RESUMO
BACKGROUND: Listeria monocytogenes is a bacterial pathogen known for causing listeriosis, a foodborne illness with a wide spectrum of clinical presentations ranging from mild gastroenteritis to severe invasive disease, particularly affecting immunocompromised individuals, pregnant women, newborns, and the elderly. Successful treatment of patients with recurring listeria episodes due to colonised foreign material is often challenging, typically requiring a combination of antimicrobial treatment and surgical removal. CASE PRESENTATION: Here, we present a particularly complex case of chronic invasive listeriosis with a total of six relapses. After extensive investigations, the patient's ICD device was identified as the focus of infection. CONCLUSION: The confirmation of relapses through cgMLST analysis highlights the persistence of Listeria monocytogenes and the potential for recurrence even after apparent resolution of symptoms in patients with foreign material. It emphasises the necessity for a comprehensive assessment to identify and mitigate the risk of relapses, thereby ensuring optimal management and outcomes.
Assuntos
Bacteriemia , Listeria monocytogenes , Listeriose , Embolia Pulmonar , Humanos , Listeriose/tratamento farmacológico , Listeriose/microbiologia , Listeriose/diagnóstico , Listeria monocytogenes/isolamento & purificação , Bacteriemia/microbiologia , Bacteriemia/tratamento farmacológico , Embolia Pulmonar/microbiologia , Embolia Pulmonar/tratamento farmacológico , Recidiva , Desfibriladores Implantáveis/efeitos adversos , Masculino , Feminino , Antibacterianos/uso terapêutico , IdosoRESUMO
Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (>/=25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.
Assuntos
Albuminúria/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Albuminúria/complicações , Albuminúria/urina , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Nefropatias Diabéticas/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversosRESUMO
Over the past 5 years several case reports and cohort studies have been published that describe a sprue-like enteropathy (SLE) with abdominal pain, chronic diarrhea and weight loss, after taking angiotensin type 1 receptor blockers (ARB). The initial case series from the Mayo Clinic, which described 22 cases of olmesartan-induced SLE, was followed by numerous case descriptions for almost all ARBs. A total of 73 case reports have been described so far that show evidence of ARB-associated enteropathy with villous atrophy and full recovery 3-12 months after discontinuation of the sartan in question. Of these, 59 cases were olmesartan-associated cases of SLE, another 14 case reports have been published for telmisartan (4), valsartan (3), losartan (2), candesartan (1) and eprosartan (1). Based on the available cohort studies, ARB-associated intestinal malabsorption occurs in 9.8-14 cases per 100,000 patients treated with ARBs, the number treated to harm is over 31,000 patient-years. Although the majority of case reports have been published with olmesartan, in the cohort studies no clear difference within the ARBs can be ruled out. The SLE is rare but must be suspected and diagnostically investigated in every patient presenting with abdominal discomfort, chronic diarrhea and weight loss who is being treated with an ARB, after other causes have been ruled out. In such cases, discontinuing the ARB leads to a full recovery.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Enteropatias , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Antagonistas de Receptores de Angiotensina , Diarreia/induzido quimicamente , Humanos , Imidazóis/efeitos adversos , Enteropatias/induzido quimicamente , Enteropatias/patologia , Síndromes de Malabsorção/induzido quimicamente , Tetrazóis/efeitos adversosRESUMO
Elevated blood pressure remains a major cause of cardiovascular disease, disability, and premature death in Austria, with suboptimal rates of detection, treatment and control also in recent years. Management of hypertension is a common challenge for physicians with different spezializations. In an attempt to standardize diagnostic and therapeutic strategies and, ultimately, to increase the rate of patients with controlled blood pressure and to decrease the burden of cardiovascular disease, 13 Austrian medical societies reviewed the evidence regarding prevention, detection, workup, treatment and consequences of high blood pressure in general and in various clinical scenarios. The result is presented as the first national consensus on blood pressure. The authors and societies involved are convinced that a joint national effort is needed to decrease hypertension-related morbidity and mortality in our country.
