Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and can contribute to hypertension via endothelial dysfunction in Dahl salt-sensitive rats. Obese Zucker rats (ZR) are models of metabolic syndrome. This study tests the hypothesis that endogenous CO formation is increased and contributes to hypertension and endothelial dysfunction in obese ZR. Awake obese ZR showed increased respiratory CO excretion, which was lowered by HO inhibitor administration [zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) 25 micromol.kg(-1).24 h(-1) ip]. In awake obese ZR, chronically instrumented with femoral arterial catheters, blood pressure was elevated but was decreased by the HO inhibitor ZnDPBG. Body weight, blood glucose, glycated hemoglobin, plasma insulin, total and LDL cholesterol, oxidized LDL, and triglyceride levels were elevated in obese ZR, and, except for LDL cholesterol, were unchanged by HO inhibition. Total HO-1 protein levels were not different between lean and obese ZR aortas. In vitro experiments used isolated skeletal muscle arterioles with constant pressure and no flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow. In obese ZR arterioles, responses to ACh and flow were attenuated. Acute in vitro pretreatment with an HO inhibitor, chromium mesoporphyrin, enhanced ACh and flow-induced dilation and abolished the differences between groups. Furthermore, exogenous CO prevented the restoration of flow-induced dilation by the HO inhibitor in obese ZR arterioles. These results suggest that HO-derived CO production is increased and promotes hypertension and arteriolar endothelial dysfunction in obese ZR with metabolic syndrome independent of affecting metabolic parameters.
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PMID:Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats. 1628 90

Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1beta, IL-1alpha, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier. Thereafter, this induction occurs in the hypothalamic regions (such as the temperature-regulating centers), paraventricular nucleus (releasing and inhibiting hormone neurons), and the arcuate nucleus (a region containing these neurons and axons bound for the median eminence). Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. NO may play a role in the progression of Alzheimer's disease and parkinsonism. LPS similarly activates cytokine and iNOS production in the cardiovascular system leading to coronary heart disease. Fat is a major source of NO stimulated by leptin. As fat stores increase, leptin and NO release increases in parallel in a circadian rhythm with maxima at night. NO could be responsible for increased coronary heart disease as obesity supervenes. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play important roles in reducing or eliminating the oxidant damage produced by NO.
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PMID:The nitric oxide theory of aging revisited. 1639 88

We investigated the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in hemodynamic action of leptin. The effect of leptin (1 mg/kg i.p.) on systolic blood pressure (SBP) was examined in lean rats and in rats made obese by feeding highly palatable diet for either 1 or 3 months. Separate groups received NO synthase inhibitor, L-NAME, or EDHF inhibitors, the mixture of apamin+charybdotoxin or sulfaphenazole, before leptin administration. Leptin increased NO production, as evidenced by increase in plasma and urinary NO metabolites and cyclic GMP. This effect was impaired in both obese groups. In lean rats either leptin or EDHF inhibitors had no effect on blood pressure. L-NAME increased blood pressure in lean animals and this effect was prevented by leptin. However, when leptin was administered to animals pretreated with both L-NAME and EDHF inhibitors, blood pressure increased even more than after L-NAME alone. In the 1-month obese group leptin had no effect on SBP, however, pressor effect of leptin was observed in animals pretreated with EDHF inhibitors. In the 3-month obese group leptin alone increased SBP, and EDHF inhibitors did not augment its pressor effect. The results suggest that leptin may stimulate EDHF when NO becomes deficient, e.g. after NOS blockade or in short-term obesity. Although the effect of leptin on NO production is impaired in the 1-month obese group, BP does not increase, probably because EDHF compensates for NO deficiency. In contrast, leptin increases BP in 3-month obesity because its effect on EDHF is also attenuated.
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PMID:Role of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood pressure by leptin in lean and obese rats. 1645 10

