Efectos de la yerba mate (Ilex paraguariensis) en los niveles plasmáticos de glucosa, lípidos, urea y creatinina de ratas Wistar / Effects of yerba mate (Ilex paraguariensis) in the plasma levels of glucose, lipids, urea and creatinine of Wistar rats

INTRODUCCIÓN: La yerba mate (Ilex paraguariensis) es un vegetal nativo de las regiones subtropicales de Sudamérica utilizada en la preparación de infusiones que se beben en ciertos países de la región. El objetivo del estudio fue determinar los efectos de extractos acuosos de Ilex paraguariensis en los niveles plasmáticos de glucosa, lípidos, urea y creatinina en ratas Wistar. MATERIALES Y MÉTODO: Estudio experimental. Se distribuyeron al azar 20 ratas Wistar en 2 grupos de 10 animales cada uno; el grupo control recibió como bebida agua y el grupo expuesto a yerba recibió como bebida una infusión de Ilex paraguariensis. El periodo de experimentación fue de 60 días, a cuyo término se determinaron las concentraciones plasmáticas de glucosa, colesterol, triglicéridos, urea y creatinina. Las medias de los parámetros fueron comparadas por la prueba U de Mann-Whitney, considerándose significativas las diferencias con p<0,05. RESULTADOS: El consumo de yerba mate disminuyó los niveles de glicemia en el grupo expuesto en comparación con el grupo control, siendo la diferencia altamente significativa (p<0,001). Se observaron niveles significativamente mayores de urea (p=0,04) y creatinina (p=0,02)en el grupo expuesto en comparación con el grupo control. No hubo diferencias significativas entre los niveles de colesterol y triglicéridos entre ambos grupos. DISCUSIÓN: Los resultados sugieren que el consumo de Ilex paraguariensis reduce los niveles plasmáticos de glucosa y podrían poseer un efecto nocivo en la función renal.

INTRODUCTION: yerba mate (Ilex paraguariensis) is a plant species native to subtropical regions of South America and is used to make tea in local countries. The aim of the study was to determine the effects of aqueous extracts of Ilex paraguariensis in plasmatic levels of glucose, lipids, urea and creatinine in Wistar rats. MATERIALS AND METHODS: Experimental study. 20 Wistar rats were randomized in two groups of ten animals each: control group received water while the exposed group received an infusion of Ilex paraguariensis. After 60 days of experiment, plasmatic concentrations of glucose, cholesterol, triglycerides,urea and creatinine were determined. Mann- Whitney U test was used to compare means, differences were considered statistically significant atp <0.05. RESULTS: Blood glucose levels were lower in the exposed group compared with the control group(p <0.001).Plasmatic levels of urea and creatinine were signiticantly higher in the exposed group (p=0.04 and p=0.02 respectively). No significant differences were observed in the levels of cholesterol and triglycerides among the groups. DISCUSSION: The results suggest that consumption of Ilex paraguariensis reduces plasma glucose levels and could have an adverse effect on renal function.

[Sub-cortico-frontal encephalopathy and choreic movements related to recombinant interferon-alpha 2b]. / Encéphalopathie sous-cortico-frontale et mouvements choréiques liés à l'interféron-alpha 2b recombinant.

Interferon (IFN)-alpha is associated with central nervous system (CNS) side effects such as depression and suicide ideation, somnolence, confusion, drowsiness, psychomotor slowing, memory impairment and visual disorientation. More severe complications are uncommon and include frank paranoia, dementia, coma, seizures and neuropathy. With the increasing long-term and extensive use of interferon (IFN)-alpha several new neurologic adverse effects have been recognized. We report on two patients who developed severe subcortico-frontal impairment, associated in one case with choreic movements, after a long-term treatment with IFN-alpha 2b for hematologic malignancies. Our patients rapidly and completely recovered from their cognitive and motor symptoms after the discontinuation of the drug. The same neurologic symptoms reappeared when we attempted to reintroduce lower doses of IFN-alpha in one case. Although little is known regarding IFN-alpha actions in the CNS, several possible mechanisms may underlie its neurotoxicity and might result from complex direct and indirect effects involving brain vasculature, neuroendocrine system, neurotoxic secondary cytokines'release and neurotransmitters.

Taurine depletion, a novel mechanism for cardioprotection from regional ischemia.

Three processes that have been implicated in ischemic injury are impaired Ca2+ movement, altered osmoregulation, and membrane remodeling. Because the amino acid, taurine, affects all three processes, it seemed logical that changes in the myocardial content of taurine might affect ischemic injury. To test this hypothesis, infarct size and areas at risk were compared in isolated hearts from control and taurine-depleted rats after a 45-min ligation of the left anterior descending coronary artery and 2 h of reperfusion. Hearts of rats treated for 4 wk with the taurine inhibitor, beta-alanine, exhibited a 57% reduction in the infarct size-to-risk area ratio. The degree of cardioprotection was found to correlate (r = 0.85) with the extent of taurine depletion, the latter dependent on the length of beta-alanine feeding. When the taurine-depleted rats were fed taurine, myocardial taurine levels were restored and the cardioprotection was lost. However, addition of neither beta-alanine (3%) nor taurine (20 mM) to the perfusion medium altered infarct size. We conclude that taurine depletion renders the heart resistant to injury caused by regional ischemia.

