Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bosentan has proven 4-month efficacy in patients with HIV-associated pulmonary arterial hypertension (PAH-HIV). Herein, the long-term outcome of unselected PAH-HIV patients treated with first-line bosentan is described. Data for 59 consecutive World Health Organization (WHO) functional class II-IV PAH-HIV patients treated with first-line bosentan between May 2002 and July 2007 were analysed. HIV status, 6-min walk distance and haemodynamics were assessed at baseline, after 4 months and every 6-12 months thereafter. After 4 months, 6-min walk distance increased from 358+/-98 to 435+/-89 m and pulmonary vascular resistance decreased from 737+/-328 to 476+/-302 dyn x s x cm(-5). At the final evaluation (29+/-15 months), 6-min walk distance remained stable and pulmonary vascular resistance decreased further to 444+/-356 dyn x s x cm(-5). Haemodynamics normalised in 10 patients. At their last evaluation, these 10 patients were in WHO functional class I, with a 6-min walk distance of 532+/-52 m. Overall survival estimates were 93, 86 and 66% at 1, 2 and 3 yrs, respectively. Bosentan was safe when combined with highly active antiretroviral therapy, with no negative impact on HIV infection control. The present data confirm the long-term benefits of bosentan therapy in HIV-associated pulmonary arterial hypertension patients with improvements in symptoms, 6-min walk distance and haemodynamics, and with favourable overall survival.
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PMID:Long-term effects of bosentan in patients with HIV-associated pulmonary arterial hypertension. 1879 6

Small doses of DCA administered at intervals in pellet form are capable of raising the blood pressure, altering renal function, and changing the electrolyte pattern in the intact rat. The concomitant feeding of 1 per cent saline intensifies the process. The elevation in blood pressure occurs prior to demonstrable changes in renal excretory function. The alteration in renal function consists first of a reduction in C(PAH) with the maintenance of a normal filtration rate. Filtration fraction is elevated while there is no reduction in renal plasma flow per unit of tubular excretory tissue. Later, filtration is interfered with and renal ischemia occurs. The electrolyte change is characterized by a sustained fall in plasma K and Cl, a rise in plasma Na, an increase in the Na/Cl ratio, and finally an elevation of Na plus K. Plasma Ca is unaffected. These observations suggest the possible etiological significance of the adrenal cortex in some types of hypertension.
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PMID:The effect of desoxycorticosterone acetate on blood pressure, renal function, and electrolyte pattern in the intact rat. 1890 18

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF-alpha on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF-alpha (0.33 ng.g(-1).min(-1)) in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. The urine was collected from a cannula inserted into the bladder. Following the 60-min control clearance period, TNF-alpha infusion was initiated and 15 min were given for stabilization followed by another 60-min clearance period. TNF-alpha alone (n = 7) caused decreases in RBF (7.9 +/- 0.3 to 6.4 +/- 0.3 ml.min(-1).g(-1)) and GFR (1.04 +/- 0.06 to 0.62 +/- 0.08 ml.min(-1).g(-1)) as well as increases in absolute (0.8 +/- 0.3 to 1.4 +/- 0.3 micromol.min(-1).g(-1)) and fractional excretion of sodium (0.5 +/- 0.2 to 1.5 +/- 0.4%) without affecting arterial pressure. TNF-alpha also increased 8-isoprostane excretion (8.10 +/- 1.09 to 11.13 +/- 1.34 pg.min(-1).g(-1)). Pretreatment with TNF-alpha blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF-alpha infusion; n = 6) abolished these responses. However, TNF-alpha induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O(2)(-)) scavenger tempol (2 microg.g(-1).min(-1); n = 6). Pretreatment with nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (0.1 microg.g(-1).min(-1); n = 6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-alpha. These data suggest that TNF-alpha induces renal vasoconstriction and hypofiltration via enhancing the activity of O(2)(-) and thus reducing the activity of NO. The natriuretic response to TNF-alpha is related to its direct effects on tubular sodium reabsorption.
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PMID:Tumor necrosis factor-alpha induces renal vasoconstriction as well as natriuresis in mice. 1892 87

Pulmonary hypertension (PH) can occur as either a primary or a secondary process, and in general, its presence increases overall morbidity and mortality. Importantly, the majority of prior studies have been in the setting of idiopathic pulmonary arterial hypertension (IPAH); thus the following discussion focuses on IPAH. Because the majority of available diagnostic strategies lack sensitivity and specificity, the physician must maintain a high index of suspicion in considering PAH. This article provides an overview of the available diagnostic studies for PAH with a particular focus on hemodynamic assessment. Novel approaches to the often delayed diagnosis of PAH are being studied and are also discussed here.
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PMID:Diagnosis and hemodynamic assessment of pulmonary arterial hypertension. 1963 79

