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Objectives: Methylglyoxal is a reactive dicarbonyl intermediate of metabolism produced in the body. It reacts with certain proteins and forms damaging advanced glycation endproducts (AGEs) such as N epsilon-carboxyethyl-lysine (CEL) and N epsilon-carboxymethyl-lysine (CML). Increased methylglyoxal levels are found in diabetes mellitus and associated with hypertension development in the spontaneously hypertensive rats (SHR). The purpose of this study was to investigate whether increased endogenous formation of methylglyoxal and methylglyoxal-induced AGEs caused hypertension development in normotensive Sprague Dawley rats., Methods: The rats were fed chronically for 16 weeks with fructose, a known precursor of methylglyoxal formation. One group of rats was cotreated with fructose and metformin, an AGEs formation inhibitor. Methylglyoxal and reduced glutathione (GSH) were measured by high performance liquid chromatography, whereas hydrogen peroxide was measured by a dicholorofluorescin assay. Immunohistochemistry was performed for endothelial nitric oxide synthase (eNOS), CEL and CML., Results: Fructose-fed rats had elevated blood pressure, serum methylglyoxal and triglycerides and reduced serum levels of GSH. Methylglyoxal, hydrogen peroxide and CEL were increased in the aorta, whereas eNOS was reduced. CEL and CML were also increased in the mesenteric artery endothelium along with media/lumen ratio, signifying structural remodelling. All the harmful changes in fructose-fed rats were attenuated in metformin and fructose cotreated rats., Conclusion: Increased methylglyoxal, AGEs, oxidative stress and reduced eNOS along with structural remodeling of the vessel wall in the aorta and mesenteric artery likely play a role in the pathogenesis of hypertension.

Background: Methylglyoxal (MG), a metabolite of glucose, and MG-induced advanced glycation endproducts (AGEs) are causatively associated with vascular complications of diabetes mellitus. We have previously reported elevated levels of MG and MG-induced AGEs in spontaneously hypertensive rats (SHR). The purpose of this study was to investigate the causative role of MG and MG-induced AGEs in the pathogenesis of hypertension in SHR., Methods: Young SHR were treated with an AGE inhibitor, aminoguanidine, for 9 weeks. HPLC was used to determine plasma and aortic MG and reduced glutathione levels. The MG-induced AGEs, N epsilon-carboxyethyl-lysine (CEL) and argpyramidine, in the aorta were determined by immunohistochemistry. Vascular relaxation of small mesenteric arteries was measured using myograph., Results: Chronic treatment with aminoguanidine attenuated age-dependent blood pressure (BP) increase in SHR. Plasma and aortic MG levels, and aortic levels of MG-induced AGEs, were significantly reduced after aminoguanidine treatment, which were comparable to those from age-matched Wistar Kyoto rats. Free radical level was significantly lowered, whereas reduced glutathione level was significantly increased by aminoguanidine treatment in the aortic tissues from SHR. Moreover, aminoguanidine therapy prevented the morphologic damage of vascular tissues in SHR and restored the endothelium-dependent relaxation to acetylcholine. Chronic aminoguanidine treatment also increased aortic endothelial nitric oxide synthase expression and reduced inducible nitric oxide synthase expression., Conclusions: The MG and MG-induced AGEs contribute to the pathogenesis of hypertension by altering the redox balance, causing vascular eutrophic inward remodeling, and inducing endothelial dysfunction in SHR.

Pathogenic mechanisms for essential hypertension are unclear despite striking efforts from numerous research teams over several decades. Increased production of reactive oxygen species (ROS) has been associated with the development of hypertension and the role of ROS in hypertension has been well documented in recent years. In this context, it is important to better understand pathways and triggering factors for increased ROS production in hypertension. This review draws a causative linkage between elevated methylglyoxal level, methylglyoxal-induced production of ROS, and advanced glycation end products in the development of hypertension. It is proposed that elevated methylglyoxal level and resulting protein glycation and ROS production may be the upstream links in the chain reaction leading to the development of hypertension.

