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

Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and alpha 2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal alpha 2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal alpha 2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal alpha 2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and alpha 2-adrenergic receptors while on normal salt diets. Short-term (10-14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal alpha 2-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal alpha 2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.
 ...
PMID:Renal catecholamines and alpha 2-adrenergic receptors in salt-related and genetic hypertension. 303 85

The prostaglandin G2/H2 synthase (cyclooxygenase, COX) is a key regulatory enzyme of prostanoid synthesis pathway. The message-encoding COX isoenzymes (constitutive COX-1 and inducible COX-2) have been described in the rat kidney. However, there is scarce information on the localization of COX-2 in the kidney, although it has been recently reported to be localized in the macula densa. The present study was designed to evaluate the localization of COX-2 in adult rat kidneys. Normal rat kidneys (n=10) were fixed in Bouin and were immunostained with specific antibodies against COX-2 by the peroxidase method. The cellular origin of COX-2 was assessed by the immunostaining of serial consecutive sections with antibodies against Na-K-ATPase, Tamm-Horsfall glycoprotein, H-K-ATPase, kallikrein, and macrophages. COX-2 was consistently observed in a subset of tubular cells located in the cortex and in the outer medulla. The staining of serial sections showed that the COX-2+ cells contained both Na-K-ATPase and Tamm-Horsfall, indicating that they corresponded to thick ascending limb (TAL) cells. They were observed at a considerable distance from the corresponding macula densa, although occasionally they were observed close to glomeruli. The COX-2 staining in the TAL cells was not abolished by dexamethasone treatment (1 to 20 mg/kg), suggesting its constitutive expression in normal kidneys. The presence of COX-2 in TAL (a tubular segment postulated to be devoid of COX-1) may contribute to the handling of ions through local production of prostaglandins.
Hypertension 1997 Sep
PMID:Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells. 932 6

The proinflammatory cytokine interleukin-1beta (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A2 (PLA2), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA2 and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in approximately 200-fold and 15-fold increases in PGE2 and 6-keto-PGF1alpha (the stable metabolite of PGI2), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA2 inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA2 products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.
Hypertension 1998 Jan
PMID:Phospholipase A2 metabolites regulate inducible nitric oxide synthase in myocytes. 945 6

Kidney failure is the common end of hypertension and renal diseases. Several authors have suggested that vasodilatory prostaglandins participate in the hemodynamic mechanism responsible for the development of kidney failure. However, the mechanism by which prostaglandins are increased in renal disease is not clear. Recently, 2 isoforms of the enzyme responsible for prostaglandin synthesis, cyclooxygenase, have been described as cyclooxygenase-1 (COX-1), a constitutive isoform, and cyclooxygenase-2 (COX-2), an inducible isoform. In the present study, we investigated whether COX-2-dependent prostaglandins participate in the evolution of renal functional changes after renal ablation. We inhibited prostaglandin synthesis by COX-1 and COX-2 with indomethacin (3 mg/kg) and prostaglandin synthesis by COX-2 with NS-398 (3 mg/kg) and tested the effect of these inhibitors on the renal functional changes elicited by renal ablation. Renal ablation produced an increase in urinary volume, protein, and prostaglandin E(2), whereas urinary sodium and potassium were not affected and urinary osmolarity decreased; treatment with indomethacin or NS-398 partially prevented the renal functional changes elicited by renal ablation. Immunoblots for COX showed an increase in the expression of COX-2 protein 2 days after renal ablation. Furthermore, COX-2 mRNA expression was increased 1 day after renal ablation. These data suggest that COX-2-dependent prostaglandins participate in the renal mechanisms associated with the development of renal functional changes after renal ablation.
Hypertension 1999 Oct
PMID:Effect of cyclooxygenase-2 inhibition on renal function after renal ablation. 1052 72

Prostaglandins are local mediators/modulators of kinin effects in the kidney. The prostaglandin G2/H2 synthase (cyclooxygenase, COX) is the key regulatory enzyme of prostanoid synthesis pathway. Two COX isoenzymes (constitutive or COX-1 and inducible or COX-2) have been described in the rat kidney. We have demonstrated the presence of COX-2 in a subset of thick ascending limb of Henle (TAL) cells in normal adult rats [Vio, C.P., Cespedes, C., Gallardo, P., Masferrer, J.L., 1997. Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells. Hypertension 30, 687-692]. The present work was designed to evaluate COX-2 during the postnatal development of the rat kidney. Kidneys from Sprague-Dawley rats were studied during postnatal days 5, 10, 15 days and adult (60 days) (n = 8 each group). Renal tissue was immunostained with specific antibodies against COX-2. COX-2 was observed exclusively in TAL. A small number of COX-2 cells were observed during early postnatal life, increasing from day 5 to 15, and decreasing thereafter to reach adult levels. During maximal expression, near 20% of TAL were COX-2 positive whereas in early postnatal period and adults, only 2% of TAL cells contain COX-2. This transient induction of COX-2 during development suggest that the enzyme is necessary for the postnatal development of the kidney. This change in COX-2 seems to correspond to a derepression of COX-2 gene expression secondary to low levels of glucocorticoids.
 ...
PMID:Postnatal development of cyclooxygenase-2 in the rat kidney. 1060 46

