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)

Enhancement of the heme oxygenase/carbon monoxide (HO/CO) system has been shown to lower blood pressure (BP) in young (8 weeks), but not in adult (20 weeks) spontaneously hypertensive (SHR) rats. The reasons for this selective effect still remain puzzling. We investigated the effects of hemin on the HO/CO system of the pulmonary artery (PA) in SHR and Wistar-Kyoto (WKY) rats at different ages and evaluated the hemin-dependent changes in sGC and cGMP pathways. Hemin administration resulted in an evident reduction of BP (from 148.6 +/- 3.2 to 125.8 +/- 2.6 mmHg, P < 0.01) in young, but not in prehypertensive (4 weeks) or adult SHR or WKY rats at all ages. Coadministration of the HO inhibitor, chromium mesoporphyrin, with hemin, cancelled the BP-lowering effect of hemin. Remarkably, lower expression levels of HO-1, HO-2, and sGC paralleled with reduced HO activity and cGMP content were observed in PA from 8-week SHR rats, but not from adult SHR or WKY rats of all ages. Interestingly, hemin treatment restored these deficiencies, although the expression level of non-inducible HO-2 protein remained unchanged. We conclude that in young and prehypertensive SHR rats, an impaired HO/CO-sGC/cGMP system in the PA might be indicative of the pathogenesis and development of hypertension. In contrast, the HO/CO system in the PA of adult SHR rats was upregulated as a compensatory reaction to elevated BP and desensitization of the downstream targets of the sGC/cGMP pathway occurred.
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PMID:Alterations in heme oxygenase/carbon monoxide system in pulmonary arteries in hypertension. 1270 86

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor ( tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 microM: 51.3+/-5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.
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PMID:Androgen receptor independent cardiovascular action of the antiandrogen flutamide. 1280 2

Our laboratory has recently shown increased renal expression of NO synthase 3 (NOS3) in the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension suggesting an up-regulation of the nitric oxide (NO)-cyclic guanosine-3',5'-monophosphate (cGMP) pathway. The present study was designed to determine changes in renal soluble guanylyl cyclase (sGC) activity and expression in the DOCA-salt hypertensive rat. Rats were uninephrectomized and subcutaneously implanted with either a placebo or DOCA-salt pellet. Placebo-treated animals were given tap water ad libitum, while DOCA-treated animals received 0.9% NaCl solution to drink. Each week, rats were placed in metabolic cages for 24 h collection of urine samples. Urine samples were measured for cGMP concentrations using a scintillation proximity method. After 3 weeks, kidneys were removed and dissected into cortex, outer medulla, and inner medulla. Each region of the kidney was further separated into detergent-soluble and detergent-insoluble fractions. DOCA-treated rats exhibited significant increases in urinary cGMP excretion (27.0+/-1.4 fmol/mg creatinine) after 1 week compared to placebo control animals (8.7+/-0.6 fmol/mg creatinine). This was followed by a significant decrease by the second week of treatment (5.4+/-1.0 and 11.4+/-0.6 fmol/mg creatinine in DOCA-salt and placebo, respectively) and a return to placebo values by the third week of treatment (16.2+/-3.1 and 12.9+/-1.0 fmol/mg creatinine in DOCA-salt and placebo, respectively). Western blot analysis of inner medullary detergent-soluble fraction indicated a decrease in the expression of the beta(1)-subunit of sGC in the third week of DOCA-salt-treated animals as compared to placebo controls (n=5 animals per group) while expression of the alpha(1)-subunit was unchanged. Western blot analysis of cortex and outer medullary preparations comparing placebo controls and DOCA-salt-treated animals revealed no difference in alpha(1)- or beta(1)-sGC protein expression. These data suggest an uncoupling of NOS/NO and sGC/cGMP pathways in the renal inner medulla of the DOCA-salt hypertensive rat.
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PMID:Down-regulation of soluble guanylyl cyclase in the inner medulla of DOCA-salt hypertensive rats. 1367 47