Assuntos
Anti-Hipertensivos , Doenças Cardiovasculares , Hipertensão , Anti-Hipertensivos/uso terapêutico , Áustria , Pressão Sanguínea , Doenças Cardiovasculares/prevenção & controle , Consenso , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológicoRESUMO
BACKGROUND: Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS: This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS: Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION: The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.
Assuntos
Anti-Hipertensivos/administração & dosagem , Complicações do Diabetes/tratamento farmacológico , Di-Hidropiridinas/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Idoso , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Complicações do Diabetes/complicações , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/complicações , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nitrobenzenos , Piperazinas , Resultado do TratamentoAssuntos
Nefropatias Diabéticas/complicações , Endotelinas/antagonistas & inibidores , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Albuminúria/tratamento farmacológico , Albuminúria/etiologia , Atrasentana , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Proteinúria/fisiopatologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Resultado do TratamentoRESUMO
OBJECTIVE: We investigated the influence of angiotensin II receptor blockade on angiotensin II-induced, endothelin 1 (ET-1)-induced, and norepinephrine-induced vasoconstriction to further characterize interactions of the 3 major pressor systems. ET-1, angiotensin II, and norepinephrine act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to angiotensin II antagonism in the presence of ET-1, norepinephrine, and angiotensin II. METHODS: Twenty-five healthy men (mean age, 28.6 +/- 4 years; n = 14 CC, n = 9 CT, and n = 2 TT) were included in a double-blind, randomized, placebo-controlled crossover study. We used a laser Doppler imager to evaluate skin perfusion changes after injection of ET-1, angiotensin II, and norepinephrine (10(-18), 10(-16), and 10(-14) mol) after oral intake of the angiotensin II receptor antagonist valsartan (80 mg) or placebo. Data were analyzed with ANOVA or t test and are expressed as arbitrary perfusion units (PU) (mean +/- SEM). RESULTS: Valsartan abolished angiotensin II-induced vasoconstriction and, more importantly, also ET-1-induced vasoconstriction in the skin microcirculation (ET-1 placebo versus valsartan, - 33 +/- 10 PU versus +33 +/- 21 PU for CC [P = .02] and -71 +/- 25 PU versus +108 +/- 21 PU for CT/TT [P < .001]). For both ET-1 and angiotensin II, valsartan effects were greater in GNB3 835T-allele carriers (P = .007 and P = .03 for ET-1 and angiotensin II, respectively, for CC versus CT/TT). Norepinephrine-mediated constriction was not influenced by valsartan. These effects were independent of blood pressure. CONCLUSION: Our results indicate that the renin-angiotensin system may significantly contribute to ET-1-mediated microvascular responses. Valsartan inhibited local vasoconstriction to angiotensin II and ET-1 to a greater degree in carriers of the GNB3 825T allele, which adds to data from earlier studies implicating the C825T polymorphism as a pharmacogenetic marker for drug effects.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/genética , Proteínas Heterotriméricas de Ligação ao GTP/fisiologia , Polimorfismo Genético/genética , Pele/irrigação sanguínea , Tetrazóis/farmacologia , Valina/análogos & derivados , Vasoconstrição/efeitos dos fármacos , Adulto , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Genótipo , Humanos , Fluxometria por Laser-Doppler , Masculino , Microcirculação/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacologia , Polimorfismo Genético/fisiologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Pele/efeitos dos fármacos , Valina/farmacologia , Valsartana , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologiaRESUMO
High blood pressure is a major modifiable risk factor for all clinical manifestations of coronary artery disease (CAD). In people without known cardiovascular disease, the lowest systolic (down to 90-114 mmHg) and the lowest diastolic (down to 60-74 mmHg) pressures are associated with the lowest risk for developing CAD. Although diastolic blood pressure is the strongest predictor of CAD in younger and middle-aged people, this relationship becomes inverted and pulse pressure shows the strongest direct relationship with CAD in people above 60 years of age.Pathophysiological mechanisms of blood pressure as a risk factor for CAD are complex and include the influence of blood pressure as a physical force on the development of the atherosclerotic plaque, and the relationship between pulsatile hemodynamics/arterial stiffness and coronary perfusion. Treatment of arterial hypertension has been proven to prevent coronary events in patients without clinical CAD. In patients with established CAD, the effect of blood pressure lowering per se is beneficial, probably more than specific drugs or drug classes. The important exceptions are beta blockers (BBs), which are superior to all other drug classes for use after a recent myocardial infarction. Blood pressure targets in patients with established CAD have created controversy in the light of the so-called J-curve phenomenon, which describes an increase in coronary events at lower diastolic blood pressures. One explanation for this observation is that perfusion of the left ventricle occurs predominantly during diastole, and that coronary autoregulation may be exhausted with low diastolic blood pressure in the setting of left ventricular hypertrophy and atherosclerotic narrowing of the epicardial coronaries. The worst situation is a high systolic blood pressure in the presence of a low diastolic blood pressure, both a hallmark of increased aortic stiffness. However, the lowering of systolic blood pressure is clearly beneficial in this setting, even at the price of further lowering diastolic pressure. Primary blood pressure goal in patients with established CAD is below 140/90 mmHg. Recent studies suggest that a lower systolic blood pressure may be appropriate, whereas caution is advised with diastolic blood pressure below 60 mmHg.
