Hibiscus sabdariffa Linnaeus (Malvaceae), curcumin and resveratrol as alternative medicinal agents against metabolic syndrome.

Metabolic syndrome (MS) is an obesity-associated collection of disorders, each of which contributes to cardiovascular risk. For patients with MS, it is difficult to follow a diet/exercise regime that would improve their symptoms. Therefore, the investigation of agents that may deal with its more serious aspects is an important medical field for research. Numerous experimental studies have confirmed the important role of medicinal plants or their active components in the prevention and treatment, and in lowering risk factors of MS. As oxidative stress and inflammation are involved in the association between obesity, insulin resistance (IR) and hypertension, antioxidant and anti-inflammatory plant components like polyphenols might be useful as a treatment for MS. The aqueous extract of Hibiscus Sabdariffa L (HSE), rich in several polyphenols, is commonly and effectively used in native medicines against hypertension, diabetes and liver disorders. HSE has also shown therapeutic promise in the prevention of MS in patients, probably due to its polyphenol content. Curcumins, derived from the spice turmeric, and resveratrol, polyphenols found in grapes and red wine respectively, in addition to their antioxidant and anti-inflammatory properties, inhibit preadipocyte proliferation, de novo lipogenesis and fat accumulation in liver. Thus, due to their efficacy in the regulation of multiple targets, polyphenols have received considerable interest as potential therapeutic agents for the prevention and treatment of MS. This review discusses the therapeutic use of HSE, as well as curcumin and resveratrol, in the context of obesity as an initiator of insulin resistance and hypertension, the two main features of MS, together with the underlying mechanisms of action.

Effect of glycine on the cyclooxygenase pathway of the kidney arachidonic acid metabolism in a rat model of metabolic syndrome.

The kidneys are organs that can be severely impaired by metabolic syndrome (MS). This is characterized by the association of various pathologies such as hypertension, dyslipidemia, and type-2 diabetes. Glycine, a nonessential amino acid, is known to possess various protective effects in the kidney, such as a decrease in the deterioration of renal function and a reduction of the damage caused by hypoxia. In a rat model of MS, the effect of glycine on the cyclooxygenase (COX) pathway of arachidonic acid (AA) metabolism was studied in isolated perfused kidney. MS was induced in Wistar rats by feeding them a 30% sucrose solution for 16 weeks. The addition of 1% glycine to their drinking water containing 30% sucrose, for 8 weeks, reduced high blood pressure, triglyceride levels, insulin concentration, homeostatis model assessment (HOMA) index, albuminuria, AA concentration in kidney homogenate, renal perfusion pressure, prostaglandin levels, PLA2 expression, and COX isoform expression, compared with MS rats that did not receive the glycine supplement. Glycine receptor expression decreased significantly with MS, but glycine treatment increased it. The results suggest that in the MS model, 1% glycine treatment protects the kidney from damage provoked by the high sucrose consumption, by acting as an anti-inflammatory on the COX pathway of AA metabolism in kidney.

Effect of gonadectomy on the metabolism of arachidonic acid in isolated kidney of a rat model of metabolic syndrome.

Influence of sex on arachidonic acid metabolism, a pathway involved in the link between metabolic syndrome (MS) and renal damage, was studied in isolated perfused kidney. Metabolic syndrome was induced by feeding 30% sucrose solution for 24 weeks to intact and gonadectomized female (Ovx) and male (Cas) rats. Systolic blood pressure, albuminuria, as well as prostaglandin E(2) and thromboxane B(2) from urine and perfusate increased in MS male and MS ovariectomized females; castration reduced them in MS males. Perfusion of arachidonic acid in kidneys from MS males increased perfusion pressure compared with controls. No difference appeared in perfusion pressure between control and MS females. Castration diminished perfusion pressure in MS; the opposite was observed in Ovx MS. Perfusion with arachidonic acid plus indomethacin decreased perfusion pressure in MS male kidneys and in Cas MS. In Ovx MS, arachidonic acid plus indomethacin decreased perfusion pressure, but not in female control, MS, and Ovx control. Increase in perfusion pressure with arachidonic acid in both male MS and Ovx MS was related to cyclooxygenase (COX)-1 and COX-2 overexpression in kidney. Castration reduced the expression of COX-1 and COX-2 in MS to control levels. The results suggest that the alteration in arachidonic acid metabolism associated with changes in the expression of COX-1 and COX-2 induced by sucrose intake, and influenced by sex hormones, may contribute to renal damage.