Nitrate tolerance (NT) in hypertension is attributed to reduced activity of soluble guanylyl cyclase (sGC). We examined NT in basilar artery vascular smooth muscle cells (VSMCs) from control rats, rats infused with angiotensin II (Ang; 240 microg/kg per hour for 4 days), which were normotensive, and Ang-hypertensive rats (AHR; 240 microg/kg per hour for 28 days). Ca2+-activated K+ (Maxi-K) channels in VSMCs from AHR showed reduced activation by NO donor, consistent with NT. The concentration-response relationship for 8-Br-cGMP was shifted 2.5-fold to the right, indicating that abnormal sGC alone could not account for NT. Inside-out patches from AHR showed normal activation with exogenous cGMP-dependent protein kinase I (cGKI), suggesting no abnormality downstream of cGKI. We hypothesized that the reduction in apparent affinity of 8-Br-cGMP for cGKI in AHR might be due to a change in relative amounts of cGKIalpha versus cGKIbeta, since cGKIbeta is less sensitive to cGMP activators than cGKIalpha. This was substantiated by showing the following in AHR: (1) reduced effect of the cGKIalpha-selective activator 8-APT-cGMP; (2) reduced total cGKI protein (both isoforms), but an increase in cGKIbeta protein in quantitative immunofluorescence and Western blots; (3) similar changes in cGKI isoforms immunoisolated with Maxi-K channels; and (4) a large increase in cGKIbeta mRNA and a decrease in cGKIalpha mRNA in real-time PCR and Northern blots. Upregulation of cytosolic cGKIbeta was evident 4 days after Ang infusion, before development of hypertension. Our data identify a functional role for cGKIbeta in VSMCs previously ascribed exclusively to cGKIalpha. Ang-induced alternative splicing of cGKI represents a novel mechanism for reducing sensitivity to NO/cGMP.
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PMID:Alternative splicing of cGMP-dependent protein kinase I in angiotensin-hypertension: novel mechanism for nitrate tolerance in vascular smooth muscle. 1464 36

The present study was designed to determine the capability of human renal proximal tubule (RPT) to generate and export guanosine cyclic 3', 5' monophosphate (cGMP) in response to direct stimulation of soluble guanylyl cyclase by nitric oxide (NO) donors. In addition, we investigated whether cGMP extrusion from human RPT cells is required for inhibition of cellular sodium uptake. RPT cells were cultured from fresh human kidneys (normotensive subjects, n=4, mean age 65+/-4.7 years, 3 men, 1 woman; hypertensive patients, n=6, mean age 64+/-6.1 years, 4 men, 2 women) after unilateral nephrectomy. The fluorescence dye Sodium Green was employed to determine cytoplasmic Na+ concentration. In the presence of the Na+/K+ ATPase inhibitor ouabain, fluorescence was monitored at the appropriate wavelength (excitation 485 nm, emission 535 nm). Nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP, 10(-4) M), increased both intracellular and extracellular cGMP (from 1.26+/-0.21 to 88.7+/-12.6 pmol/mg protein and from 0.58+/-0.10 to 9.24+/-1.9 pmol/mL, respectively, P<0.01) and decreased cellular Na+ uptake by 37.4+/-6.8% (P<0.05) compared with control. The effects of SNAP on cGMP production were similar in normotensive and hypertensive subjects. The increases in intracellular and extracellular cGMP concentration because of SNAP were blocked completely by soluble guanylyl cyclase inhibitor ODQ (1-H-[1,2,4] oxadiazolo [4,2-alpha] quinoxalin-1-one). Probenecid, an organic anion transport inhibitor, augmented the SNAP (10(-6) M)-induced increase in intracellular cGMP accumulation (from 4.9+/-0.9 to 9.8+/-1.5 pmol/mg protein, P<0.05), abrogated the SNAP-induced increase in extracellular cGMP extrusion (from 1.07+/-0.4 to 0.37+/-0.1 pmol/L, P<0.05) and blocked the SNAP-induced reduction in cellular Na+ uptake. Neither intracellular nor extracellular cGMP were influenced by l-arginine, the metabolic precursor of NO, or N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. After exogenous administration of cGMP (10(-5) M) or its membrane-permeable analogue 8-Br-cGMP (10(-5) M), only 8-Br-cGMP crossed the cell membrane to increase intracellular cGMP (from 1.36+/-0.19 to 289.7+/-29.4 pmol/mg protein, P<0.01). However, both cGMP and 8-Br-cGMP were effective in decreasing cellular Na+ uptake. In conclusion, human RPT cells contain soluble guanylyl cyclase and are able to generate and export cGMP in response to NO. Because human RPT cells do not themselves contain constitutive NO synthase, the NO-generating cGMP must be derived from sources outside the human RPT. The cGMP cellular export system is critical in the regulation of RPT cellular Na+ absorption in humans.
Hypertension 2004 Feb
PMID:Production and role of extracellular guanosine cyclic 3', 5' monophosphate in sodium uptake in human proximal tubule cells. 1471 58

