RESUMO
BACKGROUND: African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress. OBJECTIVE: To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs. METHODS: Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion. MAIN OUTCOME MEASURES: Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha). RESULTS: A total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. - 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. - 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025). CONCLUSIONS: In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02365285.
Assuntos
Doenças Cardiovasculares , Galantamina , Acetilcolinesterase , Adulto , Negro ou Afro-Americano , Colinérgicos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Galantamina/farmacologia , Galantamina/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Interleucina-6 , Leucócitos Mononucleares , Lipídeos , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Estresse OxidativoRESUMO
BACKGROUND: Postural tachycardia syndrome (POTS) is characterized by excessive upright tachycardia and disabling presyncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal; it is unknown, however, what is the precise underlying mechanism. We seek to investigate the effect of glucose intake on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. METHODS: Prospective, case-control study, 12 women with POTS who reported a postprandial worsening of their POTS symptoms and 13 age-matched female controls received 75-g oral glucose and 20 mg/kg acetaminophen to assess nutrient absorption. Hemodynamic, gastrointestinal hormone and acetaminophen levels were measured for up to 120 minutes postingestion while supine and standing. RESULTS: Patients with POTS had significant orthostatic tachycardia, 48.7±11.2 versus 23.3±8.1 bpm, P=0.012 and elevated upright norepinephrine levels, 835.2±368.4 versus 356.9±156.7 pg/mL, P=0.004. After oral glucose, upright heart rate significantly increased in POTS, 21.2±11.9% versus 6.0±19.9%, P=0.033 with a concomitant decline in upright stroke volume, -10.3±11.90% versus 3.3±13.7%, P=0.027; total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707), indicating comparable nutrient absorption rates. POTS had increased plasma levels of C-peptide (P=0.001), GIP (glucose-dependent insulinotropic polypeptide; P=0.001), peptide YY (P=0.016), and pancreatic polypeptide (P=0.04) following glucose consumption, but only GIP had a time-dependent association with the worsening upright tachycardia and stroke volume fall. CONCLUSIONS: The glucose-induced worsening orthostatic tachycardia in POTS was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, was maximally elevated.
Assuntos
Hormônios Gastrointestinais , Síndrome da Taquicardia Postural Ortostática , Acetaminofen/efeitos adversos , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Feminino , Glucose , Frequência Cardíaca/fisiologia , Humanos , Masculino , Estudos Prospectivos , TaquicardiaRESUMO
Postural Tachycardia Syndrome (POTS) is a chronic disorder characterized by symptoms of orthostatic intolerance such as fatigue, lightheadedness, dizziness, palpitations, dyspnea, chest discomfort and remarkable tachycardia upon standing. Non-invasive transdermal vagal stimulators have been applied for the treatment of epilepsy, anxiety, depression, headache, and chronic pain syndromes. Anti-inflammatory and immunomodulating effects after transdermal vagal stimulation raised interest for applications in other diseases. Patients with sympathetic overactivity, reduced cardiac vagal drive and presence of systemic inflammation like POTS may benefit from tVNS. This article will address crucial methodological aspects of tVNS and provide preliminary results of its acute and chronic use in POTS, with regards to its potential effectiveness on autonomic symptoms reduction and heart rate modulation.
Assuntos
Síndrome de Fadiga Crônica , Intolerância Ortostática , Síndrome da Taquicardia Postural Ortostática , Frequência Cardíaca , Humanos , Síndrome da Taquicardia Postural Ortostática/terapia , TaquicardiaRESUMO
OBJECTIVE: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure. METHODS: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure. RESULTS: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex. CONCLUSIONS: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.
Assuntos
Doenças do Sistema Nervoso Autônomo/genética , Mutação , Receptores Nicotínicos/genética , Adolescente , Adulto , Constipação Intestinal/genética , Feminino , Genes Recessivos , Humanos , Hipotensão Ortostática/genética , Masculino , Miose/genética , Linhagem , Sequenciamento do ExomaRESUMO
Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology, and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure, which is rarely achievable. Long-acting central sympatholytic drugs are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension, but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short-acting pressor agents if necessary.
Assuntos
Barorreflexo/fisiologia , Determinação da Pressão Arterial/métodos , Pressão Sanguínea/fisiologia , Gerenciamento Clínico , Hipotensão Ortostática/diagnóstico , Humanos , Hipotensão Ortostática/fisiopatologiaRESUMO
Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there are currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.
