Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.
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PMID:Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension. 1064 41

HIV infection has reached endemic proportions in many African countries. In addition, HIV infection is a significant cause of renal dysfunction in the United States. HIV patients are at higher risk of developing hypertension at a younger age than the general population. Predisposing factors for developing hypertension include vasculitis in small, medium, and large vessels in the form of leukocytoclastic vasculitis, and aneurysms of the large vessels such as the carotid, femoral, and abdominal aorta with impairment of flow to the renal arteries. A syndrome of acquired glucocorticoid resistance has been described in patients with HIV with hypercortisolism and a lower affinity of the glucocorticoid receptors. The syndrome is characterized clinically by weakness, hypertension or hypotension, and skin pigmentation changes. Acute and chronic renal failure is often associated with HIV infection. The associated dysfunction in water and salt handling often induces hypertension. Finally, atherosclerosis has been described in young adults with HIV infection secondary to receiving highly active antiretroviral therapy.
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PMID:Hypertension in the HIV-infected patient. 1099 24

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.
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PMID:Role of endothelin-1 in hypertension and vascular disease. 1141 70

1. Over the past decade, aldosterone has been shown to have direct extra-epithelial actions and substantial (patho)physiological roles in the cardiovascular system in the context of inappropriate salt status. In experimental studies on uninephrectomized rats given 0.9% NaCl solution to drink, these include blood pressure elevation via activation of circumventricular mineralocorticoid receptors in the central nervous system and production of pressure-independent cardiac hypertrophy and fibrosis by a direct effect on the heart. 2. In the Randomized Aldactone Evaluation Study (RALES) trial, patients with severe congestive heart failure (CHF) were continued on their current therapy (angiotensin-converting enzyme inhibitor, diuretic etc.) and given either placebo or spironolactone at an average dose of 26 mg/day. Mineralocorticoid receptor inhibition was accompanied by a 30% improvement in mortality and 35% less hospitalization, striking confirmation of a pathophysiological role for aldosterone in CHF. 3. Although the current basic and clinical studies are conflicting, there is evidence both for aldosterone synthesis by the failing human heart and for substantial cardiac metabolism of aldosterone. The extent to which this potential paracrine source for aldosterone may be involved in cardiac hypertrophy and cardiac fibrosis remains to be established. 4. Belatedly, aldosterone-induced proteins (e.g. serum and glucocorticoid-regulated kinase (SGK)) have been identified in epithelial mineralocorticoid target tissue. Studies are currently in progress on the cellular and molecular mechanisms involved in the coronary vasculitis provoked early in the mineralocorticoid/salt model, which, in turn, appears to trigger the subsequent perivascular and interstitial fibrotic response.
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PMID:Mineralocorticoids and cardiac fibrosis: the decade in review. 1190 3

There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.
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PMID:Mineralocorticoid action and sodium-hydrogen exchange: studies in experimental cardiac fibrosis. 1293 57

We report one new case of hemolytic-uremic syndrome (HUS) and one case of digital necrosis after treatment with gemcitabine (Gemzar). Case 1, a 34-year-old man, was given first-line metastatic treatment with gemcitabine for a adenocarcinoma of the pancreas. After a cumulative dose of 10 000 mg/m2 gemcitabine, the onset of subacute renal failure associated with hemolytic anemia of mechanical origin was observed. A diagnosis of probable gemcitabine-induced thrombotic microangiopathy was arrived at. Symptoms resolved after stopping the chemotherapy, in spite of the progression of the disease. Case 2, a 61-year-old man, was administered a combination of gemcitabine and a platinum salt as first-line metastatic treatment for carcinoma of the bladder urothelium. Following a cumulative dose of 10 000 mg/m2 of gemcitabine, the patient suffered from bilateral peripheral vascular disease of somewhat acute onset with hemorrhagic lesions of the finger pads that became necrotic. The work-up was negative and a causal relationship was attributed to gemcitabine. The patient made good progress when given an i.v. infusion of Ilomedine (iloprost trometamol) and chemotherapy was withdrawn. We conclude that gemcitabine must be added to the list of drugs that cause HUS and necrotizing vasculitis.
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PMID:Thrombotic microangiopathy and digital necrosis: two unrecognized toxicities of gemcitabine. 1459 78

In recent years, it has been clarified that aldosterone can directly damage various organs, such as the heart, blood vessel, and kidneys, via non-epithelial mineralocorticoid receptors, independent of changes in blood pressure. Anti-aldosterone drugs have been clinically reported to be useful for their organ-protecting effects. The fact that these effects have been considered important for almost 10 years seems to indicate that aldosterone-induced organ damage can develop as a consequence of plasma aldosterone levels being in disproportion to salt status. In a previous study, cardiac fibrosis could not be induced in an experimental model of hyperaldosteronism with a low-salt diet. It is, therefore, extremely important to understand the relationship between plasma aldosterone level and inappropriate salt balance when considering diseases or states for which an anti-aldosterone drug is called for. In this paper we review the fundamental and clinical studies reported to date, mainly to investigate the pathology of organ damage induced by aldosterone and excess salt. Aldosterone-induced direct organ damage mediated through vasculitis essentially requires salt, which is inappropriate for plasma aldosterone level, and studies performed from this standpoint may provide a clue to the clarification of the involvement of salt in the actions of aldosterone via non-epithelial mineralocorticoid receptors. In humans, it is also strongly suggested that organ damage may occur, even at a plasma aldosterone level within a normal range, if salt intake is imbalanced to the aldosterone level. This means that the new aldosterone blocker eplerenone may also have significance as a drug inhibiting inflammation, possibly serving as a trigger of organ damage.
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PMID:Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. 1519 76