Assuntos
Cardiologia/normas , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/prevenção & controle , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Guias de Prática Clínica como Assunto , Anti-Hipertensivos/administração & dosagem , Áustria , Causalidade , Medicina Baseada em Evidências/normas , Humanos , Prevalência , Fatores de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: A C825T polymorphism has been identified for the gene encoding the G-protein beta 3 subunit ( GNB3 ). The 825T allele is associated with hypertension and obesity, which in turn are closely linked with resistance to the metabolic and vascular effects of insulin. We hypothesized that venodilation in response to insulin would be impaired in GNB3 825T-allele carriers. Because vasodilatory properties of insulin are mainly mediated by nitric oxide, we also investigated the influence of the T-786C polymorphism of the gene for endothelial nitric oxide synthase ( NOS3 ) on insulin-mediated venous responses. METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 31 young, healthy men ( GNB3 C825T: 15 CC, 14 CT, and 2 TT; NOS3 T-786C: 14 TT, 13 TC, and 4 CC). Individual dose-response curves to phenylephrine (3.2-10,000 ng/min) were established, and veins were preconstricted by a constant infusion of phenylephrine at the individual dose needed to procure 70% of maximal constriction. Then insulin was infused (50-250,000 microU/min), and the changes in venous diameter were recorded. RESULTS: Venous response to insulin was biphasic, with venoconstriction at low doses being followed by venodilation at higher doses. Insulin dose-response curves of GNB3 825T-allele carriers were significantly shifted to the right (ANOVA, P < .001, versus CC). NOS3 T-786C-allele carrier status had no influence on insulin-induced vascular responses ( P = .60 for TC/CC versus TT). CONCLUSION: This study is the first to show the influence of a genetic polymorphism on insulin-mediated venodilation in men in vivo. Further studies are needed to determine whether these results translate to other vascular beds, and possible gender-specific differences remain to be investigated.
Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/genética , Insulina/farmacologia , Óxido Nítrico Sintase/genética , Vasodilatação/efeitos dos fármacos , Adulto , Alelos , Humanos , Insulina/genética , Masculino , Óxido Nítrico Sintase Tipo III , Polimorfismo Genético , Vasodilatação/genéticaRESUMO
OBJECTIVES: The present study sought to investigate the use of transthoracic Doppler harmonic echocardiography (TTDHE) to evaluate changes in coronary flow dynamics due to microvascular dysfunction. BACKGROUND: Coronary flow velocity reserve (CFVR) measurements by TTDHE are useful for assessing epicardial coronary artery stenoses. It remains unclear, however, if microvascular disease can be detected. METHODS: In 54 patients with chest pain, intracoronary Doppler (ICD) and TTDHE were used to measure average peak velocity at baseline and hyperemia. Significant coronary lesions had been ruled out by both angiography and intravascular ultrasound. Comparative measurements were performed in the distal left anterior descending coronary artery after intracoronary and intravenous administration of adenosine, and CFVR was calculated. Hypertensive patients (n = 25) were studied and compared to a control group (26 normotensive individuals). RESULTS: Three patients (5%) had to be excluded because of insufficient image quality or side effects. In both groups, TTDHE-derived CFVR data correlated closely with ICD measurements (group 1: y = 0.67x + 0.076, standard error of estimate [SEE] = 0.25, r = 0.87, p < 0.001; group 2: y = 0.64x + 1.11, SEE = 0.26, r = 0.87, p < 0.001). CFVR was lower in hypertensives than in normotensive controls (2.44 +/- 0.49 vs. 3.33 +/- 0.40, p < 0.001, cut point = 2.84). CONCLUSIONS: The newly described echocardiographic method is suitable for assessing microvascular dysfunction noninvasively and corresponds well to invasive measurements.