Assuntos
Antiparkinsonianos/uso terapêutico , Droxidopa/uso terapêutico , Hipotensão Ortostática/tratamento farmacológico , Hipotensão Ortostática/fisiopatologia , Idoso , Amiloidose/complicações , Amiloidose/epidemiologia , Antiparkinsonianos/efeitos adversos , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/epidemiologia , Doenças Cardiovasculares/epidemiologia , Comorbidade , Estado Terminal/enfermagem , Estudos Transversais , Droxidopa/efeitos adversos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipotensão Ortostática/etnologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Hydrogen sulfide (H2S) and NO are important gasotransmitters, but how endogenous H2S affects the circulatory system has remained incompletely understood. Here, we show that CTH or CSE (cystathionine γ-lyase)-produced H2S scavenges vascular NO and controls its endogenous levels in peripheral arteries, which contribute to blood pressure regulation. Furthermore, eNOS (endothelial NO synthase) and phospho-eNOS protein levels were unaffected, but levels of nitroxyl were low in CTH-deficient arteries, demonstrating reduced direct chemical interaction between H2S and NO. Pretreatment of arterial rings from CTH-deficient mice with exogenous H2S donor rescued the endothelial vasorelaxant response and decreased tissue NO levels. Our discovery that CTH-produced H2S inhibits endogenous endothelial NO bioavailability and vascular tone is novel and fundamentally important for understanding how regulation of vascular tone is tailored for endogenous H2S to contribute to systemic blood pressure function.
Assuntos
Pressão Sanguínea/fisiologia , Cistationina gama-Liase/farmacologia , Sulfeto de Hidrogênio/metabolismo , Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , CamundongosRESUMO
Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.
Assuntos
Albuminúria/metabolismo , Endotélio Vascular/metabolismo , Receptores ErbB/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Albuminúria/induzido quimicamente , Albuminúria/genética , Albuminúria/patologia , Angiotensina II , Animais , Endotélio Vascular/patologia , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Fosforilação , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologiaRESUMO
Sympathetic activation is thought to contribute to the inflammatory process associated with obesity, which is characterized by elevated circulating C-reactive protein (hsCRP) and interleukin-6 (IL-6). To evaluate whether sympathetic activation is associated with inflammation in the absence of obesity, we studied patients with postural tachycardia syndrome (POTS), a condition characterized by increased sympathetic tone in otherwise healthy individuals. Compared with 23 lean controls, 43 lean female POTS had greater vascular sympathetic modulation (low-frequency blood pressure variability, LFSBP, 3.2 ± 0.4 vs. 5.5 ± 0.6 mmHg(2), respectively, P = 0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1,414 ± 398 vs. 369 ± 66 ms(2), P = 0.001), and increased serum IL-6 (2.33 ± 0.49 vs. 4.15 ± 0.54 pg/ml, P = 0.011), but this was not associated with increases in hsCRP, which was low in both groups (0.69 ± 0.15 vs. 0.82 ± 0.16 mg/l, P = 0.736). To explore the contribution of adiposity to inflammation, we then compared 13 obese female POTS patients and 17 obese female controls to matched lean counterparts (13 POTS and 11 controls). Compared with lean controls, obese controls had increased LFSBP (3.3 ± 0.5 vs. 7.0 ± 1.1 mmHg(2); P = 0.016), IL-6 (2.15 ± 0.58 vs. 3.92 ± 0.43 pg/ml; P = 0.030) and hsCRP (0.69 ± 0.20 vs. 3.47 ± 0.72 mg/l; P = 0.001). Obese and lean POTS had similarly high IL-6 but only obese POTS had increased hsCRP (5.76 ± 1.99 mg/l vs. 0.65 ± 0.26; P < 0.001). In conclusion, sympathetic activation in POTS is associated with increased IL-6 even in the absence of obesity. The coupling between IL-6 and CRP, however, requires increased adiposity, likely through release of IL-6 by visceral fat.
