UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The macula densa detects changes in NaCl concentration in tubular fluid and transmits a feedback signal, known as tubuloglomerular feedback (TGF), which helps to control glomerular afferent arteriole resistance. We and other investigators have reported that synthesis of NO in the macula densa inhibits TGF. NO can be scavenged by superoxide (O(-)(2)) to form peroxynitrite, effectively reducing the bioavailability of NO; there is growing evidence that O(-)(2) regulates vascular tone in the kidney. We hypothesized that O(-)(2) produced in the macula densa enhances TGF and this effect acts only in an autocrine manner within the cells of the macula densa. Afferent arterioles and attached macula densas from Sprague-Dawley rats were simultaneously microperfused in vitro and TGF response examined before and after perfusing the tubular lumen, bath, or vascular lumen with a superoxide scavenger. The macula densa was perfused with solutions containing either 5 mmol/L Na(+) and 3 mmol/L Cl(-) (low NaCl) or 80 mmol/L Na(+) and 77 mmol/L Cl(-) (high NaCl) while keeping pressure in the afferent arteriole constant at 60 mm Hg. When 10(-4) M Tempol, a stable membrane-permeant superoxide dismutase (SOD) mimetic, was added to the tubular lumen, it inhibited TGF by 56% (before Tempol: TGF, 3.2 +/- 0.3 microm; after Tempol: TGF, 1.4 +/- 0.2 microm; n=6; P<0.05, control versus Tempol). Adding Tempol to the bath inhibited TGF by 48% (before Tempol: TGF, 2.5 +/- 0.25 microm; after Tempol: TGF, 1.3 +/- 0.18 microm; n=6; P<0.05). However, adding Tempol to the vessel lumen did not change TGF response significantly (before Tempol: TGF, 2.7 +/- 0.37 microm; after Tempol: TGF, 3.2 +/- 0.25 microm; n=7; P=0.25). When 300 U/mL of the enzyme SOD, which is not membrane-permeant, was added to either the tubular lumen or bath, it had no effect on TGF response. Finally, to determine whether the effect of O(-)(2) in the macula densa is mediated by its scavenging of NO, 7-nitroindazole (7-NI) was added to the macula densa to inhibit neuronal nitric oxide synthase (nNOS). In the presence of 7-NI, Tempol had no effect (7-NI only: TGF, 3.0 +/- 0.4 microm; 7-NI plus Tempol: TGF, 2.8 +/- 0.5 microm; n=6; P=0.343). Our findings suggest that (1) reducing O(-)(2) increases the bioavailability of NO, which inhibits TGF, (2) both O(-)(2) and NO act within the macula densa, and (3) O(-)(2) appears to have no effect on its own.
Hypertension 2002 Feb
PMID:Mechanism by which superoxide potentiates tubuloglomerular feedback. 1188 20

This study investigated the role of NO in mediating the renal sympathetic nerve-mediated increases in proximal tubular fluid reabsorption (Jva). In inactin-anesthetized Wistar rats, renal sympathetic nerve stimulation (15 V, 2 ms) at 0.75 and 1.0 Hz did not change blood pressure or glomerular filtration rate but did decrease urine flow and sodium excretion in a frequency-related fashion by 40% to 50% at 1.0 Hz (both, P<0.01). Renal nerve stimulation in control animals increased Jva by 11% at 0.75 Hz (P<0.05) and 31% at 1.0 Hz (P<0.01). Intraluminal N(omega)-nitro-L-arginine methyl ester (L-NAME) resulted in a higher basal Jva (19%, P<0.05), and renal nerve stimulation had no effect on Jva. When L-NAME plus sodium nitroprusside was present intraluminally, however, there were frequency-dependent increases in Jva that were similar in pattern and magnitude to the control rats. Introduction of the relatively selective nNOS blocker 7-nitroindazole intraluminally, at 10(-6) and 10(-4) M, raised basal Jva by 18% and 24%, respectively (P<0.01), and renal nerve stimulation did not change Jva. Intraluminal aminoguanidine (10(-4) M), a relatively selective iNOS blocker, did not affect basal Jva, which remained unchanged during renal nerve stimulation. These data are consistent with NO exerting a tonic inhibitory action on the basal levels of Jva, which, in part, is caused by NO generated by the nNOS isoform. Moreover, the findings have revealed that the presence of NO is necessary to ensure that renal nerves can stimulate fluid reabsorption by the proximal tubules, requiring NO generated from both nNOS and iNOS.
Hypertension 2002 Mar 01
PMID:Nitric oxide modulation of neurally induced proximal tubular fluid reabsorption in the rat. 1189 65