Assuntos
Circulação Coronária , Ecocardiografia Doppler , Hipertensão/fisiopatologia , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Vasos Coronários/fisiopatologia , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fluxo Sanguíneo Regional , Sensibilidade e EspecificidadeRESUMO
Hypertension is common in chronic renal disease and is a risk factor for the faster progression of renal damage, and reduction of blood pressure (BP) is an efficient way of preventing or slowing the progression of this damage. International guidelines recommend lowering BP to 140/90 mm Hg or less in patients with uncomplicated hypertension, and to 130/80 mm Hg or less for patients with diabetic or chronic renal disease. The attainment of these goals needs to be aggressively pursued with multidrug antihypertensive regimens, if needed. The pathogenesis of hypertensive renal damage involves mediators from various extracellular systems, including the renin-angiotensin system (RAS). Proteinuria, which occurs as a consequence of elevated intraglomerular pressure, is also directly nephrotoxic. As well as protecting the kidneys by reducing BP, antihypertensive drugs can also have direct effects on intrarenal mechanisms of damage, such as increased glomerular pressure and proteinuria. Antihypertensive drugs that have direct effects on intrarenal mechanisms may, therefore, have nephroprotective effects additional to those resulting from reductions in arterial BP. Whereas BP-lowering effects are common to all antihypertensive drugs, intrarenal effects differ between classes and between individual drugs within certain classes. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have beneficial effects on proteinuria and declining renal function that appear to be mediated by factors additional to their effects on BP. These RAS inhibitors are recommended as a first-line antihypertensive approach in patients with chronic kidney disease. The addition of diuretics and calcium channel antagonists to RAS inhibitor therapy is also considered to be a rational strategy to reduce BP and preserve renal function. Calcium channel antagonists are a highly heterogeneous class of compounds, and it appears that some agents are more suitable for use in patients with chronic renal disease than others. Manidipine is a third-generation dihydropyridine (DHP) calcium channel antagonist that blocks both L and T-type calcium channels. Unlike older-generation DHPs, which preferentially act on L-type channels, manidipine has been shown to have beneficial effects on intrarenal haemodynamics, proteinuria and other measures of renal functional decline in the first clinical trials involving hypertensive patients with chronic renal failure. Preliminary results from a trial in diabetic patients who had uncontrolled hypertension and microalbuminuria despite optimal therapy with an ACE inhibitor or an ARB suggest that manidipine may be an excellent antihypertensive drug in combination with RAS inhibitor treatment in order to normalise BP and albumin excretion in patients with diabetes.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Complicações do Diabetes/tratamento farmacológico , Hipertensão/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Di-Hidropiridinas/uso terapêutico , Quimioterapia Combinada , Humanos , Hipertensão/fisiopatologia , Hipertensão Renal/tratamento farmacológico , Rim/irrigação sanguínea , Rim/fisiopatologia , Nitrobenzenos , Piperazinas , Proteinúria/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Circulação Renal/efeitos dos fármacosRESUMO
Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.