Assuntos
Proteína C-Reativa/metabolismo , Interleucina-6/sangue , Obesidade/metabolismo , Obesidade/fisiopatologia , Síndrome da Taquicardia Postural Ortostática/metabolismo , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adiposidade , Adulto , Pressão Sanguínea , Composição Corporal , Citocinas/sangue , Feminino , Humanos , Inflamação/patologia , Masculino , Neurotransmissores/sangueRESUMO
The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with N(ω)-monomethyl-l-arginine (L-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to L-NMMA. We enrolled a total of 66 subjects (39 ± 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as "positive" controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting increased sympathetic tone contributing to hypertension. In contrast, L-NMMA produced similar increases in systolic blood pressure in normal, prehypertensive, and hypertensive subjects (31 ± 2, 32 ± 2, and 30 ± 3 mmHg, respectively), whereas the response of smokers was blunted (16 ± 5 mmHg, P = 0.012). Our results suggest that sympathetic activity plays a role in hypertension. NO tonically restrains blood pressure by â¼30 mmHg, but we found no evidence of impaired modulation by NO of vascular tone contributing to the early development of hypertension. If NO deficiency contributes to hypertension, it is likely to be through its modulation of the autonomic nervous system, which was excluded in this study.
Assuntos
Hipertensão/fisiopatologia , Óxido Nítrico/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Adolescente , Adulto , Envelhecimento/fisiologia , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Inibidores Enzimáticos/farmacologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Tono Muscular/efeitos dos fármacos , Tono Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Antagonistas Nicotínicos/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Receptores Nicotínicos/efeitos dos fármacos , Fumar/fisiopatologia , Sistema Nervoso Simpático/efeitos dos fármacos , Trimetafano/farmacologia , Adulto Jovem , ômega-N-Metilarginina/farmacologiaRESUMO
Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS-POTS) to those without CFS (non-CFS-POTS), to determine whether CFS-POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS-POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS-POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS-POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS-POTS patients had greater orthostatic tachycardia than the non-CFS-POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS-POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.
Assuntos
Síndrome de Fadiga Crônica/complicações , Síndrome da Taquicardia Postural Ortostática/complicações , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Volume Sanguíneo , Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/fisiopatologia , Feminino , Humanos , Norepinefrina/sangue , Síndrome da Taquicardia Postural Ortostática/sangue , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , SudoreseRESUMO
BACKGROUND: Due to lack of efficacy in recent trials, current guidelines for the treatment of neurally-mediated (vasovagal) syncope do not promote cardiac pacemaker implantation. However, the finding of asystole during head-up tilt -induced (pre)syncope may lead to excessive cardioinhibitory syncope diagnosis and treatment with cardiac pacemakers as blood pressure is often discontinuously measured. Furthermore, physicians may be more inclined to implant cardiac pacemakers in older patients. We hypothesized that true cardioinhibitory syncope in which the decrease in heart rate precedes the fall in blood pressure is a very rare finding which might explain the lack of efficacy of pacemakers in neurally-mediated syncope. METHODS: We studied 173 consecutive patients referred for unexplained syncope (114 women, 59 men, 42 ± 1 years, 17 ± 2 syncopal episodes). All had experienced (pre)syncope during head-up tilt testing followed by additional lower body negative suction. We classified hemodynamic responses according to the modified Vasovagal Syncope International Study (VASIS) classification as mixed response (VASIS I), cardioinhibitory without (VASIS IIa) or with asystole (VASIS IIb), and vasodepressor (VASIS III). Then, we defined the exact temporal relationship between hypotension and bradycardia to identify patients with true cardioinhibitory syncope. RESULTS: Of the (pre)syncopal events during tilt testing, 63% were classified as VASIS I, 6% as VASIS IIb, 2% as VASIS IIa, and 29% as VASIS III. Cardioinhibitory responses (VASIS class II) progressively decreased from the youngest to the oldest age quartile. With more detailed temporal analysis, blood pressure reduction preceded the heart-rate decrease in all but six individuals (97%) overall and in 10 out of 11 patients with asystole (VASIS IIb). CONCLUSIONS: Hypotension precedes bradycardia onset during head-up tilt-induced (pre)syncope in the vast majority of patients, even in those classified as cardioinhibitory syncope according to the modified VASIS classification. Furthermore, cardioinhibitory syncope becomes less frequent with increasing age.