Calcitonin gene-related peptide is a potent vasodilator neuropeptide that is localized in perivascular sensory nerves. To determine whether alpha-calcitonin gene-related peptide possesses protective activity against hypertension-induced end organ damage, hypertension was induced in alpha-calcitonin gene-related/calcitonin peptide knockout and wild-type mice by uninephrectomy, deoxycorticosteroid administration, and 0.9% saline drinking water. These mice were instrumented previously for long-term telemetric blood pressure recording. Control groups were sham-operated and given tap water. Mean arterial pressures were determined, and 3 weeks after initiation of each protocol, tissues were taken for histopathologic studies. The deoxycorticosteroid-salt protocol produced a significant 35% mean arterial pressure increase in both mouse strains. No pathological changes were observed in sections of aortas and femoral arteries from any of the groups studied. Likewise, heart and kidney sections from the hypertensive wild-type mice showed no pathological changes compared with their normotensive counterparts. In contrast, marked vasculitis was seen in the heart sections from the deoxycorticosteroid-salt-treated alpha-calcitonin gene-related peptide knockout mice with thickening and inflammation of the vessel walls. In addition, myocarditis and focal epicarditis with areas of myocardial necrosis were present. Kidneys of these mice exhibited prominent glomerular changes including congestion of the capillary loops, focal mesangial and crescent proliferation, and focal histocytic infiltration. Urinary microalbumin was significantly higher in the hypertensive alpha-calcitonin gene-related peptide knockout compared with hypertensive wild-type mice. These data suggest that deletion of the alpha-calcitonin gene-related peptide gene makes the heart and kidneys more vulnerable to hypertension-induced end organ damage.
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PMID:Calcitonin gene-related peptide protects against hypertension-induced heart and kidney damage. 1558 78

Loma salmonae is a common gill parasite of salmonids, and essentially all species in the genus Oncorhynchus are susceptible. Infections occur in both fresh and salt water. Loma salmonae is directly transmissible by ingestion of spores or infected tissue. The parasite infects the wall of blood vessels of various organs, but the gill is the primary site of infection. Initial infection occurs in the intestine, and xenomas are easily detected in the gills by standard histology at 4-6 wk post-exposure. A few presporogonic stages of the parasite are found in the heart endothelium prior to xenoma formation in the gills. Ultrastructure studies of early infections demonstrated that wandering blood cells transport the meronts to the gills, and that merogony occurs in pillar cells and other cells underlying the gill endothelium. Xenomas develop in these cells, resulting in hypertrophied host cells filled with spores. Xenomas ultimately rupture, and are associated with severe inflammation in which free spores are found in macrophages. The parasites are most pathogenic during this phase of the infection, resulting in severe vasculitis and clinical disease. Both rainbow trout (Oncorhynchus mykiss) and Chinook salmon (Oncorhynchus ishawytscha) recover from infections, but free spores persist in kidney and spleen phagocytes for many months after xenomas are absent in Chinook salmon. Fish that have recovered from the infection show strong immunity against the parasite, lasting up to 1 year. Fish are susceptible to infection by other routes of exposure by spores; co-habitation, anal gavage, and intramuscular, intraperitoneal and intravascular injection. Autoinfection probably occurs following release of spores in blood vessels after xenomas rupture. The optimal temperature for L. salmonae infections is 15-17 degrees C, with a permissive range of 11-20 degrees C.
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PMID:Review of the sequential development of Loma salmonae (Microsporidia) based on experimental infections of rainbow trout (Oncorhynchus mykiss) and Chinook salmon (O. tshawytscha). 1600 65

A 9-week-year-old boy was admitted to the pediatric clinic after 12 hours of fever and diarrhoea. On admission he had a fever of 40 degrees C, rhinitis and moderate diarrhoea. Blood tests were normal, except for elevated CRP (89 mg/L). The tentative diagnosis was viral gastroenteritis, and peroral rehydration with a hypertone glucose-salt-mixture was started. CRP reached a maximum of 199 mg/L, and the boy stayed febrile throughout the next days. Stool examination revealed Enterovirus. After several clinical examinations, findings included a reactive cervical glandular node and mild conjunctivitis. When the child had been febrile for five days, he was admitted to an echocardiography, which showed dilated coronary arteries with abnormal caliber variations and a small amount of pericardial fluid. Since he fulfilled only three of the five criteria of classical Kawasaki disease, he was diagnosed as having neonatal, incomplete Kawasaki disease. Kawasaki disease is an immunologic vasculitis that appears mainly in children between three months and 12 years of age. Only 2% of patients with Kawasaki disease are less than three months old. Neonates with Kawasaki disease often have an atypical presentation of symptoms and have a particular risk of developing coronary artery aneurysms with potentially fatal outcome. With this case-report we will stress the importance of considering Kawasaki disease in neonates with fever of unknown origin.
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PMID:[A 9-week-old boy with fever and diarrhoea]. 1794 Nov 56


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