There is ample evidence from many epidemiological studies that lower urinary tract symptoms (LUTS) and sexual dysfunction are strongly linked, independently of age and comorbidities such as hypertension, diabetes, dyslipidaemia and coronary heart disease. However, a causal link between both conditions is not yet established. Four pathophysiological mechanisms currently support the relationship between LUTS and erectile dysfunction (ED): (i) The nitric oxide synthase (NOS)/NO theory; there is a reduction in NOS-containing nerves in the prostate and bladder/urethra in patients with bladder outlet obstruction (BOO), and that lack of NO or loss of protein kinase G causes ED; (ii) The autonomic hyperactivity and metabolic syndrome hypothesis: benign prostatic hyperplasia (BPH) may be part of the metabolic syndrome, which includes cardiovascular diseases (e.g. hypertension, ischaemic heart disease) and diabetes mellitus, known risk factors for ED. Hypertension, obesity, and hyperinsulinaemia have all been claimed to be associated with an increased sympathetic activity. Increased sympathetic activity is involved in LUTS/BPH and may have a role in ED/sexual dysfunction, with noradrenaline and alpha1-adrenoceptors representing a common link; (iii) the Rho-kinase activation/endothelin pathway; there can be increased Rho-kinase activity, and consequently calcium sensitivity of the contractile machinery, in prostate smooth muscle in BPH, the detrusor in BOO, corpora cavernosa in ED, and in the resistance vessels in hypertension. The actions of several factors beside noradrenaline (e.g. endothelin-1, angiotensin II), possibly involved in the increased smooth muscle activity found in both LUTS/BPH and sexual dysfunction, are dependent on Rho-kinase activity. Thus increased Rho-kinase activity might represent a common link between LUTS and sexual dysfunction; (iv) Pelvic atherosclerosis; animal models mimicking pelvic ischaemia and hypercholesterolaemia show similar smooth muscle alterations of the detrusor and corpora. Pelvic ischaemia may induce the biological modifications described above and may thus represent as well a common link between LUTS and sexual dysfunction. Studies treating one condition (e.g. ED) and measuring the impact on the other (e.g. LUTS) should further contribute to support this common link.
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PMID:Lower urinary tract symptoms and sexual dysfunction: epidemiology and pathophysiology. 1650 50

Nitric oxide (NO) is known to be a messenger molecule that plays an important role in physiological and pathological conditions. It is synthesized by an enzyme called nitric oxide synthase (NOS). Inducible NOS (iNOS), one of the three isomers of NOS, has both protective and toxic properties. In this study, the role of NO has been evaluated by gastrointestinal symptoms induced by orlistat which is used in obesity treatment. Orlistat was given to Wistar rats with and without iNOS inhibition. The effects of orlistat and inhibition of NOS were studied. Glucose, urea, alanine transaminase (ALT), and gamma glutamil transpeptidase (GGT) were descreased after short- and long- term orlistat applications. Dexamethasone increased level of these enzymes. Cholesterol and triglyceride were increased in all experimental groups than the controls. This increment was more severe in animals received orlistat and dexamethasone together. Small intestinal tissue also were researched histologically and NADPH-diaphorase (NADPH-d) histochemistrically. Orlistat caused histological damages in brush border membranes, connective tissues of villi, and lymphocyte migration also increased. Dexamethasone treatment prevented these damages partially while orlistat increased the NOS distribution in the tissue sections. Dexamethasone, which is an iNOS inhibitor, decreased NADPH-d histochemistry. There was a similiar NOS distribution both in the control and orlistat+dexamethasone group. Hence, we concluded that long- term trials with orlistat and similar drugs are needed.
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PMID:Effects of orlistat and its relationship with nitric oxide in the small intestinal mucosa. 1654 24

Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-delivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I(2) synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I(2) synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.
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PMID:Adiponectin replenishment ameliorates obesity-related hypertension. 1665 65