Assuntos
Síncope Vasovagal/diagnóstico , Síncope Vasovagal/fisiopatologia , Adulto , Fatores Etários , Feminino , Hemodinâmica , Humanos , Hipotensão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Teste da Mesa InclinadaRESUMO
OBJECTIVE: Many drugs can interfere with baroreflex mechanisms thereby impairing blood pressure control, but few have undergone sufficient testing. The state of affairs may be explained by the lack of simple and inexpensive screening tests. METHODS: In eleven healthy men, we tested the hypothesis that a simple Valsalva maneuver could detect drug-induced changes in baroreflex function that have previously been described using more elaborate and invasive methodologies. They performed Valsalva maneuvers after selective pharmacological inhibition of the norepinephrine transporter (NET) in a placebo-controlled, double-blind, randomized, crossover fashion. Patients with severe autonomic failure served as positive controls. RESULTS: NET inhibition profoundly augmented the blood pressure decrease during phase II and attenuated the blood pressure overshoot in phase IV compared with placebo. Furthermore, NET inhibition increased the heart rate response during the Valsalva maneuver. INTERPRETATION: The Valsalva maneuver recapitulated complex alterations in baroreflex regulation during NET inhibition. Thus, this simple and inexpensive test could be employed as a screening tool for drug-induced baroreflex dysfunction.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Barorreflexo/efeitos dos fármacos , Programas de Rastreamento/métodos , Morfolinas/farmacologia , Manobra de Valsalva , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , ReboxetinaRESUMO
Gender differences in human cardiovascular norepinephrine transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25+/-1 years) during the early follicular phase (day 5+/-0) and midluteal phase (day 22+/-0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective norepinephrine transporter inhibitor reboxetine or placebo. We monitored heart rate, blood pressure, and thoracic bioimpedance at rest and during standard autonomic function tests, including head-up tilt. Venous estradiol and progesterone concentrations were higher in the luteal than in the follicular phase but did not differ between placebo and norepinephrine transporter inhibition testing days. On placebo, hemodynamics at rest and in response to different stressors were mostly identical between cycle phases. In the supine position, norepinephrine transporter inhibition increased blood pressure and stroke volume to a greater extent during the follicular than during the luteal phase. Conversely, the increase in heart rate and cardiac output with norepinephrine transporter inhibition was augmented in the luteal compared with the follicular phase. During head-up tilt with norepinephrine transporter inhibition, blood pressure and stroke volume decreased to a greater extent in the follicular than in the luteal phase. The tachycardic response to head-up tilt with norepinephrine transporter inhibition was augmented in the follicular phase. Our study suggests that sex hormones alter the hemodynamic response to norepinephrine transporter inhibition in women. The phenomenon may be explained by an effect of female sex hormones on norepinephrine transporter function, on compensatory cardiovascular responses, or both.
Assuntos
Inibidores da Captação Adrenérgica/administração & dosagem , Estrogênios/sangue , Morfolinas/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Progesterona/sangue , Adulto , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Feminino , Fase Folicular/fisiologia , Força da Mão , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Contração Isométrica , Fase Luteal/fisiologia , Reboxetina , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologiaRESUMO
Impaired endothelial-derived NO (eNO) is invoked in the development of many pathological conditions. Systemic inhibition of NO synthesis, used to assess the importance of NO to blood pressure (BP) regulation, increases BP by approximately 15 mm Hg. This approach underestimates the importance of eNO, because BP is restrained by baroreflex mechanisms and does not account for a role of neurally derived NO. To overcome these limitations, we induced complete autonomic blockade with trimethaphan in 17 normotensive healthy control subjects to eliminate baroreflex mechanisms and contribution of neurally derived NO. Under these conditions, the increase in BP reflects mostly blockade of tonic eNO. N(G)-Monomethyl-l-arginine (250 microg/kg per minute IV) increased mean BP by 6+/-3.7 mm Hg (from 77 to 82 mm Hg) in intact subjects and by 21+/-8.4 mm Hg (from 75 to 96 mm Hg) during autonomic blockade. We did not find a significant contribution of neurally derived NO to BP regulation after accounting for baroreflex buffering. To further validate this approach, we compared the effect of NOS inhibition during autonomic blockade in 10 normotensive individuals with that of 6 normotensive smokers known to have endothelial dysfunction but who were otherwise normal. As expected, normotensive smokers showed a significantly lower increase in systolic BP during selective eNO blockade (11+/-4.5 versus 30+/-2.3 mm Hg in normotensive individuals; P<0.005). Thus, we report a novel approach to preferentially evaluate the role of eNO on BP control in normal and disease states. Our results suggest that eNO is one of the most potent metabolic determinants of BP in humans, tonically restraining it by approximately 30 mm Hg.
