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)

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.
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PMID:Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. 1061 71

The most common form of familial vascular dementia is considered to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is now also increasingly manifest in the United Kingdom. CADASIL has been previously dubbed as a familial form of Binswanger disease. However, unlike in Binswanger disease CADASIL does not involve hypertension or other risk factors associated with cardiovascular disease. CADASIL appears to be essentially a disorder of the arteries that is linked to single missense mutations in the NOTCH 3 gene locus on chromosome 19. The pathogenesis of the disorder or the genetic mechanism leading to brain infarcts and dementia is not known. The elucidation of the microvascular pathology evident in CADASIL may be an interesting way to delineate effects of defective genes on brain cells from systemic vascular influences.
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PMID:Hereditary vascular dementia linked to notch 3 mutations. CADASIL in British families. 1081 18

Wild-type or equipotent variants of recombinant staphylokinase (rSak) were given intra-arterially (as a 2 mg bolus injection followed by an infusion of 1 mg/h or 0.5 mg/h overnight, with concomitant heparin [1000 IU/h]) to 191 patients of less than 80 years (62 +/- 1 years, mean +/- SEM), with a peripheral arterial occlusion (PAO) of less than 120 days (mean 14 +/- 1 days, median 11 days, 5 to 95 percentiles 3 to 30 days). Ninety nine patients presented with acute or subacute ischemia, 57 with severe claudication, 33 with chronic rest pain and 2 with gangrene. Occlusion occurred in 122 native arteries and in 69 grafts. Revascularization was complete in 83 percent (158/191), partial in 13 percent (24/191) and absent in 4 percent (7/191) after administration of 12 +/- 0.5 mg rSak over 14 +/- 0.7 h. Complete revascularization of acute occlusions of popliteal or more distal arteries was less frequent (60 percent, 15/25) than of acute occlusions of more proximal native arteries (95 percent, 37/39, p <0.001) or grafts (89 percent, 50/56, p = 0.005). Additional endovascular procedures were performed in 47 percent and subsequent elective bypass surgery in 23 percent of patients. Major bleeding occurred in 12 percent (23/191), one month mortality was 3.1 percent (6/191) and one year mortality was 6.9 percent (12/174). However, four patients (2.1 percent) had an intracranial bleeding following therapy: a 85 year old woman with severe diabetic arteriopathy, who was included in violation of the protocol, a 79 and a 74-year-old woman and a 74-year-old man, all with severe hypertension and limb threatening ischemia; these four patients died within two months after treatment. Amputations were performed within the first year in 16 of 162 surviving patients (9.8 percent): in 7 percent (7/96) with an occluded native artery and 14 percent (9/66) with an occluded graft (p = 0.19). No significant difference in lysis rate, one month mortality or one year amputation-free survival was observed in occlusions of recent onset (< or =14 days, n = 126) as compared to occlusions of longer duration (>14 days, n = 65). Treatment was interrupted prematurely in 4 patients because of a suspected allergic reaction. Fibrinogen levels remained unaffected during treatment (3.3 +/- 0.1 g/l before vs. 3.3 +/- 0.1 g/l after infusion, n = 167). In conclusion, rSak appears to be a highly effective thrombolytic agent in patients with PAO, resulting in a low one month mortality (3.1 percent) and a high one year amputation free survival (84 percent), with an acceptable incidence of major bleedings, but with occasional fatal intracranial hemorrhages.
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PMID:Outcome and one year follow-up of intra-arterial staphylokinase in 191 patients with peripheral arterial occlusion. 1082 59

Chronic inhibition of the renin angiotensin system prevents increased BP and renal injury in N(G)-nitro-L-arginine methyl ester (L-NAME) hypertension. However, a relationship between plasma renin activity and the protective effect of chronic angiotensin II (Ang II) blockade has not been established. With this background, this study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in L-NAME hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 +/- 6 mmHg for control, 107 +/- 2 mmHg for DOCA, 151 +/- 5 mmHg for L-NAME, 123 +/- 2 mmHg for L-NAME + losartan, 170 +/- 3 mmHg for L-NAME + DOCA, and 171 +/- 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA-treated rats. Plasma protein was significantly reduced in the L-NAME + DOCA group when compared with control and L-NAME groups, whereas no significant differences were observed in the other groups. Plasma renin activity was suppressed in the DOCA (0.55 +/- 0.2) and L-NAME + DOCA (0.60 +/- 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 +/- 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, which suggests that DOCA transforms L-NAME hypertension into an Ang II-independent model of hypertension. These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.
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PMID:Deoxycorticosterone suppresses the effects of losartan in nitric oxide-deficient hypertensive rats. 1105 74

The middle aortic syndrome, with diffuse narrowing of the thoracic and abdominal aorta, was present in 10 of 18 patients with Williams' syndrome (55%). There were 3 thoracic coarctations, and 2 abdominal coarctations, with gradients greater than 20 mmHg across the zone of narrowing. Seven patients had mild renal arterial stenosis, and 6 had visceral arterial stenoses. Ten were hypertensive. Measured dimensions of the aortic lumen failed to increase with age in 3 males who had serial angiographic studies. One developed mesenteric arterial stenosis, with mild bilateral renal arterial stenoses, between the ages of 9 and 19 years. Aortic intravascular ultrasound performed in 2 patients confirmed abnormally thick vessel walls with small lumens. Diffusely narrowed and thick-walled stiff arteries, lacking elastin, are a feature of Williams' syndrome. The arteriopathy tends to progress with age, and systemic hypertension is common in teenagers and beyond. The middle aortic syndrome was present in more than half our patients, and does not necessarily reflect a bias because of cardiologic referral. Aortography with measurement of aortic diameters and delineation of the visceral branches is an important requirement for complete evaluation of patients with Williams' syndrome.
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PMID:The middle aortic syndrome: an important feature of Williams' syndrome. 1111 92