Assuntos
Angiotensina II/farmacologia , Endotelina-1/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/genética , Norepinefrina/farmacologia , Pele/irrigação sanguínea , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Adulto , Alelos , Sinergismo Farmacológico , Antagonistas dos Receptores de Endotelina , Inibidores Enzimáticos/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Heterozigoto , Humanos , Fluxometria por Laser-Doppler , Masculino , Microcirculação/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Subunidades Proteicas , Ioimbina/farmacologia , ômega-N-Metilarginina/farmacologiaRESUMO
OBJECTIVE: We used the orally available endothelin A (ETA) receptor antagonist darusentan to characterize interactions between the major blood pressure-regulating systems in healthy men. Mediators of the endothelin system, the sympathetic nervous system, and the renin-angiotensin system act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to ETA antagonism in the presence of endothelin 1 (ET-1), norepinephrine (NA), and angiotensin II (ANGII). METHODS: Thirty-seven individuals were included in a randomized, double-blind, placebo-controlled, crossover trial with 100 mg darusentan. Systemic hemodynamics and plasma ET-1, NA, and ANGII concentrations were assessed. Local studies were performed in the dorsal hand veins (n=18) and skin microcirculation (n=12), respectively. RESULTS: Darusentan lowered systolic and diastolic blood pressure ( P <.001 versus placebo) without any differences according to genotype (mean maximum Delta systolic blood pressure, -7 +/- 2 mmHg for CT/TT versus -5 +/- 3 mmHg for CC, P=.37; mean maximum Delta diastolic blood pressure, -3 +/- 2 mmHg for CT/TT versus -4 +/- 2 mmHg for CC, P=.96). Venoconstriction to ET-1 and NA was not affected by ET A blockade in either group; however, carriers of the 825T allele demonstrated a markedly enhanced venoconstriction to ET-1 and NA (median effective concentration [ED50] for ET-1 after darusentan [placebo]: 2.5 +/- 0.2 pmol/min for CT/TT [2.7 +/- 0.3 pmol/min], P=.42; 3.9 +/- 0.6 pmol/min for CC [4.6 +/- 0.3 pmol/min], P=.42; P=.046 [P=.0005] for CT/TT versus CC) (ED50 for NA after darusentan [placebo]: 5.2 +/- 1.2 ng/min for CT/TT [7.3 +/- 1.2 ng/min], P=.20; 32.9 +/- 7.1 ng/min for CC [19.7 +/- 5.5 ng/min], P=.75; P=.0008 [P=.026] for CT/TT versus CC). Darusentan dilated veins at baseline in CC homozygous subjects (+0.21 +/- 0.05 mm, P=.004 versus placebo). Systemic ET A antagonism inhibited constriction to ET-1 and also to NA and ANGII in the skin microcirculation without differences according to genotype (ET-1, P=.017 for all individuals versus placebo; NA, P=.0005; and ANGII, P=.002). CONCLUSION: GNB3 C825T allele carrier status did not influence systemic hemodynamic or local vascular responses to ET A blockade with darusentan in young, healthy men. However, it determined venoconstriction to exogenous ET-1 and NA. Darusentan markedly inhibited not only ET-1-induced but also NA-induced and ANGII-induced vasoconstriction in the skin microcirculation. In contrast, it had no effects on either ET-1-mediated or NA-mediated venoconstriction, indicating that, in the presence of high local ET-1 concentrations, constrictive endothelin B receptors may be of greater importance in the venous vasculature than has been recognized so far.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Antagonistas do Receptor de Endotelina A , Proteínas Heterotriméricas de Ligação ao GTP/genética , Polimorfismo Genético/genética , Adulto , Angiotensina II/sangue , Estudos Cross-Over , Método Duplo-Cego , Endotelinas/genética , Endotelinas/fisiologia , Feminino , Genótipo , Mãos/irrigação sanguínea , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Microcirculação/efeitos dos fármacos , Neurotransmissores/metabolismo , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/genética , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Pele/irrigação sanguíneaRESUMO
OBJECTIVE: The ultimate mode of action by which nitroglycerin elicits vasodilation remains elusive. Animal studies point to an involvement of pertussis toxin-sensitive G proteins. The 825T allele of the GNB3 C825T polymorphism in the gene encoding the G protein beta3 subunit is associated with enhanced signal transduction via pertussis toxin-sensitive pathways in vitro. We hypothesized that G proteins have a role in nitroglycerin-mediated vasodilation and that carriers of the 825T allele would exhibit a stronger response to nitroglycerin. METHODS: We used the linear variable transducer technique to compare dorsal hand vein compliance in 28 young, healthy men with and without the T allele (n = 15 CC, n = 8 CT, and n = 5 TT). After individual dose-response curves to phenylephrine had been established, veins were preconstricted to 70% of the maximal phenylephrine-induced constriction. Nitroglycerin was then infused in ascending doses (0.02-2000 ng/min), and the vasodilatory response was measured. RESULTS: The vasodilatory response to nitroglycerin was significantly greater in carriers of the 825T allele. The maximal response to nitroglycerin was 102% +/- 6% venodilation in the CT/TT group and 78% +/- 5% in the CC control group (P =.0045) (mean difference, -24% +/- 8%; 95% confidence interval, 8%-40%). Comparison of the nitroglycerin dose-response curves by ANOVA confirmed an enhanced nitroglycerin-induced venodilation in 825T-allele carriers (P <.0001). CONCLUSION: Our results suggest that the GNB3 C825T polymorphism determines venous response to nitroglycerin and that G proteins may be involved in the signal transduction pathway.
Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/genética , Nitroglicerina/farmacologia , Vasodilatadores/farmacologia , Adulto , Alelos , Índice de Massa Corporal , Relação Dose-Resposta a Droga , Mãos/irrigação sanguínea , Heterozigoto , Homozigoto , Humanos , Masculino , Polimorfismo Genético/genética , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
The T allele of the C825T polymorphism in the gene encoding the G-protein beta 3 subunit (GNB3) is associated with hypertension. An enhanced signal transduction in response to alpha(2)-adrenergic receptor stimulation has been shown in carriers of the T allele in vitro. We hypothesized that T allele carriers would show an enhanced antihypertensive response to stimulation of central alpha(2)-adrenergic receptors by clonidine. We compared the response to intravenous clonidine in 30 young, healthy male subjects with and without the T allele (15 CC, 10 CT, and 5 TT). Clonidine lowered blood pressure and total peripheral resistance, lengthened the duration of electromechanical systole (QS(2)c), and slowed down pulse wave velocity. Carriers of the T allele showed significantly greater reductions in systolic blood pressure (P =.009; mean change +/- SEM: CC, -8.9 +/- 0.5; CT and TT, -10.6 +/- 0.4) and total peripheral resistance (P <.0001; mean change +/- SEM: CC, 40 +/- 17; CT and TT, -48 +/- 14) and more marked lengthening of QS(2)c (P =.002; mean change +/- SEM: CC, 2.2 +/- 0.5; CT and TT, 4.7 +/- 0.6) and slowing of pulse wave velocity (P =.012; mean change +/- SEM: CC, -0.25 +/- 0.02; CT and TT, -0.33 +/- 0.03). The results of this study suggest that the 825T allele may be a relevant pharmacogenetic marker in the use of centrally acting sympatholytic drugs.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Clonidina/farmacologia , Citosina , Proteínas Heterotriméricas de Ligação ao GTP/genética , Polimorfismo Genético/fisiologia , Subunidades Proteicas/genética , Timina , Adulto , Análise de Variância , Humanos , MasculinoRESUMO
OBJECTIVES: Augmentation index is a parameter measured by pulse wave analysis (PWA) and is used as a surrogate measure of arterial stiffness. The aim of this study was to assess whether augmentation index is associated with cardiovascular risk, as well as to evaluate whether the determinants of augmentation index are different in patients with cardiovascular disease compared to healthy subjects. DESIGN AND METHODS: We related augmentation index to risk scores in 216 subjects with or without a cardiovascular disease. Subjects without cardiovascular disease were classified according to the 'coronary risk chart' of the European Society of Cardiology (ESC), and those with cardiovascular disease were classified using the SMART (Second Manifestations of ARTerial disease) score and the EPOZ (Epidemiological Prevention study Of Zoetermeer) function. Augmentation index was derived by PWA using carotid applanation tonometry. Augmentation index was also correlated to age, blood pressure, heart rate, smoking history, cholesterol, height, body mass index and gender in subjects categorized as healthy or with cardiovascular disease. RESULTS: Augmentation index significantly increased with increasing risk scores (P < 0.0001) and was significantly correlated to cardiovascular risk (ESC: P < 0.0001; SMART: P < 0.0001; EPOZ: P < 0.0001). In subjects with and without cardiovascular disease, augmentation index was correlated with diastolic blood pressure, heart rate, height and gender. Age was found to be significantly correlated with augmentation index only in healthy subjects but not in those with atherosclerotic disease. CONCLUSIONS: Our findings suggest that augmentation index may be a useful marker of cardiovascular risk. Further studies are required to investigate the relationship between age and augmentation index in subjects with atherosclerotic disease.