Activation of the arterial baroreceptors induces expression of the proto-oncogene c-fos in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents in the medulla oblongata. This induced expression is an intracellular event that is crucial to long-term maintenance of stable blood pressure. Using Sprague-Dawley rats maintained under propofol anesthesia, we evaluated the role and delineated the underlying molecular mechanisms of nitric oxide (NO) in this process. Baroreceptor activation induced by 30 min of sustained hypertension significantly and sequentially increased the level of cyclic GMP-dependent protein kinase I (PKG-I), phosphorylated cyclic AMP response element-binding protein (pCREB), c-fos mRNA, and Fos protein in the NTS. All of these up-regulated expressions were significantly attenuated in animals that were pretreated immediately before baroreceptor activation with bilateral microinjection into the NTS of a selective neuronal nitric-oxide synthase (nNOS) inhibitor, 7-nitroindazole (2.5 pmol), or a soluble guanylyl cyclase (sGC) inhibitor, 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (1 nmol). Bilateral NTS microinjection of a cell-permeable cGMP analog, 8-bromoguanosine-3',5'-cyclic monophosphate (10 nmol) significantly elevated the level of pCREB or c-fos mRNA in the NTS. On the other hand, the up-regulated CREB phosphorylation or c-fos induction evoked in the dorsomedial medulla by baroreceptor activation was significantly antagonized by NTS application of a cell-permeable cGMP antagonist, (R)p-8-bromoguanosine-3',5'-cyclic monophosphorothioate (5 nmol), or a PKG inhibitor, (8R,9S,11S)-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H,-2,7b,11a-trizadizo-benzo(a,g)cycloocta(c,d,e)-trinden-1-one (1 nmol). We conclude that NO derived from nNOS in the NTS on baroreceptor activation may participate in c-fos expression via phosphorylation of CREB in a process that engages the sGC/cGMP/PKG-I signaling cascade.
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PMID:Nitric oxide regulates c-fos expression in nucleus tractus solitarii induced by baroreceptor activation via cGMP-dependent protein kinase and cAMP response element-binding protein phosphorylation. 1474 73

The peroxisome proliferator activated receptor (PPARgamma) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R(+)A(+)). Rosiglitazone decreased systolic (138+/-5 versus 128+/-5 mm Hg) and mean blood pressure (145+/-5 versus 126+/-7 mm Hg) of R(+)A(+) mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R(+)A(+) mice when compared with littermate controls (RA(-)). There were no effects of rosiglitazone on RA(-) mice; however, relaxation to acetylcholine (49+/-10 versus 82+/-9% at 100 micromol/L) and nitric oxide (51+/-11 versus 72+/-6% at 10 micromol/L) was significantly improved in treated R(+)A(+) mice. Rosiglitazone treatment of R(+)A(+) mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R(+)A(+) and RA(-) mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARgamma-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (200 micromol/L) or the PPARgamma antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 micromol/L). These data suggest that in addition to potential genomic regulation caused by PPARgamma activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
Hypertension 2004 Mar
PMID:PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. 1474 30

Research on the biochemistry and physiology of l-arginine has remained an attractive area for scientists over the last 100 years due to its diverse physiological functions in mammals. Research on l-arginine was boosted after the identification of nitric oxide (NO) and agmatine and their physiological importance. NO directly modulates ion channels, activates soluble guanylyl cyclase and other important proteins by ADP ribosylation and nitrosylation and binding to heme or iron-sulfur clusters. These modifications and interaction with heme might activate or inhibit various protein kinases, phosphatases and modulate transcription of various nuclear factors to possibly cause cardiovascular diseases like hypertension, ischemia, diabetes, atherosclerosis and angiogenesis. Agmatine holds the key to prevent the toxic effects associated with induction of NO synthesis by its ability to inhibit inducible nitric oxide synthase (iNOS). Agmatine is also synthesized from l-arginine by the enzyme arginine decarboxylase and displays a significant potential in cardiovascular system. Agmatine, with the myriad of effects on calcium homeostasis, seems to modulate various functions in the heart, brain and vasculature. The present review compiles the recent development to improve the understanding the role played by l-arginine-metabolic pathways in cardiovascular system. Though l-arginine and its metabolites are well known to affect various cardiovascular physiologies, the currently available literature is still not sufficient to validate the prophylactic/therapeutic efficacy of l-arginine. l-Arginine and its metabolites, NO and agmatine still hold the key for future research in cardiovascular system.
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PMID:Vascular regulation by the L-arginine metabolites, nitric oxide and agmatine. 1499 49