Association of renal damage and oxidative stress in a rat model of metabolic syndrome. Influence of gender.

This study investigated the association between nephropathy and oxidative stress, by measurement of systolic blood pressure, lipid peroxidation, activities of catalase, manganese- and copper-zinc-superoxide dismutase and endothelial nitric oxide synthase expression and concentrations of nitrates/nitrites in kidneys from rats with Metabolic Syndrome. Weaning female or male rats had 30% sucrose to drink for 24 weeks (Metabolic Syndrome). Modulation by sex hormones was investigated by gonadectomy and hormone replacement. In Metabolic Syndrome, Castrated Metabolic Syndrome + Testosterone males and Ovariectomized Metabolic Syndrome females had increased blood pressure, proteinuria and lipid peroxidation. Nitrates/nitrites and activities of catalase, manganese and copper-zinc-superoxide dismutase decreased vs intact Control, Castrated Metabolic Syndrome males, intact Metabolic Syndrome and Ovariectomized Metabolic Syndrome + Estradiol females. The results suggest that sex hormones modulate the activity of superoxide-dismutase, catalase and endothelial nitric oxide-synthase. Ovariectomy decreased the protection against oxidative stress in females; the opposite occurred in castrated males.

Castration modifies aortic vasoreactivity and serum fatty acids in a sucrose-fed rat model of metabolic syndrome.

Levels of testosterone and estradiol influence the incidence of cardiovascular diseases: generally, estrogens in females are protective before menopause; coronaropathies, hypertension, and dyslipidemias in normal men are more frequent at comparable ages. We investigated the modulation by castration of in vitro vasoreactivity, serum lipid content, and systolic blood pressure (SBP) in rats with sucrose-induced metabolic syndrome. The main characteristics of the rat model are: hypertriglyceridemia, moderately high blood pressure, intra-abdominal accumulation of adipose tissue, hyperinsulinemia, nephropathy, increased oxidative stress, and altered vasoreactivity. Male weanling rats received 30% sucrose solution for 16 weeks (metabolic syndrome; MS), controls (C) had plain water; both had commercial rodent chow. They were subdivided into five groups with two subgroups each: Group 1, intact C and MS rats, Groups 2-5, C and MS rats castrated for periods of 16, 12, 8, and 4 weeks. At the end of the study period, systolic blood pressure was measured, and blood and aortas were obtained for fatty acid determination and vasoreactivity assays, respectively. After 16 weeks' sucrose treatment MS aortas showed hypercontractility and decreased vasodilation. Palmitic and palmitoleic acids were increased in MS versus C. Arachidonic acid levels in MS were lower than in intact or castrated C. Long-term castration of 16 weeks normalized the levels of palmitic and oleic acids. With the shorter periods of castration, contractility increased and relaxation decreased in C and MS, but it was more significant in C. Regarding fatty acid composition, long-term castration increased polyunsaturated (arachidonic and eicosapentaenoic) fatty acids. The shorter periods did not modify the fatty acid profile in either C or MS. Metabolic syndrome altered SBP, aortic reactivity, and levels of fatty acids; castration of long duration normalized them in some cases.

Effects of sex hormone levels on aortic vascular reactivity and variables associated with the metabolic syndrome in sucrose-fed female rats.

We studied the effect of varying levels of sex hormones, induced by ovariectomy and administration of testosterone or estradiol, on aortic reactivity in female rats with metabolic syndrome (MS) induced by a sucrose diet. Vasoreactivity of aortic rings, blood pressure, intra-abdominal fat, serum triglycerides, nitrates and nitrites, and TBARS were evaluated. Intact MS and ovariectomized MS had higher BP than intact control (C) and ovariectomized C, respectively; estradiol administration decreased BP in ovariectomized MS but not in ovariectomized C. Triglycerides and fat were both higher in MS. Triglycerides were not modified by surgery or hormone treatment, but ovariectomy increased fat. When ovariectomy was combined with hormones, however, fat was reduced to the level of intact rats. Ovariectomy decreased, but hormones increased, serum nitrates and nitrites. Vasoconstriction was larger in intact MS and ovariectomized MS + testosterone aortas than in intact C and ovariectomized C + testosterone, respectively. Vasodilation was reduced in intact MS and ovariectomized MS + testosterone compared with intact C, ovariectomized C + testosterone, ovariectomized MS, and ovariectomized MS + estradiol. The results suggest endothelial dysfunction in intact MS and ovariectomized MS + testosterone, but protection by ovariectomy + estradiol in MS due to hormones. Indomethacin reduced all contractions, but the effect was greater in estradiol-treated rats. L-NAME increased contractility, more in the ovariectomized C and MS groups and less in the estradiol-treated groups.

