Role of methylglyoxal in essential hypertension

Abstract

Altered glucose metabolism due to insulin resistance is a common feature of essential hypertension in humans and in animal models. Elevated endogenous aldehydes in genetic (spontaneously hypertensive rats) and acquired (fructose-induced hypertensive rats) models of essential hypertension may be due to increased production of the reactive aldehyde methylglyoxal, resulting from altered glucose metabolism. Excess methylglyoxal binds sulfhydryl groups of membrane proteins, altering calcium channels and increasing cytosolic free Ca(2+) and blood pressure. It has been demonstrated that methylglyoxal, when given in drinking water to Wistar-Kyoto rats, leads to an increase in kidney aldehyde conjugates, cytosolic free Ca(2+) concentration, decreased serum nitric oxide, renal vascular hyperplasia and hypertension. N-acetylcysteine (NAC) in the diet of these animals prevented hypertension and associated biochemical and morphological changes. NAC normalizes blood pressure by directly binding to excess methylglyoxal, thus normalizing Ca(2+) channels, cytosolic Ca(2+) and nitric oxide. NAC also leads to increased levels of tissue glutathione, a storage form of cysteine. Glutathione acts as a cofactor in the enzymatic catabolism of methylglyoxal. Cysteine and other antioxidants, such as vitamins B(6), C and E, and lipoic acid, prevented hypertension and associated biochemical and morphological changes in both genetic and acquired rat models of hypertension. The antihypertensive effect of dietary antioxidants may be due to an increase in tissue cysteine and glutathione, which improves glucose metabolism and decreases tissue methylglyoxal. A diet rich in these antioxidants may be effective in preventing and controlling hypertension in humans.

Figure 1)

Role of aldehydes in the development of hypertension. [Ca²⁺]_i Free Ca²⁺ concentration; SH Sulfhydryl

Figure 2)

The bar graph shows kidney aldehyde conjugates, platelet free Ca²⁺ concentration ([Ca²⁺]_i) and systolic blood pressure (BP) in spontaneously hypertensive rats (SHRs) and fructose-induced hypertensive Wistar-Kyoto (WKY) rats. Starting at seven weeks of age, rats were divided into three groups of six animals each. For a period of 14 weeks, animals in the WKY-control and SHR-control groups were given a normal diet and normal drinking water; the WKY-fructose group was given a normal diet and 4% fructose in drinking water. All values (mean ± SD) are expressed as a percentage of the WKY-control group at the completion of the study at 21 weeks of age. *Values are significantly different (P<0.05) from other groups. Data from references and

Figure 3)

Formation of excess methylglyoxal due to altered glucose metabolism in genetic and acquired models of hypertension. GAPDH Glyceraldehyde-3-phosphate dehydrogenase

Figure 4)

A Reaction of methylglyoxal with the free sulfhydryl (HS or SH) group of a protein, with a further reaction with a free amino (NH₂) group of protein forming a stable adduct, thus permanently altering its function. B Protective effect of endogenous cysteine from methylglyoxal by forming a thiazolidine-carboxylic acid derivative, which is excreted in bile and urine

Figure 5)

A The line graph shows the effect of N-acetylcysteine (NAC) on systolic blood pressure in methylglyoxal-treated Wistar-Kyoto (WKY) rats. Starting at seven weeks of age, WKY rats were divided into three groups of six animals each. For the next 18 weeks, animals in the WKY-control group were given a normal diet and normal drinking water; the WKY-methylglyoxal group was given a normal diet and methylglyoxal in drinking water; and the WKY-methylglyoxal + NAC group was given 1.5% NAC in the diet and methylglyoxal in the drinking water. Methylglyoxal was given in the drinking water at a concentration of 0.2% during weeks 0 to 5; 0.4% at weeks 6 to 10; and 0.8% at weeks 11 to 18. Data are presented as mean ± SD of the six animals in each group for each week. Values are significantly different (P<0.05) from one to 18 weeks in the methylglyoxal groups compared with other groups of the same age. B The bar graph shows the effect of NAC on platelet free Ca²⁺ concentration ([Ca²⁺]_i), kidney aldehyde conjugates and circulating nitric oxide in methylglyoxal-treated WKY rats. The experimental groups and treatment period were the same as in A. All values (mean ± SD) are expressed as a percentage of the control group values at the completion of the study at 25 weeks of age. *Values are significantly different (P<0.05) from other groups. Data from reference