Sympathetic nervous system (SNS) activity, measured by norepinephrine (NE) turnover rate, was greater in the posterior hypothalamic (PH) nuclei, the paraventricular nuclei (PVN), and the locus coeruleus (LC) of 5/6 nephrectomised (CRF) rats than of control rats. NE secretion from the PH was also greater in CRF than in control rats. These findings demonstrate that SNS activity plays an important role in the genesis of hypertension associated with CRF. The increase in central SNS activity was mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NOx) production. Because angiotensin II may stimulate the central SNS, we tested the hypothesis that losartan, a specific angiotensin II AT(1)-receptor antagonist, may lower blood pressure (BP), at least in part, by central noradrenergic inhibition. To this end, we studied two groups of CRF rats. One group received losartan (10 mg/kg body weight) in drinking water between the 3rd and 4th week after nephrectomy, the second group received drinking water without losartan. SNS activity was measured by NE secretion from the PH using the microdialysis technique. NOS-mRNA gene expression was also measured by RT-PCR in the PH, PVN, and LC of CRF and control rats. Losartan reduced systolic BP from 184+/-3.7 to 152+/-3.1 mmHg and NE secretion from the PH from 340+/-9.7 to 247+/-4.8 pg/ml. CRF rats treated with losartan manifested a significant (p<0.01) increase in the expression of nNOS-mRNA in the PH (from 84+/-1.2 to 99+/-2.6), the PVN (from 44+/-1.5 to 63+/-2.1), and the LC (from 59+/-6.7 to 76+/-2.1). CRF rats also manifested a significant increase (p<0.01) in the expression of IL-1beta the PH (from 41.6+/-2.8 to 54.3+/-1.4), PVN (from 44+/-1.9 to 54+/-1.5), and LC (from 35.5+/-1.6 to 53.5+/-1.9). In conclusion, these studies suggest that the antihypertensive action of losartan in CRF rats may be mediated, at least in part, by inhibition of central SNS outflow. The studies also suggest that the inhibitory action of losartan on the SNS may be mediated by activation of IL-1beta, which, in turn, stimulates nNOS, an important modulator of central SNS activity.
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PMID:Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure. 1196 14

Intrarenal injection of phenol in rats causes a persistent elevation in blood pressure (BP) and in norepinephrine (NE) secretion from the posterior hypothalamus (PH), and downregulation of neuronal nitric oxide synthase (nNOS) and interleukin-1beta (IL-1beta) in the PH. These studies suggest that afferent impulses from the kidney to the brain may be responsible for hypertension associated with renal injury. Downregulation of nNOS and IL-1beta, two modulators of sympathetic nervous system (SNS) activity may mediate this activation. In this study we measured the effects of intrarenal phenol injection on peripheral SNS activity by direct renal nerve recording, plasma NE, nNOS, and IL-1beta abundance in the brain. We also determined whether renal denervation or administration of clonidine prevented these effects of phenol. Acutely, the phenol injection increased both afferent and efferent renal sympathetic nerve activity, decreased urinary sodium excretion, and increased plasma NE. Three weeks after the phenol injection, BP and plasma NE remained elevated. Renal denervation and pretreatment with clonidine prevented the increase in BP and plasma NE caused by phenol. Chronic renal injury caused by phenol was associated with decreased abundance of IL-1beta and nNOS in the PH. These studies have shown that a renal injury caused by phenol injection increases BP and central as well as peripheral SNS activity, which persist long after the injury. Renal denervation and antiadrenergic drugs abolish the effects of phenol on BP and plasma NE. Because NO and IL-1beta modulate SNS activity, the stimulatory action of phenol on the SNS could be mediated by downregulation of nNOS and IL-1beta in the brain.
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PMID:Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. 1216 Jan 95