Correlation of blood pressure (BP) with expression levels of large-conductance, voltage- and Ca2+-activated K+ (BK) channel beta1 subunit in vascular tissues from spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) at different ages was investigated. Systolic BP and BK beta1 expression in mesenteric arteries at either mRNA or protein levels were not different among 4-week-old SHR, WKY, and SD. With hypertension developed at 7 weeks and reached plateau at 12 weeks, expression levels of BK beta1 mRNA in mesenteric arteries and aortae from SHR during this period of time were significantly higher than in age-matched normotensive WKY. The BK beta1 protein expression was significantly higher in mesenteric arteries from 12-week-old but not 7-week-old SHR when compared with age-matched WKY and SD. The BK beta1 protein levels in aortae were not different among 7-week-old SHR, WKY, and SD but were significantly lower in 12-week-old WKY than in age-matched SHR and SD. Captopril treatment normalized BP of 12-week-old SHR. This treatment downregulated BK beta1 protein in mesenteric arteries but upregulated it in aortae. No significant difference in BK alpha subunit expression was detected in mesenteric arteries from three strains of rats as well as the captopril-treated SHR. It appears that expression patterns of BK beta1 in vascular tissues vary depending on tissue types, animal age, and animal strains. Expression of BK beta1 in mesenteric arteries is closely correlated with BP in SHR. Increased BK beta1 expression in mesenteric arteries may represent a compensatory reaction to limit the development of hypertension.

Objectives: The pathogenic process of diabetes mellitus is associated with increased methylglyoxal (MG). MG causes non-enzymic glycation of proteins to form irreversible advanced glycation endproducts (AGEs). However, the correlation between MG and essential hypertension is unknown. The aim of the present study was to investigate whether MG, MG-induced AGEs, and oxidative stress were increased in the aorta of spontaneously hypertensive rats (SHR) and whether an increased formation of MG and related AGEs was correlated with the development of high blood pressure in these rats., Methods: High-performance liquid chromatography (HPLC) was used to determine MG and reduced glutathione levels in plasma and aorta. MG-induced AGEs, N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-carboxymethyl-lysine (CML), in aorta were determined using immunohistochemistry. Hydrogen peroxide and superoxide levels in aorta and glutathione peroxidase and reductase activities were also determined., Results: Aortic and plasma MG levels were significantly elevated in SHR, but not in Wistar-Kyoto (WKY) rats, at 8, 13 and 20 weeks of age, in parallel with blood pressure increase. Immunohistochemistry revealed more intense staining for CML and CEL in aorta from SHR than those of WKY rats from 8 weeks onwards. Most of the staining was localized to endothelial cells. Superoxide and hydrogen peroxide levels were significantly elevated in aorta of SHR at 13 weeks, whereas reduced glutathione levels, glutathione peroxidase and glutathione reductase activities were significantly decreased compared to WKY rats., Conclusions: Increased aortic MG, AGE formation and oxidative stress were associated with blood pressure increase in SHR, which may cause endothelial dysfunction and altered vascular reactivity.

The metabolic syndrome is a group of abnormalities including obesity, high blood pressure, hyperinsulinemia, high blood glucose levels and hyperlipidemia that together greatly increase the risk of developing cardiovascular disease and Type 2 diabetes. Hydrogen sulfide (H2S) is a vasodilatory gasotransmitter mediator in the cardiovascular system, proposed as an endothelium-derived relaxing factor. A lack of H2S and its synthesizing enzyme, cystathionine γ-lyase, in the vasculature causes hypertension, whereas an increase in the pancreas reduces insulin secretion. Thus, research is making inroads to determine whether H2S is involved in the pathogenesis of the metabolic syndrome. Several laboratories are synthesizing and testing clinically used drugs that release H2S. Some of these compounds are being tested for effectiveness in the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Correlation of blood pressure (BP) with expression levels of large-conductance, voltage- and Ca2+-activated K+ (BK) channel β1 subunit in vascular tissues from spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) at different ages was investigated. Systolic BP and BK β1 expression in mesenteric arteries at either mRNA or protein levels were not different among 4-week-old SHR, WKY, and SD. With hypertension developed at 7 weeks and reached plateau at 12 weeks, expression levels of BK β1 mRNA in mesenteric arteries and aortae from SHR during this period of time were significantly higher than in age-matched normotensive WKY. The BK β1 protein expression was significantly higher in mesenteric arteries from 12-week-old but not 7-week-old SHR when compared with age-matched WKY and SD. The BK β1 protein levels in aortae were not different among 7-week-old SHR, WKY, and SD but were significantly lower in 12-week-old WKY than in age-matched SHR and SD. Captopril treatment normalized BP of 12-week-old SHR. This treatment downregulated BK β1 protein in mesenteric arteries but upregulated it in aortae. No significant difference in BK α subunit expression was detected in mesenteric arteries from three strains of rats as well as the captopril-treated SHR. It appears that expression patterns of BK β1 in vascular tissues vary depending on tissue types, animal age, and animal strains. Expression of BK β1 in mesenteric arteries is closely correlated with BP in SHR. Increased BK β1 expression in mesenteric arteries may represent a compensatory reaction to limit the development of hypertension. [Copyright &y& Elsevier]