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)

Tetrahydrobiopterin (BH4) acts as an important co-factor for endothelial nitric oxide synthase (eNOS). Glucocorticoids have been shown to inhibit expression of the rate-limiting enzyme for tetrahydrobiopterin synthesis, GTP cyclohydrolase, in other cell types. We hypothesized that endothelium-dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone. Further, we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression. We report that endothelium-dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone-hypertensive rats compared with sham values. Dexamethasone incubation abolishes contraction to Nomega-nitro-L-arginine (L-NNA, 10(-5) M) in endothelium-intact aortic rings, and inhibits expression of GTP cyclohydrolase. We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium-dependent vasodilation characteristic of glucocorticoid-induced hypertension.
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PMID:Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function. 1136 34

Synthetic glucocorticoids are among the most widely prescribed medications by physicians. Although they have a vast array of beneficial effects such as immunosuppression and anti-inflammation, excess glucocorticoids can lead to iatrogenic Cushing's syndrome, which includes hypertension and cardiovascular disease. The exact mechanism by which glucocorticoids elevate blood pressure is not completely understood, but it appears to be a complex pathology that involves increased responsiveness to vasoconstrictors and decreased vasodilator production. Nitric oxide is a vasodilator that plays a key role in blood pressure regulation, and previous studies have shown that a reduction in nitric oxide production or bioavailability contributes to hypertension. Tetrahydrobiopterin, a necessary cofactor for nitric oxide synthase activity, can affect nitric oxide production and bioavailability, with low levels causing decreased nitric oxide production. However, little is known about the interaction between glucocorticoids and tetrahydrobiopterin levels. In this review, the roles of nitric oxide and tetrahydrobiopterin in the pathogenesis of glucocorticoid hypertension will be discussed. Furthermore, the authors propose that glucocorticoids exert a genomic effect to decrease guanosine triphosphate cyclohydrolase I, the rate-limiting enzyme in the production of tetrahydrobiopterin. In the future, tetrahydrobiopterin supplementation in patients with iatrogenic Cushing's syndrome may prove to be beneficial and decrease mortality attributed to cardiovascular disease.
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PMID:Impaired vasodilation and nitric oxide synthase activity in glucocorticoid-induced hypertension. 1236 78

Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemoreceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O2) or to sustained hypoxia (10% O2) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small.
Hypertension 2003 Dec
PMID:Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons. 1459 43

Although the proinflammatory and profibrotic actions of aldosterone (Aldo) on the vasculature have been reported, the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined. We investigated how Aldo regulates endothelial NO synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hours with Aldo 10(-7) mol/L. The concentration of reactive oxygen species was estimated by measuring 2',7'-dichlorodihydrofluorescein diacetate chemiluminescence. Signal transduction was estimated by Western immunoblots. Real-time RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 and components of reduced nicotinamide-adenine dinucleotide phosphate oxidase. To eliminate the possible effect of the glucocorticoid receptor (GR) and to emphasize the role of mineralocorticoid receptor, we used GR small interfering RNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. Reactive oxygen species production increased significantly in Aldo-treated HUVECs but was abolished by pretreatment with eplerenone. Transcripts of p47(phox) were increased by Aldo treatment. Vascular endothelial growth factor-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with Aldo. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in Aldo-treated cells, suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor. The decrease in NO output caused by Aldo pretreatment was reversed significantly by 5,6,7,8-tetrahydrobiopterin, GTP cyclohydrolase-1 overexpression, or p47(phox) knockdown. These results suggest that Aldo inhibits eNOS function through bimodal mechanisms of 5,6,7,8-tetrahydrobiopterin deficiency and protein phosphatase 2A activation.
Hypertension 2006 Jul
PMID:Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. 1675 96