Assuntos
Doenças Cardiovasculares/etiologia , Artérias Carótidas/fisiopatologia , Pulso Arterial , Adulto , Idoso , Arteriosclerose/fisiopatologia , Pressão Sanguínea , Estatura , Doenças Cardiovasculares/fisiopatologia , Estudos de Casos e Controles , Doença das Coronárias/etiologia , Doença das Coronárias/fisiopatologia , Estudos Transversais , Elasticidade , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Fatores de Risco , Caracteres SexuaisRESUMO
OBJECTIVE: Endothelin-A-receptor-antagonists inhibit angiotensin II- and noradrenaline-induced vasoconstriction. Whether functional constrictive endothelin-B-receptors play a role in the endothelin-1-mediated potentiation of vasoconstriction to angiotensin II and noradrenaline is thus far unknown. METHODS: We studied the effects of noradrenaline and angiotensin II (10 mol/l) in the presence of exogenous endothelin-1 (10 mol/l) with and without selective endothelin-B-receptor-blockade by BQ-788 (10 mol/l) and dual receptor blockade with BQ-788 and the endothelin-A-selective antagonist BQ-123 (10 mol/l) in 14 healthy male volunteers (aged 20-28). Studies were performed in the human skin microcirculation under in vivo conditions using laser-Doppler flowmetry and double injection technique. The area under the time-response curve of all doses was calculated. RESULTS: Endothelin-1 potentiated the effects of angiotensin II and noradrenaline (-944 +/- 139 perfusion units (PU), P < 0.01; -926 +/- 117 PU, P < 0.05, respectively). In the presence of BQ-788, the potentiating effect of endothelin-1 was significantly blunted (-624 +/- 132 PU, P < 0.01; -549 +/- 136 PU, P < 0.01, respectively). In the presence of BQ-123 and BQ-788 the vasoconstriction was fully inhibited (431 +/- 108 PU, P < 0.001 and 421 +/- 86 PU, P < 0.001, respectively). CONCLUSIONS: These data suggest that functional vasoconstrictive endothelin-B receptors on vascular smooth muscle cells may contribute to the potentiating effects of high local concentrations of endothelin-1 on the vasoconstriction to noradrenaline and angiotensin II in human microcirculation.
Assuntos
Angiotensina II/farmacologia , Antagonistas do Receptor de Endotelina B , Endotelina-1/farmacologia , Norepinefrina/farmacologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Adulto , Angiotensina II/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Antagonistas do Receptor de Endotelina A , Humanos , Fluxometria por Laser-Doppler , Masculino , Microcirculação/efeitos dos fármacos , Norepinefrina/administração & dosagem , Peptídeos Cíclicos/farmacologia , Pele/irrigação sanguínea , Vasoconstritores/administração & dosagemRESUMO
OBJECTIVE: Pulse wave velocity (PWV) is a classic marker of vascular stiffness. Recent studies showed that heart rate is an important determinant of PWV. The purpose of this study was to evaluate the role of myocardial function in determining PWV under resting conditions and under adrenergic stimulation. DESIGN AND METHODS: Hemodynamic parameters were investigated under resting conditions in 102 young, healthy males and under stimulation of either beta- or alpha(2)-adrenoceptors in six young, healthy males. PWV was determined from pressure tracing over the carotid and femoral artery. Central hemodynamics were assessed by impedance cardiography and systolic time intervals. Simple (r) and multiple (beta) regression analyses were used to assess the relationships between PWV and hemodynamic parameters. RESULTS: Under resting conditions, PWV was correlated to age (beta = 0.259, P = 0.0052), diastolic blood pressure (beta = 0.279, P = 0.0072) and left ventricular ejection time (beta = -0.314, P = 0.0277). Under alpha(2)-adrenergic stimulation PWV was only correlated to diastolic blood pressure (DBP) (beta = 0.806, P = 0.0020). Under beta-adrenergic stimulation PWV was only correlated to left ventricular ejection time index (r = -0.52, P = 0.0325). CONCLUSIONS: Left ventricular ejection time may be an important determinant of pulse wave velocity under resting and adrenergic conditions in young, healthy males. Further studies are needed to evaluate this relationship in other populations including females and patients with cardiovascular disease.