Figure 6)

A Light micrograph of a kidney from a Wistar-Kyoto (WKY) rat given methylglyoxal in drinking water for 18 weeks, showing smooth muscle cell hyperplasia with some narrowing of the lumen in the arteriole (hematoxylin and eosin stain, original magnification ×100). B Light micrograph of a kidney from a WKY rat given methylglyoxal in drinking water and N-acetylcysteine in the diet for 18 weeks, showing an almost normal-appearing arteriole (hematoxylin and eosin stain, original magnification ×100). Reproduced from reference

Figure 7)

A The line graph shows the effect of N-acetylcysteine (NAC) on systolic blood pressure in spontaneously hypertensive rats (SHRs). Starting at 12 weeks of age, animals were divided into three groups of six animals each. For the next 11 weeks, the SHR-control and Wistar-Kyoto (WKY)-control groups were given a normal diet and normal drinking water and the SHR-NAC group was given 1.5% NAC in the diet and normal drinking water. Data are presented as mean ± SD of the six animals in each group. Values are significantly different (P<0.05) from one to 11 weeks in the SHR-control group compared with the other groups of the same age. B The bar graph shows the effect of NAC on kidney aldehyde conjugates and platelet free Ca²⁺ concentration ([Ca²⁺]_i) in SHRs and WKY rats. The experimental groups and treatment period were the same as in A. All values (mean ± SD) are expressed as a percentage of the WKY-control group at the completion of the study at 23 weeks of age. *Values are significantly different (P<0.05) from other groups. Data from reference

Figure 8)

A The line graph shows the effect of vitamin (Vit) B₆, Vit E, Vit C and lipoic acid supplemented in the diet on systolic blood pressure in spontaneously hypertensive rats (SHRs). Starting at 12 weeks of age, animals were divided into six groups of six animals each. For nine weeks, animals in the Wistar-Kyoto (WKY)-control and SHR-control group were given a normal diet; the SHR-Vit B₆ group was given a diet supplemented with 20 mg Vit B₆; the SHR-Vit C group was given a diet supplemented with 100 mg Vit C; the SHR-Vit E group was given a diet supplemented with 3.4 mg Vit E; and the SHR-lipoic acid group was given a diet supplemented with 50 mg of lipoic acid per 100 g of diet. All animals were given normal drinking water. Values are given as the mean of the six animals in each group. SDs did not vary more than 6 mmHg in each case. Values are significantly different (P<0.05) from one to nine weeks in the SHR-control group compared with other groups of the same age. B The bar graph shows the effect of an antioxidant-supplemented diet on kidney and aortic aldehyde conjugates in SHRs. The experimental groups and treatment period were the same as in A. Data are presented as mean ± SD of the six animals in each group at the completion of the study at 21 weeks of age. *Values are significantly different (P<0.05) from other groups. QS Quinine sulphate. Data from references to

Figure 9)

The bar graph shows the effect of vitamin (Vit) B₆, Vit C, Vit E and lipoic acid supplemented in the diet on systolic blood pressure, kidney and aortic aldehyde conjugates, and platelet free Ca²⁺ concentration ([Ca²⁺]_i) in fructose-induced hypertensive Wistar-Kyoto (WKY) rats. Starting at seven weeks of age, rats were divided into six groups of six animals each. For 14 weeks, animals in the control group were given a normal diet and normal drinking water; fructose group, a normal diet and 4% fructose in drinking water; fructose + Vit B₆ group, a diet supplemented with 20 mg of Vit B₆ and 4% fructose in drinking water; fructose + Vit C group, a diet supplemented with 100 mg of Vit C and 4% fructose in drinking water; fructose + Vit E group, a diet supplemented with 3.4 mg of Vit E and 4% fructose in drinking water; and fructose + lipoic acid group, a diet supplemented with 50 mg of lipoic acid and 4% fructose in drinking water per 100 g of diet. Data (mean ± SD) are expressed as a percentage of the WKY-control group at the completion of the study at 21 weeks of age. *Values are significantly different (P<0.05) from other groups. Data from references to