Vascular smooth muscle cell (VSMC) proliferation is pivotal in the progression of hypertension, atherosclerosis, and restenosis. Resveratrol is a grape polyphenol that is implicated as an important contributor to red wine's vascular protective effects. Its antimitogenic action on VSMC is attributed to an array of pleiotropic effects, including modulation of the estrogen receptor (ER). To elucidate the mechanisms underlying resveratrol-mediated ER modulation and its inhibition of VSMC proliferation, we treated VSMC with resveratrol with or without the ER antagonist ICI 182,780 and measured cell proliferation and nitric oxide (NO) production. Resveratrol dose-dependently decreased VSMC DNA synthesis, with a half maximal inhibitory concentration (IC50) of 3.73+/-0.57 microM, and dramatically slowed cell growth, but did not induce VSMC apoptosis. Resveratrol-mediated decrease in proliferation was reversed by cotreatment with ICI 182,780, and resveratrol effectively competed with 17beta-estradiol for binding to the ER, exhibiting an IC50 of 8.92+/-0.14 microM. Resveratrol induced a sustained increase in ER-dependent NO production. Further, resveratrol-mediated decrease in VSMC proliferation was blunted by cotreatment with the general nitric oxide synthase (NOS) inhibitor N5-(1-Iminomethyl)-L-ornithine, dihydrochloride or with the inducible NOS (iNOS)-selective inhibitor S,S'-1,4-phenylene-bis (1,2-ethanediyl)bis-isothiourea, dihydrobromide, but not with the neuronal NOS-selective inhibitor 7-nitroindazole. Though resveratrol did not alter iNOS protein levels, it dose-dependently increased levels of iNOS activity, of the iNOS cofactor tetrahydrobiopterin (BH4), and of guanosine triphosphate cyclohydrolase I protein, the rate-limiting enzyme in BH4 biosynthesis. In addition, all of these effects were abolished by cotreatment with ICI 182,780. Thus, the antimitogenic effects of resveratrol on VSMC may be mediated by an ER-induced increase in iNOS activity.
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PMID:Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production. 1766 20

Sphingosine 1-phosphate (S1P) is a lipid mediator that exerts potent and diverse biological effects on several cardiovascular cells. We investigated the effect of S1P on interleukin (IL)-1beta-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in rat vascular smooth muscle cells (VSMCs). S1P inhibited NO production at concentrations higher than 0.1 muM; this was associated with the inhibition of iNOS protein and mRNA expression. S1P also inhibited IL-1beta-induced GTP cyclohydrolase I (GTPCH) mRNA expression. Pertussis toxin (PTX) partially attenuated the inhibitory effects of S1P on NO production and iNOS protein induction, whereas it completely blocked the inhibitory effects on iNOS and GTPCH mRNA expression. S1P inhibited iNOS expression in Ca(2+)-depleted conditions; PTX did not modify this effect. The Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in Ca(2+)-depleted condition but did not affect it in the presence of Ca(2+). S1P significantly inhibited IL-1beta-induced persistent activation of extracellular signal-regulated kinase (ERK) but had no effect in Ca(2+)-depleted conditions. Thus, S1P inhibits IL-1beta induction of NO production and iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca(2+)-dependent ERK inhibition and Ca(2+)-independent Rho kinase activation might be involved in the inhibitory mechanism of iNOS expression. Through its action on NO production by VSMCs, S1P may play an important role in the progression of local vascular injury associated with thrombosis, atherosclerosis, and hypertension.
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PMID:Sphingosine 1-phosphate inhibits nitric oxide production induced by interleukin-1beta in rat vascular smooth muscle cells. 1817 8

Hypertension affects approximately 25% of adults and is a major risk factor for cardiovascular disease. Although there are currently adequate therapeutic options for humans with hypertension, the molecular mechanisms underlying hypertension are still relatively unknown. The generation of hypertensive animal models provides an excellent modality to not only study the pathophysiology but also test innovative therapeutics. This chapter describes the detailed methods that utilize the drinking water of rats to develop models of nitric oxide synthase (NOS) inhibition-induced, guanosine triphosphate cyclohydrolase (GTPCH) inhibition-induced, and glucocorticoid-induced hypertension.
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PMID:Animal models of hypertension. 1828 67

Tetrahydrobiopterin is an essential cofactor required for the synthesis of NO. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin production in endothelial cells, yet little is known about the subcellular localization of this enzyme. In this study, we demonstrated that GTPCH I is localized to caveolar membrane microdomains along with caveolin-1 and endothelial NO synthase. GTPCH I activity was detected in isolated caveolar membranes from cultured endothelial cells. Confocal and electron microscopy analyses confirmed GTPCH I colocalization with caveolin-1. Consistent with in vitro studies, GTPCH I activity was evident in isolated caveolar microdomains from lung homogenates of wild-type mice. Importantly, a 2-fold increase in GTPCH I activity was detected in the aortas of caveolin-1-deficient mice, suggesting that caveolin-1 may be involved in the control of GTPCH I enzymatic activity. Indeed, overexpression of caveolin-1 inhibits GTPCH I activity, and tetrahydrobiopterin biosynthesis is activated by the disruption of caveolae structure. These studies demonstrate that GTPCH I is targeted to caveolae microdomains in vascular endothelial cells, and tetrahydrobiopterin production occurs in close proximity to endothelial NO synthase. In addition, our findings provide new insights into the regulation of GTPCH I activity by the caveolar coat protein, caveolin-1.
Hypertension 2009 Feb
PMID:Guanosine triphosphate cyclohydrolase I expression and enzymatic activity are present in caveolae of endothelial cells. 1910 2