Gene therapy refers to the transfer of specific genes to the host tissue to intervene in a disease process, with resultant alleviation of the symptoms of a particular disease. Cardiovascular gene transfer is not only a powerful technique for studying the function of specific genes in cardiovascular biology and pathobiology, but also a novel and promising strategy for treating cardiovascular diseases. Since the mid-1990s, nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO) from L-arginine, has received considerable attention as a potential candidate for cardiovascular gene therapy, because NO exerts critical and diverse functions in the cardiovascular system, and abnormalities in NO biology are apparent in a number of cardiovascular disease processes including cerebral vasospasm, atherosclerosis, postangioplasty restenosis, transplant vasculopathy, hypertension, diabetes mellitus, impotence and delayed wound healing. There are three NOS isoforms, i.e., endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results. This review will discuss the rationale of NOS gene therapy in different cardiovascular disease settings and summarize the results of experimental NOS gene therapy from various animal models of cardiovascular disease to date.
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PMID:Nitric oxide synthase gene therapy for cardiovascular disease. 1223 10

The pathophysiology of hypertension in chronic renal failure is complex, but sodium retention and volume expansion play an important role. High salt intake may aggravate hypertension in chronic renal failure, but the mechanisms of this action are not well established. In this study, we have tested the hypothesis that high salt intake aggravates hypertension in rats with chronic renal failure by decreasing nitric oxide synthase (NOS) expression and by increasing sympathetic nervous system activity. Sprague-Dawley rats were subjected to 5/6 nephrectomy (CRF) or sham-operation and fed a regular rat chow. Half of the rats were allowed to drink distilled water and half water containing 1% NaCl. Blood pressure was measured weekly by tail-cuff. Four weeks after nephrectomy or sham-surgery, animals were sacrificed and brains immediately separated and frozen. Norepinephrine (NE) content and NOS-mRNA gene expression were measured in the posterior hypothalamic (PH) nuclei, the locus coeruleus (LC), the paraventricular nuclei (PVN), and in the mesenteric vessels. The endogenous concentration of NE was greater in the PH, LC, and PVN of CRF rats than it was in control animals both during a normal and a high dietary salt intake. In control and CRF rats, the concentration of NE was greater (p < 0.01) during a high than during a normal salt intake in the PH, LC, PVN, and in the mesenteric vessels. A high salt intake reduced the nNOS-mRNA gene expression in the PH (from 100 +/- 2.4 to 46 +/- 1.0;p < 0.01), LC (from 92 +/- 1.9 to 69 +/- 1.2; p < 0.01) and PVN (from 63 +/- 0.8 to 46 +/- 1.3) of CRF rats. A similar reduction occurred in the PH (from 36 +/- 0.8 to 23.6 +/- 1.2), LC (from 33 +/- 1.4 to 24 +/- 1.1) and PVN (from 37 +/- 1. to 27 +/- 1.0) of control rats. High salt intake significantly reduced the nNOS-mRNA gene expression in the mesenteric arteries of control rats, but not in those of CRF rats. In conclusion, these studies provide evidence that in control and CRF rats, high salt intake inhibits nNOS-mRNA expression in the brain, resulting in activation of the sympathetic nervous system and higher blood pressure.
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PMID:High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure. 1224 72