Pressure-natriuresis is the physiological protective mechanism whereby elevation of blood pressure induces a rapid increase in renal sodium (Na+) excretion. Pressure-natriuresis abnormalities are common to all forms of hypertension. We tested the hypothesis that pressure-natriuresis is mediated by renal interstitial (RI) cGMP and protein kinase G (PKG). We used anesthetized, uninephrectomized Sprague-Dawley rats and a standard pressure-natriuresis model in which bilateral adrenalectomy and renal denervation was done on rats. Renal perfusion pressure (RPP) was adjusted by manipulating clamps above and below the renal artery, and RI cGMP was quantified by microdialysis. RI cGMP increased from 3.1+/-0.5 to 5.5+/-0.4 fmol/min (P<0.05) when RPP was raised from 100 to 140 mm Hg. This increase in RI cGMP was eliminated by RI infusion of soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ). Raising RPP from 100 to 140 mm Hg increased urinary sodium excretion from 0.2+/-0.1 to 0.8+/-0.1 micromol/min, fractional sodium excretion from 0.2+/-0.1% to 0.8+/-0.1%, and fractional lithium excretion from 20.1+/-3.0% to 62.7+/-3.7% (all P<0.05). These responses were eliminated by RI infusion of nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester, ODQ, and PKG inhibitors Rp-8-pCPT-cGMP and Rp-8-Br-cGMP. Increasing RPP from 100 to 140 mm Hg decreased fractional proximal sodium reabsorption without influencing fractional distal Na+ reabsorption or glomerular filtration rate. In conclusion, pressure-natriuresis is mediated by RI cGMP and a PKG signaling pathway in target renal proximal tubule cells.
Hypertension 2004 May
PMID:Renal interstitial guanosine cyclic 3', 5'-monophosphate mediates pressure-natriuresis via protein kinase G. 1500 31

The enzymatic action of heme oxygenase yields carbon monoxide, biliverdin and iron. Carbon monoxide is implicated in many physiological processes, including the regulation of vascular tissue contractility and apoptosis. By stimulating the soluble guanylyl cyclase (sGC)/cGMP pathway and activating K channels in vascular smooth muscle cells (SMCs), carbon monoxide relaxes vascular tissues under physiological conditions. Altered metabolism and functions of carbon monoxide have been linked to the pathogenesis and maintenance of hypertension. The expression and activity of heme oxygenase-1, sGC and cGMP in vascular SMCs are associated with different stages of development of hypertension in spontaneously hypertensive rats (SHRs). The importance of altered heme oxygenase-2 expression in vascular tissues in hypertension remains unclear. Increased vascular contractility, unbalanced cellular apoptosis and proliferation in the vascular wall, increased oxidative stress, and the altered interaction of carbon monoxide and nitric oxide are among the consequences of heme oxygenase/carbon monoxide system dysfunction in hypertension. Acute application of pharmacological inducers to upregulate the expression of heme oxygenase-1 or the use of gene delivery method to overexpress heme oxygenase-1 decreases blood pressure in young SHRs and other animal models of hypertension. These blood pressure-decreasing effects are annulled by metalloporphyrins. In adult SHRs, the heme oxygenase/carbon monoxide system appears to be normalized as a compensatory reaction. To date, acute manipulation of the expression of heme oxygenase-1 has not been successful in decreasing blood pressure in adult SHRs. In conclusion, abnormality of the heme oxygenase/carbon monoxide system has a critical role in the pathogenesis of hypertension, and novel therapeutic approaches should be pursued to achieve selective improvement in the function of this system in hypertension.
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PMID:Carbon monoxide and hypertension. 1516 36


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