One key mechanism for endothelial dysfunction is endothelial NO synthase (eNOS) uncoupling, whereby eNOS generates O(2)(*-) rather than NO because of deficient eNOS cofactor tetrahydrobiopterin (BH4). This study was designed to examine the effect of BH4 deficiency on cardiac morphology and function, as well as the impact of metallothionein (MT) on BH4 deficiency-induced abnormalities, if any. Friend virus B (FVB) and cardiac-specific MT transgenic mice were exposed to 2,4-diamino-6-hydroxy-pyrimidine (DAHP; 10 mmol/L, 3 weeks), an inhibitor of the BH4 synthetic enzyme GTP cyclohydrolase I. DAHP reduced plasma BH4 levels by 85% and elevated blood pressure in both FVB and MT mice. Echocardiography found decreased fractional shortening and increased end-systolic diameter in DAHP-treated FVB mice. Cardiomyocytes from DAHP-treated FVB mice displayed enhanced O(2)(*-) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, reduced intracellular Ca(2+) rise, and clearance. DAHP triggered mitochondrial swelling/myocardial filament aberrations and mitochondrial O(2)(*-) accumulation, assessed by transmission electron microscopy and MitoSOX Red fluorescence, respectively. DAHP also promoted the N(G)-nitro-l-arginine methyl ester-inhibitable O(2)(*-) production and eNOS phosphorylation at Thr497. Although MT had little effect on cardiac mechanics and ultrastructure, it attenuated DAHP-induced defects in cardiac function, morphology, O(2)(*-) production, and eNOS phosphorylation (Thr497). The DAHP-induced cardiomyocyte mechanical responses were alleviated by in vitro BH4 treatment. DAHP inhibited mitochondrial biogenesis, mitochondrial uncoupling protein 2, and chaperone heat shock protein 90, and all but uncoupling protein 2 were rescued by MT. Our data suggest a role for BH4 deficiency in cardiac dysfunction and the therapeutic potential of antioxidants against eNOS uncoupling in the heart.
Hypertension 2009 Jun
PMID:Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis. 1939 53

Sauna therapy has been used to treat a number of different diseases known or thought to have a tetrahydrobiopterin (BH4) deficiency. It has been interpreted to act in multiple chemical sensitivity by increasing chemical detoxification and excretion but there is no evidence that this is its main mode of action. Sauna therapy may act to increase BH4 availability via two distinct pathways. Increased blood flow in heated surface tissues leads to increased vascular shear stress, inducing increased activity of GTP cyclohydrolase I (GTPCH-I) in those vascular tissues which will lead to increasing BH4 synthesis. A second mechanism involves the heat shock protein Hsp90, which is induced by even modest heating of mammalian tissues. Sauna heating of these surface tissues may act via Hsp90, which interacts with the GTPCH-I complex and is reported to produce increased GTPCH-I activity by lowering its degradation. The increased consequent availability of BH4 may lead to lowered nitric oxide synthase uncoupling, such as has been reported for the eNOS enzyme. Increased BH4 synthesis in surface tissues of the body will produce increased circulating BH4 which will feed BH4 to other body tissues that may have been BH4 deficient. Similar mechanisms may act in vigorous exercise due to the increased blood shear stresses and possibly also heating of the exercising tissues and heart. There is a large and rapidly increasing number of diseases that are associated with BH4 depletion and these may be candidates for sauna therapy. Such diseases as hypertension, vascular endothelial dysfunction, multiple chemical sensitivity and heart failure are thought to be helped by sauna therapy and chronic fatigue syndrome and fibromyalgia may also be helped and there are others that may be good candidates for sauna therapy.
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PMID:Do sauna therapy and exercise act by raising the availability of tetrahydrobiopterin? 1958 Oct 54


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