The present study was performed to evaluate the role of neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) during the developmental phase of hypertension in transgenic rats harboring the mouse Ren-2 renin gene (TGR). The first aim of the present study was to examine nNOS mRNA expression in the renal cortex and to assess the renal functional responses to intrarenal nNOS inhibition by S-methyl-L-thiocitrulline (L-SMTC) in heterozygous TGR and in age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). The second aim was to evaluate the role of the renal sympathetic nerves in mediating the renal functional responses to intrarenal nNOS inhibition. Thus, we also evaluated the effects of intrarenal L-SMTC administration in acutely denervated TGR and HanSD. Expression of nNOS mRNA in the renal cortex was significantly increased in TGR compared with HanSD. Intrarenal administration of L-SMTC decreased the glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium excretion and increased renal vascular resistance (RVR) in HanSD. In contrast, intrarenal inhibition of nNOS by L-SMTC did not alter GFR, RPF or RVR and elicited a marked increase in sodium excretion in TGR. This effect of intrarenal L-SMTC was not observed in acutely denervated TGR. These results suggest that during the developmental phase of hypertension TGR exhibit an impaired renal vascular responsiveness to nNOS derived NO or an impaired ability to release NO by nNOS despite enhanced expression of nNOS mRNA in the renal cortex. In addition, the data indicate that nNOS-derived NO increases tubular sodium reabsorption in TGR and that the renal nerves play an important modulatory role in this process.
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PMID:Role of nNOS in regulation of renal function in hypertensive Ren-2 transgenic rats. 1251 Nov 80

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in restricted subpopulations of cells. High levels of expression can be detected in the macula densa (MD) and associated cortical thick ascending limb of Henle (cTALH) cells and medullary interstitial cells (MICs). In human biopsy specimens, COX-2 expression is also detected in glomerular podocytes and increased podocyte expression is seen in experimental models of progressive glomerular injury. Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension) and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide (NO) generated by neuronal nitric oxide synthase (nNOS) is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 MAP kinase activity and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression in MICs increases in response to a high-salt diet, as well as water deprivation. Studies in cultured MICs confirm that expression is increased in response to hypertonicity, and expression is mediated at least in part by nuclear factor-kappaB (NFkappaB) activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and following water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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PMID:Cyclooxygenase-2 and the kidney: functional and pathophysiological implications. 1268 21

Deficiency of either neuronal nitric oxide synthase (NOS1) or endothelial nitric oxide synthase (NOS3) leads to cardiac hypertrophy in mice. Loss of both produces concentric left ventricular (LV) remodeling, in which increased wall thickness is accompanied by reduced cavity size. In humans, this phenotype develops in elderly hypertensive patients and independently predicts mortality. Accordingly, we tested the hypothesis that NOS1/3(-/-) mice have reduced longevity compared to either NOS1(-/-) or NOS3(-/-). Survival data on colonies of NOS1(-/-) (n = 295), NOS3(-/-) (n = 525), and NOS1/3(-/-) (n = 331) mice were collected for 2 years. NOS1(-/-) mice had increased mortality compared to NOS3(-/-) (relative risk, RR 2.5, P < 0.001), whereas NOS1/3(-/-) fared significantly worse (RR 7.3, P < 0.001 vs. NOS3(-/-)). Importantly, gender did not affect survival in NOS1(-/-) or NOS3(-/-), but male NOS1/3(-/-) mice had 2-fold increased mortality compared to females. NOS1/3(-/-) mice developed progressive myocyte hypertrophy and interstitial fibrosis with age. NOS1/3(-/-) mice underwent in vivo hemodynamic analysis with a combined pressure-volume catheter to assess age-related cardiovascular changes. Compared with control, NOS1/3(-/-) demonstrated hypertension and hypercontractility at all ages, and developed passive diastolic dysfunction with increasing age. Thus, combined deficiency of NOS1 and NOS3 causes increased mortality, myocyte hypertrophy, and an age-associated increase in ventricular stiffness. These findings suggest that cardiac NO signals may play an essential role in successful cardiac aging.
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PMID:Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. 1278 81

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.
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PMID:Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. 1285 18

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