Modulation of aortic vascular reactivity by sex hormones in a male rat model of metabolic syndrome.

Modulation by sex hormones of aortic reactivity in rats with the metabolic syndrome (MS) was investigated. The following groups of weanling male Wistar rats were used: control rats (C) received regular tap water while MS rats received 30% sucrose in their drinking water; both had rodent chow for 24 weeks. These two groups were further subdivided into the following four groups: intact (Int), castrated (Cas), castrated plus testosterone (T) and castrated plus estradiol (E). Vascular response of thoracic aortic rings to norepinephrine (NE), acetylcholine (ACh), indomethacin (Indo) and nitro-l-arginine-methyl ester (L-NAME) was investigated. Blood pressure (BP) and serum nitrates and nitrites were measured. BP and serum nitrates and nitrites were modified by castration and treatments with either T or E. Vasoconstriction in Int MS and Cas MS+T aortas was larger than in C and Cas C+T, respectively. Vasodilation in Int MS and Cas MS+T was reduced in comparison with C and Cas C+T, Cas MS and Cas MS+E. Indomethacin decreased vasoconstriction in all groups (P<0.002) but Int C and Cas C+T remained significantly smaller than Int MS and Cas MS+T. l-NAME in NE-contracted vessels induced a significant increase in vasoconstriction, except in Cas C+E rats; the responses of Int MS and Cas MS+T were significantly larger than in Int C and Cas C+T. The results suggest endothelial dysfunction in Int MS and Cas MS+T and a protective effect resulting from castration and castration plus E in MS animals, indicating a sex hormone influence.

Effect of sex hormones on non-esterified fatty acids, intra-abdominal fat accumulation, and hypertension induced by sucrose diet in male rats.

Sucrose-fed rats (1) had higher intra-abdominal fat mass and plasma non-esterified fatty acids and lower testosterone levels, (2) were hypertensive, and (3) had lower plasma NO metabolites than controls. The lack of testosterone by castration of sucrose-fed rats decreased high blood pressure and circulating non-esterified fatty acids and increased NO metabolites. The administration of testosterone to castrated sucrose-fed rats restored hypertension, fat accumulation, and high-circulating non-esterified fatty acids, and lowered NO metabolite levels whereas estradiol treatment did not significantly affect these variables in castrated animals. This study proposes that the low levels of testosterone found in sucrose-fed rats are sufficient to maintain central obesity and increased circulating non-esterified fatty acids, which contribute to the development of hypertension in sucrose-fed rats by modulating the biosynthesis of NO.

Isolated heart function after ischemia and reperfusion in sucrose-fed rats: influence of gender and treatment.

Sucrose-fed rats (HTG) develop hypertension, hypertriglyceridemia, and other features of the metabolic syndrome. This condition, nowadays a world epidemic, is more prevalent in males and increases the risk of cardiovascular diseases. Weanling male and female rats were given either tap water in control (C) or 30% sucrose solution in HTG groups and commercial rat chow for 3, 5, or 8 months. We studied possible variations in cardiac function, due to gender and length of treatment, in isolated heart after ischemia-reperfusion, since an impaired performance may be more easily detected under stress. Together, sucrose treatment and age affected all cardiac variables. Gender had significant effect on coronary vascular resistance and postischemic levels of the enzyme CK-MB; the percentages of retained cardiac enzymes after ischemia were higher in C and HTG females. C and HTG males had a higher incidence of arrhythmias than females, but only HTG males suffered lethal ventricular fibrillation.

Effect of age on insulin-induced endothelin release and vasoreactivity in hypertriglyceridemic and hypertensive rats.

In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats.

Is glycine effective against elevated blood pressure?