Previously, we have demonstrated that chronic consumption of a high-fat, high-refined sugar (HFS) diet results in metabolic syndrome which is marked by obesity, insulin resistance, hyperlipidemia, and hypertension in Fischer rats. Metabolic syndrome in this model is associated with oxidative stress, avid nitric oxide (NO) inactivation by reactive oxygen species (ROS), diminished NO bioavailability, and dysregulation of NO synthase isotypes. Although occurrence of oxidative stress and its impact on NO metabolism are well established, the molecular source(s) of ROS in this model is unknown. In an attempt to explore this issue, we measured protein expressions of the key ROS-producing enzyme, NAD(P)H oxidase, and the main antioxidant enzymes, superoxide dismutase (CuZn SOD and Mn SOD), catalase, glutathione peroxidase (GPX), and heme oxygenase-2 (HO-2), in the kidney and aorta of Fischer rats fed an HFS or low-fat, complex-carbohydrate diet for 7 months. In addition, plasma lipid peroxidation product (malondialdehyde) as well as endothelium-dependent and -independent vasorelaxation (aorta rings) was determined. The results showed a significant upregulation of gp91(phox) subunit of NAD(P)H oxidase and downregulations of SOD isoforms, GPX, and HO-2 in the kidney and aorta of the HFS-fed animals. This was associated with increased plasma malondialdehyde concentration and impaired vasodilatory response to acetylcholine, but not the NO donor, Na nitroprusside. The latter findings confirm the presence of oxidative stress and endothelial dysfunction in the HFS-fed rats. Oxidative stress and endothelial dysfunction in the diet-induced metabolic syndrome are accompanied by upregulation of NAD(P)H oxidase, pointing to increased ROS production capacity, and downregulation of SOD isoforms, GPX, and HO-2, the key enzymes in the antioxidant defense system.
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PMID:Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome. 1678 66

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.
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PMID:Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. 1690 96

The venous system plays a crucial role in regulating cardiac output and blood pressure. Although the relationship between obesity and hypertension is well recognized, little is known about the effect of obesity on venous function. We examined if 16-week-old obese Zucker rats, relative to age-matched lean Zucker rats, had altered in vivo venoconstriction to noradrenaline. The obese rats, compared to the controls, had higher mean arterial pressure (MAP), body weight, and plasma insulin and triglycerides, but reduced pressor and mean circulatory filling pressure (MCFP, index of venous tone) responses to noradrenaline (2.5-30x10(-9) mol/kg/min, i.v.). N(G)-nitro-L-arginine methyl ester (L-NAME, 8 mg/kg, i.v., non-selective inhibitor of nitric oxide synthase) did not alter MCFP in either group, but increased MAP of both groups, though the increase was markedly less in the obese than lean rats. Therefore, obese Zucker rats had increased baseline MAP, but impaired in vivo pressor and MCFP responses to noradrenaline, and reduced pressor response to L-NAME. The increased baseline MAP in the obese rats was not due to increased arterial and venous constriction to noradrenaline but rather to reduced influence of the nitric oxide/L-arginine system.
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PMID:Impaired in vivo venous constriction in conscious obese Zucker rats with metabolic syndrome. 1694 3

There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO. Translating the preclinical discoveries in NO biology to new modalities for disease management has not been as impressive. Beyond the success of drugs for erectile dysfunction, clinical trials of nitric oxide synthase inhibitor have been proven either ineffective or wrought with side effects. NO donors (e.g., nitroglycerine) remain frequently used cardiovascular agents, but were discovered before 1980. Gene therapy studies have yet to become clinically useful. There is no doubt that endothelial- and NO-dysfunction is a hallmark of cardiovascular disease, including diseases which are considered as major current public health concerns: hypertension, obesity, diabetes, malnutrition. In many cases, cardiovascular disease (CVD) can be prevented by identifying and controlling modifiable risk factors. One conceivable approach to the management of multiple risk factors in CVD could be to treat endothelial dysfunction (e.g., by enhancing eNOS expression), since many CVD risk factors are related to endothelial dysfunction. In this regard one goal may include optimizing eNOS function. This can be realized by supplementing co-factors, e.g., BH4, or substrate, L-arginine, by increasing cGMP availability via phosphodiesterase inhibitors or sGC activators or by increasing NO bioavailability via antioxidants. The association of other proteins with the nitric oxide synthase (NOS) isoforms and sGC could also serve as experimental and potentially therapeutic targets to modulate NO bioactivity. There is tremendous promise behind NO itself as well as the numerous other molecules and processes associated with the L-arginine-NO-cGMP pathway. Collaborative efforts among bench scientists, clinical investigators and epidemiologists are the key in realizing this promise.
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PMID:Nitric oxide and the endothelium: history and impact on cardiovascular disease. 1705 61


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