The basic tenet of the cyclooxygenase-2 (COX-2) hypothesis rests on the fact that sparing of inhibition of COX-1 should result in greater safety than if both COX isoforms are inhibited. This increase in safety should be most evident in those organs and tissues in which COX-1 alone has important, necessary physiologic functions (e.g., the stomach and platelets). Data from large clinical trials are now available to support the superior gastrointestinal safety of COX-2 inhibitors, not only for endoscopic endpoints but also for clinically significant outcomes. Additionally, lack of effect on platelets has been demonstrated at doses many times higher than being used clinically. Unfortunately, the COX-2 inhibitors still retain some of the side effects seen with traditional dual COX inhibitors (nonsteroidal anti-inflammatory drugs), namely, effects on the kidney that may manifest as an increased incidence of hypertension, edema, and associated clinical states. Similarly, effects on reproductive functions, endothelial function, and wound healing are theoretically possible but need to be evaluated in well-controlled clinical trials.
 ...
PMID:Cyclooxygenase-2--specific inhibitors: are they safe? 1116 97

Heme oxygenase enzymes (HO-1 and HO-2) catalyze the conversion of heme to biliverdin, free iron, and carbon monoxide (CO). Heme and products derived from its metabolism potentially influence renal function and blood pressure by affecting the expression and/or activity of hemeproteins, including cytochrome P450 (CYP4A) monooxygenases and cyclooxygenases (COX-1 and COX-2). We studied HO isoform expression and examined the effect of HO-1 induction by SnCl(2) on CYP4A and COX expression and activity in the rat kidney. HO-1 protein levels in kidney tissues from untreated rats were barely detectable, whereas HO-2 protein was expressed in all kidney structures examined and its levels were higher in the outer medulla followed by the inner medulla/papilla and cortex. HO-2 expression along the nephron followed its regional distribution, ie, the highest levels were detected in the medullary thick ascending limb (mTAL) and inner medullary collecting ducts followed by proximal tubules. SnCl(2) Treatment did not significantly affect HO-2 expression or distribution; however, it markedly increased HO-1 protein in the inner and outer medulla, specifically, in the inner medullary collecting ducts and mTAL. CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis were the highest in the outer medulla followed by the cortex and inner medulla/papilla. SnCl(2) treatment reduced cortical and inner medullary CYP4A protein levels by 60% and 50% and inhibited 20-HETE synthesis by 90% and 60%, respectively. Despite a significant induction of HO-1 protein in the outer medulla, CYP4A expression and 20-HETE synthesis were hardly affected. SnCl(2) treatment did not affect COX-1 expression but markedly reduced cortical and medullary COX-2 protein levels. We conclude that HO isoform expression is segmented within the kidney and along the nephron and that treatment with an HO-1 inducer suppressed the levels of CYP4A and COX-2 proteins in a tissue-specific manner with concomitant effects on their activity. Such interactions may play an important role in the regulation of renal function.
Hypertension 2002 Feb
PMID:Regulation of cyclooxygenase- and cytochrome p450-derived eicosanoids by heme oxygenase in the rat kidney. 1188 23

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
 ...
PMID:Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. 1196 66

Despite the ubiquitous use of both over-the-counter and prescription nonsteroidal anti-inflammatory drugs (NSAIDs), clinical syndromes-NSAID-related hypertension, salt and water retention, edema, and hyperkalemia-are highly infrequent. Nevertheless, they remain a concern, and patient populations at risk for renal adverse effects from NSAIDs can be prospectively identified. Patients at risk include those with age-related declines in glomerular filtration rate; those with hypovolemia, particularly patients taking loop diuretics; and those with congestive heart failure, cirrhosis, or nephrosis. The following patient populations are at higher risk for increases in blood pressure with concomitant use of an NSAID and an antihypertensive: those with congestive heart failure, liver disease, or kidney disease, and those taking angiotensin-converting enzyme inhibitors or diuretics. Nonselective NSAIDs and COX (cyclooxygenase)-2-selective inhibitors (coxibs) appear to have similar effects on renal function if dosed equivalently, and standard precautions to avoid renal toxicity with use of nonselective NSAIDs apply to coxibs.
 ...
PMID:Renal effects of nonselective NSAIDs and coxibs. 1208 95

Defects and variation in the relative amount of protein subunits in the mitochondrial electron transport chain (ETC) have been hypothesized to be involved, in part, in the pathogenesis of pulmonary hypertension syndrome (PHS), a costly metabolic disease. Thus, the major objective of this study was to determine whether differences in relative amounts of cytochrome c oxidase subunit I and II (COX I and II) can be detected by immunohistochemistry and digital image analysis in muscle tissue of broilers with PHS compared to control broilers. Cross sections of the breast muscle (pectoralis major) were stained with monoclonal antibodies for COX I and II. Relative areas of multiple microscope viewing fields (400x) per tissue section of COX I and II were quantified by counting immunopositive pixels on the digital images. Whereas the number of immunopositive pixels for COX II was higher in PHS birds compared to controls, there were no difference for COX I. The amount of COX II was positively correlated with the right to total ventricular weight ratio (RV:TV), suggesting that there may be increased expression of COX II associated with severity of pulmonary arterial hypertension. Thus, it is possible that COX II expression in PHS broiler may be involved in the pathogenesis of PHS.
 ...
PMID:Immunohistochemical evidence of cytochrome C oxidase subunit II involvement in pulmonary hypertension syndrome (PHS) in broilers. 1221 17


1 2 3 4 5 6 7 Next >>