One of the traits of type I and II diabetes lies in the presence of extensive rheological disorders. Rheological changes appear during infancy, mainly in type I diabetes: decreased red cell deformability, leukocyte rigidity, monocyte activation, alteration in microvessel flux (sludge) and functions. Such disorders are however sensitive to insulin and metabolic correction for a long period. Macrorheological disorders develop at the time of puberty and when lipid changes and vascular complications appear (hypertension, visceral obesity, atherosclerosis). Such changes have potent effects on diabetic arteriopathy, as shown by altered TcPO(2). Numerous medical teams are taking into account red cell aggregation measurements reflecting post-capillary flux behavior. In addition, a proposed score may be used based on fibrinogen, hematocrit, triglycerides as viscosity acting factors, and endothelial markers, Willebrand factor and VCAM-1. An increased score is an indication of suspected distal functional alteration of microvessels.
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PMID:[Are rheological markers of poor prognosis present in diabetic arteriopathies?]. 1131 17

We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracycline-controlled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10-12 weeks of age, was higher in tTA+/RVCH+ mice than in nonbinary transgenic littermates (136 +/- 4 vs. 109 +/- 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA+/RVCH+ mice vs. littermates (0.82 +/- 0.1 vs. 0.42 +/- 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA+/RVCH+ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.
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PMID:Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. 1141 17

There is currently intense interest in the development of gene therapy for cardiovascular disease. The stimulation of therapeutic angiogenesis for ischemic heart disease has been one of the areas of greatest promise. Encouraging results have been obtained with the angiogenic cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in animal models, leading to clinical trials in ischemic heart disease. VEGF also has therapeutic potential in a second area of cardiovascular gene therapy, the enhancement of arterioprotective endothelial functions to prevent postangioplasty restenosis and bypass graft arteriopathy. The endothelial cell growth and survival functions of VEGF promote endothelial regeneration, whereas VEGF-induced endothelial production of NO and prostacyclin inhibits vascular smooth muscle cell proliferation. Inhibition of neointimal hyperplasia may also be achieved by gene transfer of endothelial NO synthase (eNOS), PGI synthase, or cell cycle regulators (retinoblastoma, cyclin or cyclin-dependent kinase inhibitors, p53, growth arrest homeobox gene, fas ligand) or antisense oligonucleotides to c-myb, c-myc, proliferating cell nuclear antigen, and transcription factors such as nuclear factor kappaB and E2F. An improved understanding of etiologically complex pathologies involving the interplay of genes and the environment, such as atherosclerosis and systemic hypertension, has led to the identification of new targets for gene therapy, with the potential to alleviate inherited genetic defects such as familial hypercholesterolemia. The use of vasodilator gene overexpression and antisense knockdown of vasoconstrictors to reduce blood pressure in animal models of systemic and pulmonary hypertension offers the prospect of gene therapy for human hypertensive disease. The renin-angiotensin system has been the target of choice for antihypertensive strategies because of its wide distribution and additional effects on fibrinolytic and oxidative stress pathways. Gene therapy in cardiovascular disease has an exciting future but remains at an early stage. Further developments in gene transfer vector technology and the identification of additional target genes will be required before its full therapeutic potential can be realized.
Hypertension 2001 Nov
PMID:Gene therapy for cardiovascular disease: a case for cautious optimism. 1171 25

The clinicopathologic features of two Japanese sisters with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are described. Neither patient had a history of hypertension, and both experienced cerebrovascular events before reaching their forties. Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs. MRI showed extensive cerebral white matter lesions, which revealed remarkable arteriosclerotic changes on autopsy.
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PMID:Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. 1188 51

Pulmonary Arterial Hypertension (PAH) is a term which has been recently defined at the WHO-meeting in Evian and includes Primary Pulmonary Hypertension (PPH), as well as PAH related to specific pathological conditions. The poor prognosis of the disease seems to be related to a peculiar pathological anatomy, consisting of characteristic lesions of small, muscular pulmonary arteries. In addition to common hypertrophy of the tunica media, other proliferative lesions such as intimal thickening or plexiform lesions are summarized under the term of plexogenic arteriopathy. Moreover, in situ thrombosis and rarely isolated pulmonary arteritis can be observed in lungs of patients displaying PAH. Different pathomechanisms explaining these morphological changes of pulmonary vasculature have been discussed in the past, including endothelial and thrombocytic dysfunction, deregulated vasoconstriction, coagulation abnormalities, or cancer-like growth. Furthermore, latest studies on the importance of inflammatory mediators, so-called chemokines, in the lungs of PAH patients have brought a possible inflammatory component of the disease into consideration. Finally, recent identification of responsible gene mutations in subgroups of patients, as well as latest developments in genetic screening have shed some light into the modus of inheritance. Nevertheless, the role and impact of these different pathomechanisms have yet to be better defined.
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PMID:Pathology and aspects of pathogenesis in pulmonary arterial hypertension. 1273 75


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