Pulmonary veno-occlusive disease (PVOD) is a rare disorder and can be misdiagnosed as idiopathic pulmonary arterial hypertension (iPAH). PVOD and iPAH often share a similar clinical presentation, genetic background, and hemodynamic profile. PVOD accounts for 5 to 10% of cases initially considered as iPAH. When compared with iPAH, PVOD is characterized by a higher male:female ratio, higher tobacco exposure, and lower PaO (2) at rest, diffusing capacity for carbon monoxide (DLCO), and oxygen saturation nadir during the 6-minute walk test. High-resolution computed tomography (HRCT) of the chest may be suggestive of PVOD in the presence of centrilobular ground-glass opacities, septal lines, and lymph node enlargement. Additionally, occult alveolar hemorrhage is associated with PVOD. Definitive diagnosis necessitates a surgical lung biopsy; however, this procedure is exceedingly high risk in this patient population and is generally not recommended. Therefore, a noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests, and bronchoalveolar lavage may be helpful to detect PVOD. In contrast with iPAH, PVOD is characterized by an even poorer prognosis and the possibility of developing severe pulmonary edema with specific PAH therapy. Lung transplantation remains the treatment of choice, but cautious use of specific PAH therapy can be helpful in select patients while awaiting this intervention.
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PMID:Idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: similarities and differences. 1963 80

Voltage-gated potassium (Kv)1.5 is decreased in pulmonary arteries (PAs) of patients with idiopathic pulmonary arterial hypertension (IPAH) and in experimental models including mice with SM22alpha-targeted overexpression of the serotonin transporter (5-HTT). The mechanisms underlying these abnormalities, however, remain unknown. Dichloroacetate (DCA) inhibits chronic hypoxia- or monocrotaline-induced PAH by inhibiting nuclear factor of activated T-cells (NFAT)c2 and increasing Kv1.5. Therefore, we hypothesized that DCA could regress established PAH in SM22-5-HTT+ mice. We evaluated pulmonary hemodynamics, vascular remodeling, NFATc2, and Kv1.5 protein in 20-wk-old SM22-5-HTT+ or wild-type mice treated for 1, 7, and 21 d with DCA, cyclosporine-A (NFAT inhibitor), or vehicle. DCA partially reversed PAH in SM22-5-HTT+ mice by decreasing proliferation and increasing apoptosis in muscularized PAs. Furthermore, serotonin (10(-8)-10(-6) M) dose-dependently increased PA-smooth muscle cell (PA-SMC) proliferation in culture (EC(50)=0.97 x 10(-7) M) and DCA (5 x 10(-4) M) vs. PBS markedly reduced the growth of PA-SMC from IPAH and control patients treated with the highest dose of serotonin by 50 and 30%, respectively. Finally, although serotonin induces NFATc2 activation in PA-SMCs, inhibition of NFATc2 alone with cyclosporine-A was not sufficient for reversing PAH in this model. Our results support the possibility that DCA may be an interesting agent for investigation in patients with PAH.
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PMID:Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. 1967 40

Pulmonary arterial hypertension is a life-threatening, vasculoproliferative disease of the lung, which is characterized by vasoconstriction and remodeling of small pulmonary arteries. Drugs for the treatment of PAH mainly address the increased vascular tone. Substances like prostacyclin, endothelin-receptor-antagonists and phosphodiesterase-5-inhibitors have been approved for the treatment of PAH and represent the current therapeutic options. The development of a causal treatment aiming a normalization of the vessel wall structure is the current focus of research. The key events in disease progression are represented by increased proliferation, migration and a resistance to apoptosis of pulmonary vascular cells. Therefore, new non-vasoactive drugs are investigated in relevant preclinical animal models of pulmonary arterial hypertension. Some of these substances, like tyrosine kinase inhibitors, elastase inhibitors and phosphodiesterase-1-inhibitors, could not only attenuate (anti-remodeling) but reverse (reverse-remodeling) the disease. Additionally, new vasodilators, like soluble guanylate cyclase stimulators and activators, addressing well-known and new signaling pathways are currently under investigation. Taken together, with increasing insight into the pathology of PAH, several novel drug targets and treatments have emerged which may improve the management of patients and which efficacy is currently addressed in preclinical studies and clinical trials.
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PMID:[Update: Preclinical developments for the treatment of pulmonary arterial hypertension]. 1971 4