PURPOSE OF REVIEW: Glycine, a non-essential amino acid, has been found to protect against oxidative stress in several pathological situations, and it is required for the biosynthesis of structural proteins such as elastin. As hypertension is a disease in which free radicals and large vessel elasticity are involved, this article will examine the possible mechanisms by which glycine may protect against high blood pressure. RECENT FINDINGS: The addition of glycine to the diet reduces high blood pressure in a rat model of the metabolic syndrome. Also, glycine supplemented to the low protein diet of rat dams during pregnancy has a beneficial effect on blood pressure in their offspring. The mechanism by which glycine decreases high blood pressure can be attributed to its participation in the reduction of the generation of free radicals, increasing the availability of nitric oxide. In addition, as glycine is required for a number of critical metabolic pathways, such as the synthesis of the structural proteins collagen and elastin, the perturbation of these leads to impaired elastin formation in the aorta. This involves changes in the aorta's elastic properties, which would contribute to the development of hypertension. SUMMARY: The use of glycine to lower high blood pressure could have a significant clinical impact in patients with the metabolic syndrome and with limited resources. On the other hand, more studies are needed to explore the beneficial effect of glycine in other models of hypertension and to investigate possible side-effects of treatment with glycine.

Isolated heart function during ischemia and reperfusion in sucrose-fed rats: effect of insulin infusion.

In myocardial damage due to ischemia-reperfusion, the administration of insulin together with glucose and potassium may be protective, although in some patients and animal models, it is ineffective. In a rat model (HTG) with characteristics of the metabolic syndrome, induced by sucrose feeding, ischemia-reperfusion of the isolated heart evidences a less favorable outcome than in control animals, particularly males. We investigated the effect of insulin infusion during the reperfusion period in isolated hearts from control and HTG male and female rats. Weanling Wistar rats were given commercial rat chow and tap water (C rats) or 30% sucrose solution (HTG rats) for 8 months. They developed moderate hypertension and hyperinsulinemia, central adiposity, nephropathy, and hypertriglyceridemia. Cardiac function was recorded in a Langendorff preparation subjected to 25 min ischemia and 15 min reperfusion. The handicapped functionality of HTG hearts is more apparent under conditions of stress. Insulin administration improved particularly mechanical work and +dp/dt max variables. The effect of sex was observed on the type of arrhythmias developed during reperfusion: Only the males showed lethal ventricular fibrillation, which disappeared after insulin administration. Females had lower levels of cardiac enzymes creatine kinase (CKMB) and lactic dehydrogenase (LDH), but their performance was not hindered, probably on account of protective factors such as estrogens. Summing up, the pathological features of the HTG model did not prevent insulin from exerting some of its beneficial effects in HTG hearts. Sex differences in the outcome were more apparent in the type of arrhythmias after reperfusion; they were lethal in HTG males only, but insulin prevented their onset.

Activities of antioxidant enzymes in two stages of pathology development in sucrose-fed rats.

The activities of catalase in liver, heart and kidney as well as glutathione peroxidase and superoxide dismutase in liver, heart, kidney, and serum from hypertriglyceridemic and hypertensive female and male rats were measured at 3 and 8 months of daily administration of sucrose in their drinking water. This treatment induces high levels of serum triglycerides, central obesity, moderate hypertension, hyperinsulinemia, and an increase in lipoperoxidation, among other alterations. The experimental periods were chosen on the basis of previous observations: at 3 months the level of serum triglycerides increases significantly above the normal value and remains without major changes thereafter, but the blood pressure only rises significantly at about 4 months in males and 5 months in females. So, at 8 months the rats have been subjected to abnormal conditions for 3-4 months. The effect of these and the influence of sex on levels of antioxidant enzymes were investigated. Both factors, sucrose treatment and sex, were conducive to significant changes in those variables.

Antioxidant enzymes in hypertensive and hypertriglyceridemic rats: effect of gender.

In a model of hypertensive and hypertriglyceridemic rats (HTG), in which oxidative stress is increased, the influence of gender upon activities of catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD) was investigated. Statistically significant differences between antioxidant enzyme activities and treatment with relation to gender were analyzed. Weanling Wistar rats were given normal rat chow and either tap water for control group or 30% sucrose solution for HTG group, for 5-6 months. At the end of the experimental period, blood pressure was significantly higher in both male and female HTG groups, but males showed higher values than females. Serum, heart, kidney, and liver were obtained to determine antioxidant enzyme activities. Activities of CAT and GPX tended to be higher in male animals. A larger number of significant changes in enzyme activities associated with gender appears in HTG than in controls, which indicates the harmful effect of the treatment.

Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats.

The study investigated the mechanism by which glycine protects against increased circulating nonesterified fatty acids (NEFA), fat cell size, intra-abdominal fat accumulation, and blood pressure (BP) induced in male Wistar rats by sucrose ingestion. The addition of 1% glycine to the drinking water containing 30% sucrose, for 4 wk, markedly reduced high BP in sucrose-fed rats (SFR) (122.3 +/- 5.6 vs. 147.6 +/- 5.4 mmHg in SFR without glycine, P < 0.001). Decreases in plasma triglyceride (TG) levels (0.9 +/- 0.3 vs. 1.4 +/- 0.3 mM, P < 0.001), intra-abdominal fat (6.8 +/- 2.16 vs. 14.8 +/- 4.0 g, P < 0.01), and adipose cell size were observed in SFR treated with glycine compared with SFR without treatment. Total NEFA concentration in the plasma of SFR was significantly decreased by glycine intake (0.64 +/- 0.08 vs. 1.11 +/- 0.09 mM in SFR without glycine, P < 0.001). In control animals, glycine decreased glucose, TGs, and total NEFA but without reaching significance. In SFR treated with glycine, mitochondrial respiration, as an indicator of the rate of fat oxidation, showed an increase in the state IV oxidation rate of the beta-oxidation substrates octanoic acid and palmitoyl carnitine. This suggests an enhancement of hepatic fatty acid metabolism, i.e., in their transport, activation, or beta-oxidation. These findings imply that the protection by glycine against elevated BP might be attributed to its effect in increasing fatty acid oxidation, reducing intra-abdominal fat accumulation and circulating NEFA, which have been proposed as links between obesity and hypertension.

Impairment of glucose metabolism and energy transfer in the rat heart.

The metabolic pathways involved in ATP production in hypertriglyceridemic rat hearts were evaluated. Hearts from male Wistar rats with sugar-induced hypertriglyceridemia were perfused in an isolated organ system. Mechanical performance, oxygen uptake and beat rate were evaluated under perfusion with different oxidizable substrates. Age- and weight-matched animals were used as control. The hypertriglyceridemic (HTG) hearts showed a decrease in the mechanical work and slight diminution in the oxygen uptake when perfused with glucose, pyruvate or lactate. No differences were found when perfused with palmitate, octanoate or beta-hydroxybutyrate. The glycolytic flux in HTG hearts was 2.4 times lower than in control hearts. Phosphofructokinase-I (PFK-I) was 16% decreased in HTG hearts, whereas pyruvate kinase activity did not change. The increased levels of glucose-6-phosphate in HTG heart, suggested a flux limitation by the PFK-I. Pyruvate dehydrogenase in its active form (PDHa) diminished as well. The PDHa level in the HTG hearts was restored to control values by dichloroacetate; however, this addition did not significantly improve the mechanical performance. Levels of ATP and phosphocreatine as well as total creatine kinase activity and the MB fraction were significant lower in the HTG hearts perfused with glucose. The data suggested that supply of ATP by glucose oxidation did not suffice to support cardiac work in the HTG hearts; this impairment was exacerbated by the diminution of the creatine kinase system output.

Myocardial function and effect of serum in isolated heart from hypertriglyceridemic and hypertensive rats.

We evaluated the myocardial function of rats with sugar-induced hypertriglyceridemia (HTG) and hypertension, and the effect of serum on myocardial performance in the isolated heart preparation. Also, the response to reperfusion after 30 minutes of global ischemia was investigated. Hearts from HTG rats developed lower ventricular pressure (VP) and the conduction rate was higher than in hearts from control rats (CR). The recovery of VP after ischemia was significantly lower in HTG than in CR hearts (p < 0.05). The HTG sera produced a higher increase in the VP and in the perfusion pressure. During reperfusion, the incidence of premature beats, ventricular fibrillation and tachycardia in HTG hearts was increased so hypertriglyceridemia caused alterations in the mechanical and electrical conduction of the myocardium and exacerbated the injury produced by ischemia-reperfusion. Also a circulating factor in the HTG serum induced a vasoactive response of the heart which was reflected in its mechanical performance.