Alopurinol/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipóxia/prevenção & controle , Resistência Vascular/efeitos dos fármacos , Xantina Oxidase/antagonistas & inibidores , Acetilcolina/farmacologia , Animais , Endotélio Vascular/fisiopatologia , Sequestradores de Radicais Livres/farmacologia , Hipóxia/complicações , Masculino , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Cerebrovascular regulation is impaired in patients with moderate to severe obstructive sleep apnea; however, it is unknown whether this impairment exists in individuals with less severe sleep-disordered breathing. OBJECTIVES: To test the hypothesis that cerebrovascular responses to hypercapnia are attenuated in a nonclinical population-based cohort. METHODS: A rebreathing test that raised end-tidal CO2 tension by 10 mm Hg was performed during wakefulness in 373 participants of the Wisconsin Sleep Cohort. MEASUREMENTS AND MAIN RESULTS: We measured cerebral flow velocity (transcranial Doppler ultrasound); heart rate (electrocardiogram); blood pressure (photoplethysmograph); ventilation (pneumotachograph); and end-tidal CO2 (expired gas analysis). Cerebrovascular CO2 responsiveness was quantified as the slope of the linear relationship between flow velocity and end-tidal CO2 during rebreathing. Linear regression analysis was performed using cerebrovascular CO2 responsiveness as the outcome variable. Main independent variables were the apnea-hypopnea index and the mean level of arterial oxygen saturation during sleep. We observed a positive correlation between cerebrovascular CO2 responsiveness and the mean level of oxygen saturation during sleep that was statistically significant in unadjusted analysis and after adjustment for known confounders and the increase in arterial pressure during rebreathing. Each 5% decrease in Sa(O2) during sleep predicted a decrease in cerebrovascular reactivity of 0.4 ± 0.2 cm/second/mm Hg P(ET)CO2. In contrast, the negative correlation between cerebrovascular CO2 responsiveness and apnea-hypopnea index was statistically significant only in the unadjusted analysis. CONCLUSIONS: Hypercapnic vasodilation in the cerebral circulation is blunted in individuals with sleep-disordered breathing. This impairment is correlated with hypoxemia during sleep.
Assuntos
Circulação Cerebrovascular , Síndromes da Apneia do Sono/fisiopatologia , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Dióxido de Carbono/metabolismo , Estudos de Coortes , Feminino , Frequência Cardíaca , Humanos , Hipercapnia/etiologia , Hipercapnia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Ventilação Pulmonar , Testes de Função Respiratória/métodos , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/metabolismo , Ultrassonografia Doppler Transcraniana/métodos , Vasodilatação , WisconsinRESUMO
The evolution of the first total synthesis of perylenequinone cercosporin is described. The key features developed during these efforts include a biscuprate epoxide alkylation, installation of the methylidene acetal, palladium-catalyzed O-arylation, and C3,C3'-decarbonylation. Due to the rapid atropisomerization of the helical axis of cercosporin (at 37 degrees C), the sequencing of these transformations was critical. To this end, the developed protocol enabled the formation of a key advanced intermediate on preparative scale absent any atropisomerization. Furthermore, the O-arylation proved to be general, and the strategy was used in an improved synthesis of a helical chiral perylenequinone structure.
Assuntos
Produtos Biológicos/química , Perileno/análogos & derivados , Quinonas/química , Catálise , Conformação Molecular , Paládio/química , Perileno/síntese química , Perileno/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The first total synthesis of (+)-calphostin D and the total synthesis of (+)-phleichrome are outlined. The convergent syntheses utilize an enantiopure biaryl common intermediate, which is formed via an enantioselective catalytic biaryl coupling. The established axial chirality is transferred to the perylenequinone helical stereochemistry with good fidelity. Additionally, efforts focused on the installation of the stereogenic C7,C7'-2-hydroxypropyl groups. Three routes were evaluated to establish the C7,C7'-stereochemistry, in which the successful route involved a double epoxide alkylation with a complex axial chiral biscuprate. This strategy not only allowed the synthesis of the unnatural isomers of calphostin D and phleichrome for assessment in biological systems but also provided valuable information for the syntheses of the more complex cercosporin and hypocrellin A.
Assuntos
Produtos Biológicos/química , Naftalenos/síntese química , Perileno/análogos & derivados , Perileno/química , Quinonas/química , Catálise , Modelos Moleculares , Naftalenos/química , Oxirredução , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An enantioselective approach to the perylenequinone core found in the mold perylenequinone natural products is outlined. Specifically, the first asymmetric syntheses of helical chiral perylenequinones absent any additional stereogenic centers are described. Key elements of the synthetic venture include a catalytic enantioselective biaryl coupling, a PIFA-induced naphthalene hydroxylation, and a palladium-mediated aromatic decarboxylation. Transfer of the binaphthalene axial stereochemistry to the perylenequinone helical stereochemistry proceeded with good fidelity. Furthermore, the resultant perylenequinones were shown to possess sufficient atropisomeric stability to be viable intermediates in the biogenesis of the perylenequinone natural products. This stability supports the use of the helical axis as a stereochemical relay in synthesis of the natural products containing additional stereochemical centers.
Assuntos
Produtos Biológicos/síntese química , Naftalenos/química , Perileno/análogos & derivados , Perileno/síntese química , Quinonas/síntese química , Produtos Biológicos/química , Catálise , Ciclização , Oxirredução , Paládio/química , Perileno/química , Quinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A (1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set the centrochiral C7,C7'-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation, a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial chiral intermediate and is then utilized in a dynamic stereochemical transfer to dictate the stereochemistry of the C7,C7'-seven membered ring formed during the aldol cyclization.
Assuntos
Produtos Biológicos/síntese química , Perileno/análogos & derivados , Quinonas/síntese química , Produtos Biológicos/química , Catálise , Ciclização , Estrutura Molecular , Perileno/síntese química , Perileno/química , Fenol , Quinonas/química , EstereoisomerismoRESUMO
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.