In view of the manifold options for mono- and combination therapy that have now emerged for patients with pulmonary (arterial) hypertension (PAH/PH), controlled clinical trials can only provide part of the information needed for optimal management. In order to gather adequate data on PAH/PH treatment in routine clinical care, the ongoing CompERA-XL register prospectively documents consecutive patients with newly initiated treatment of PAH/PAH since May 2007. The internet-based register fulfils high quality standards through several measures (minimum centre contribution of at least 10 patients per year, automated plausibility checks of data at entry, queries, monitoring with source data verification). It can be applied, among further purposes, for quality assurance: individual centers can confidentially compare their results with the combined outcome of other centers and the recommendations from guidelines. The register, currently active in 7 countries, presently follows up 785 patients with any kind of treatment for PH/PAH (now at 626 patient years). It is expected that the register contributes to optimization of specific drug therapy for PAH and PH.
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PMID:[International, prospective register for the documentation of first-line and maintenance therapy in patients with pulmonary hypertension (CompERA-XL)]. 1971 9

There have been steady efforts to develop a combined response index for systemic sclerosis (CRISS). A parallel and equally successful effort has been made by an Expert Panel on Outcome Measures in PAH related to Systemic Sclerosis (EPOSS) to measure effect in treatment of pulmonary arterial hypertension of systemic sclerosis (PAH-SSc). CRISS conducted a Delphi process combined with expert review to identify 11 candidate domains for inclusion in a core set of outcomes for SSc clinical trials: soluble biomarkers, cardiac, digital ulcers, gastrointestinal, global health, health related quality of life (HRQOL) and function, musculoskeletal, pulmonary, Raynaud's, renal, and skin. Tools within domains were also agreed upon. Concentrating on one aspect of disease, PAH, EPOSS also conducted a Delphi process and judged the following domains as the most appropriate for randomized controlled trials in PAH-SSc: lung vascular/pulmonary arterial pressure, cardiac function, exercise testing; severity of dyspnea, discontinuation of treatment; quality of life/activities of daily living; global state; and survival. Possible useful tools within each domain were also agreed on. Patient derived, physician derived, and objective measures of response will be included and combined with the idea that each reflects different aspects of PAH (EPOSS) and overall disease (CRISS) although this assumption may not prove true and can be separated if statistically and clinically valid to do so. In either case, prospective studies will require measurement of all domains, and tools are required and will be developed to define appropriate combined measures of response. CRISS and EPOSS are being developed through the OMERACT process. Through Delphi process and literature review significant progress has been made for both indices, and prospective data are being collected.
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PMID:Measures of response in clinical trials of systemic sclerosis: the Combined Response Index for Systemic Sclerosis (CRISS) and Outcome Measures in Pulmonary Arterial Hypertension related to Systemic Sclerosis (EPOSS). 1982 Feb 25

The association of 9 urinary monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) with serum C-reactive protein (CRP) was investigated using the National Health and Nutrition Examination Survey (NHANES) 2003-2004. The unweighted number of participants included was 999, which represented 139,362,776 persons in the non-institutionalized US population. In adjusted logistic regressions, two OH-PAHs, 2-hydroxyphenanthrene and 9-hydroxyfluorene, were associated with elevated CRP (>3mg/l). Logistic regressions were adjusted for age, gender, race, exercise, body mass index, smoking status, diabetes, and hypertension. 2-Hydroxyphenanthrene >148ng/g creatinine had an odds ratio of 3.17 (95% CI 1.73-5.81) compared to 2-hydroxyphenanthrene < or =48ng/g creatinine, and 9-hydroxyfluorene >749ng/g creatinine had an odds ratio of 2.28 (95% CI 1.08-4.83) compared to 9-hydroxyfluorene < or =160ng/g creatinine. Intermediate levels of 2-hydroxyphenanthrene (49-148ng/g creatinine), and 9-hydroxyfluorene (161-749ng/g creatinine) were also significantly associated with elevated CRP compared to the respective reference categories. In a combined analysis, OH-PAHs were classified as low, medium, and high. Low OH-PAH was 2-hydroxyphenanthrene < or =48ng/g creatinine and 9-hydroxyfluorene < or =160ng/g creatinine. High OH-PAH was 2-hydroxyphenanthrene >148ng/g creatinine or 9-hydroxyfluorene >749ng/g creatinine. Participants not assigned to the low or high categories were classified as having medium OH-PAH concentrations. Compared to the low OH-PAH group, high OH-PAH had an odds ratio of 3.60 (95% CI 2.01-6.46) in an adjusted logistic regression. Given that inflammation (characterized here by CRP) is an important factor in the development of atherosclerosis and cardiovascular disease, these results suggest a role for OH-PAHs in the progression of atherosclerosis.
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PMID:Association of urinary polycyclic aromatic hydrocarbons and serum C-reactive protein. 1983 15


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