Assuntos
Pressão Sanguínea/fisiologia , Óxido Nítrico Sintase Tipo III/fisiologia , Adulto , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Diástole , Inibidores Enzimáticos/farmacologia , Feminino , Bloqueadores Ganglionares/farmacologia , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Fenilefrina/farmacologia , Descanso , Fumar , Sístole , Trimetafano/farmacologia , ômega-N-Metilarginina/farmacologiaRESUMO
BACKGROUND AND PURPOSE: The combination of dipyridamole and aspirin has been shown to be more effective than aspirin alone in the secondary prevention of stroke. Dipyridamole may act by inhibiting adenosine uptake, thus potentiating its actions. Dipyridamole also inhibits cGMP-specific phosphodiesterases (PDE) and, through this mechanism, could potentiate cGMP-mediated actions of nitric oxide. METHODS: To define the mechanism of action of dipyridamole, we studied the local vascular effects of adenosine, acetylcholine (NO-mediated dilation), and nitroprusside (cGMP-mediated dilation) in a double-blind study after treatment with dipyridamole/aspirin (200 mg dipyridamole/25 mg aspirin twice a day) or aspirin control for 7 days in 6 normal volunteers. Vasodilators were administered into the brachial artery in the nondominant arm in random order and forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Adenosine at a dosage of 125 mug/min increased FBF from 4.6+/-0.9 to 29.4+/-5.3 (539% increase) with dipyridamole/aspirin and from 3.9+/-0.8 to 12+/-2.5 mL/100 mL forearm/min (208% increase) with aspirin alone (P=0.007). In contrast, dipyridamole/aspirin did not alter the response to acetylcholine or to nitroprusside. The magnitude of adenosine-induced vasodilation correlated with plasma dipyridamole concentrations (r2=0.6); no correlation was observed with acetylcholine- or nitroprusside-induced vasodilation. Similar potentiation of adenosine, but not acetylcholine or nitroprusside, was observed in 7 additional subjects when adenosine, acetylcholine, and nitroprusside were given in random order before and 2 hours after a single dose of dipyridamole/aspirin. CONCLUSIONS: The effects of dipyridamole on resistance vessels are preferentially explained by potentiation of adenosine mechanisms rather than potentiation of nitric oxide or other cGMP-mediated actions.
Assuntos
Adenosina/fisiologia , Dipiridamol/farmacologia , Óxido Nítrico/fisiologia , Vasodilatadores/farmacologia , Acetilcolina/administração & dosagem , Adenosina/química , Adenosina/metabolismo , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Estudos Cross-Over , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Modelos Biológicos , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Nitroprussiato/administração & dosagem , Diester Fosfórico Hidrolases/metabolismo , Fatores de TempoRESUMO
There are significant gaps in our understanding of the pathophysiology, diagnosis and treatment of NMS (neurally mediated syncope). Contributions in this area will be welcomed by patients and physicians taking care of them alike. In this issue of Clinical Science, Simek and co-workers report a novel non-invasive physiological measurement that does not require head-up tilt to diagnose NMS. However, validation studies applied to an unselected patient population are needed before we can judge how useful this test will be in the diagnosis of NMS.
Assuntos
Síncope Vasovagal/diagnóstico , Adulto , Envelhecimento , Monitorização Ambulatorial da Pressão Arterial , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Teste da Mesa InclinadaRESUMO
BACKGROUND: Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker. METHODS AND RESULTS: We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0+/-0.7 to 10.4+/-1.9 and 13.1+/-1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88+/-21 to 65+/-23 and 85+/-26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77+/-25 to 147+/-50 nmol/L), adenosine-induced increase in FBF (from 4.1+/-0.8 to 12.6+/-3 and 15.1+/-3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290+/-80 and 299+/-143 nmol/L for the low and high dose, respectively, P=0.04). CONCLUSIONS: Intravascular adenosine is likely ineffective in inducing myocardial preconditioning because of poor interstitial delivery. This can be overcome by blocking the nucleoside transporter with dipyridamole.