Assuntos
Pulso Arterial , Volume Sistólico , Função Ventricular Esquerda , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Pressão Sanguínea/fisiologia , Diástole , Coração/efeitos dos fármacos , Hemodinâmica , Humanos , Masculino , Nordefrin/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Valores de Referência , Análise de Regressão , Descanso , Sístole , Vasoconstritores/farmacologiaRESUMO
Clinical disorders with an isolated lack of monocytes have not been reported hitherto. The authors describe the case of a 38-year-old woman with pulmonary alveolar proteinosis and nephrotic syndrome caused by membranous nephropathy and widespread papillomatosis of the vulva. Immunologic studies showed normal levels of immunoglobulins and C2, C3c, and C4. Cryoglobulins and paraproteins were not detected. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, and antiglomerular basement membrane antibodies were not detectable. Circulating immune complexes containing C1q, immunoglobulin G, and immunoglobulin M were elevated. The patient showed immunodeficiency that was characterized by complete anergy to intracutaneously administered recall antigens in vivo and to recall antigens in vitro. The immunodeficiency was accompanied by the absence of monocytes in the peripheral blood as well as in bone marrow cultures. In parallel, long-term bone marrow cultures and colony-forming cell assays did not result in the growth of monocytes. Mitogenic agents that require the presence of monocytes induced almost no T-cell proliferation (Concanavalin A: 5,841 counts per minute [cpm]), whereas agents that act directly on T cells induced intense T-cell proliferation (phytohemagglutinin: 110,001 cpm; OKT 3: 120,616 cpm; and pokeweed mitogen: 89,474 cpm). These data suggest that the pulmonary renal syndrome in this patient results from the lack of monocytes and the consecutive defect of antigen presentation and antigen clearance.
Assuntos
Monócitos , Síndrome Nefrótica/etiologia , Proteinose Alveolar Pulmonar/etiologia , Adulto , Apresentação de Antígeno , Evolução Fatal , Feminino , Glomerulonefrite Membranosa/complicações , Humanos , Hipertensão Pulmonar/etiologia , Síndrome Nefrótica/imunologia , Síndrome Nefrótica/fisiopatologia , Papiloma/complicações , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/fisiopatologia , Insuficiência Respiratória/etiologia , Neoplasias Vulvares/complicaçõesRESUMO
BACKGROUND: A C825T polymorphism was recently identified in the gene encoding the beta3 subunit of heterotrimeric G-proteins (GNB3). The T-allele is significantly associated with essential hypertension and obesity. In order to further explore a possible pathogenetic link between the T-allele and impaired glucose tolerance we studied metabolic and haemodynamic responses to oral glucose loading in young, healthy subjects with and without the 825T-allele. METHODS: Twelve subjects with and 10 without the 825T-allele were investigated at rest and following glucose ingestion (75 g). Blood glucose, serum insulin and haemodynamics were determined prior to and over 2 hours following glucose ingestion. We non-invasively measured stroke volume (SV, by impedance-cardiography), blood pressure (BP), heart rate (HR), and systolic-time-intervals. Cardiac output (CO) was calculated from HR and SV. Total peripheral resistance was calculated from CO and BP. Metabolic and haemodynamic changes were quantified by maximal responses and by calculation of areas under the concentration time profile (AUC). Significances of differences between subjects with and without the T-allele were determined by unpaired two-tailed t-tests. A p < 0.05 was considered statistically significant. RESULTS: Metabolic and haemodynamic parameters at baseline were very similar between both groups. The presence of the T-allele did not alter the response of any metabolic or haemodynamic parameter to glucose loading. CONCLUSIONS: In conclusion, this study does not support the hypothesis that the C825T polymorphism may serve as a genetic marker of early impaired glucose tolerance.