Mechanisms underlying depressed Na+/Ca2+ exchanger activity in the diabetic heart.

OBJECTIVES: Depression in Na+/Ca2+ exchanger activity is an important factor in the development of the diabetic cardiomyopathy. Since the mechanism underlying this depression remains unknown, the aim of this study was to determine the contribution of hyperglycemia and insulinopenia towards the observed impairment in Na+/Ca2+ exchanger activity. METHODS: Non-insulin-dependent diabetes was induced in neonatal Wistar rats by injection of 90 mg/kg streptozotocin. Na+/Ca2+ exchange in sarcolemmal vesicles and isolated cardiomyocytes was determined by Na(+)-dependent 45Ca2+ transport. To assess the role of insulin deficiency and hyperglycemia on Na+/Ca2+ exchanger activity, neonatal cardiomyocytes were incubated for 3 days in media containing either 5 mM glucose and 56 U/l insulin (Control), 30 mM glucose and 56 U/l insulin (High glucose) or 5 mM glucose and 0 insulin (Insulin deficiency). Since hyperglycemia has been shown to affect protein kinase C activity, Ca(2+)-dependent isoforms of protein kinase C were examined in non-diabetic and diabetic heart using hydroxylapatite chromatography. Also examined was Na+/Ca2+ exchanger mRNA levels in diabetic and non-diabetic hearts using Northern slot blot analysis. RESULTS: Acute insulin produced a dose-dependent increase in Na+/Ca2+ exchanger activity, which was dramatically attenuated in diabetic membrane. Myocytes incubated in media containing 30 mM glucose exhibited a 33% reduction in Na+/Ca2+ exchanger activity, while insulinopenia reduced activity by 63%. Exchanger mRNA levels of the diabetic heart were normal; however, diabetes was associated with major changes in protein kinase C activity. CONCLUSIONS: Reduced Na+/Ca2+ exchanger activity resulting from diabetes, hyperglycemia or insulinopenia may be related to changes in protein kinase C activity, but is not caused by altered expression of the transporter.

Acceleration of growth of cultured cardiomyocytes and translocation of protein kinase C.

Phorbol 12-myristate 13-acetate (PMA), norepinephrine (NE), and contraction stimulate cardiomyocyte growth (increased protein content). Differences exist in the time course and extent of protein and RNA accumulation. Cells plated at 4 x 10(6) cells/60-mm dish and arrested with 50 mM KCl demonstrated no significant growth. Treatment with PMA stimulated growth to a maximum of 17% at 48 h. In contrast, maximal stimulation of growth was 36% at 48 h and 31% at 72 h for contracting and NE-treated cells, respectively. Maximal stimulation of the capacity for protein synthesis (RNA content) was 32% for PMA-treated cells at 24 h compared with 59% and 77% for NE-treated and contracting cells, respectively, at 72 h. In support of a primary role for altered capacity in the regulation of protein synthesis, there was a significant correlation (r = 0.84) between RNA and protein contents that was independent of the stimulus used. Angiotensin II increased RNA content by 28% at 48 h but had no effect on growth up to 72 h. Growth stimulation and increased nuclear protein kinase C (PKC) activity were induced by contraction, NE, and PMA treatment and were inhibited by staurosporine (a PKC inhibitor), suggestive of a central role for PKC.

Phorbol ester stimulation of protein kinase C activity and ribosomal DNA transcription. Role in hypertrophic growth of cultured cardiomyocytes.

The mechanism by which phorbol esters induce hypertrophic growth of cardiomyocytes was investigated. Control and 4 alpha-phorbol 12,13-didecanoate-treated myocytes demonstrated a slow rate of growth as measured by the protein/DNA ratio and cell area. In contrast, treatment with phorbol 12-myristate 13-acetate (PMA) stimulated protein accumulation by 34%, while cell area was increased by 68% over control myocytes after 72 h. RNA content in PMA-treated myocytes was 33% higher than in control cells and 4 alpha-phorbol 12,13-didecanoate-treated cells after 72 h. Membrane-associated protein kinase C activity was transiently increased after PMA treatment but returned to normal by 48 h. Cytosolic protein kinase C activity was not significantly altered by PMA. Membrane-associated and cytosolic protein kinase C activities were not altered by 4 alpha-phorbol 12,13-didecanoate. Protein kinase C activity, RNA polymerase I activity, and the transcriptional rate of ribosomal DNA (rDNA) were increased in nuclei isolated from PMA-treated cells. However, consistent with a high rate of processing of pre-ribosomal RNA (pre-rRNA), the pool size of pre-rRNA relative to the 28 S rRNA was unaltered by PMA treatment. These data demonstrated that PMA-induced hypertrophic growth of cardiomyocytes was due to an increase in the capacity for protein synthesis (rRNA), and suggest that this results from protein kinase C mediated increase in the rate of transcription of rDNA.

Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart.

Hearts isolated from 1-yr-old non-insulin-dependent diabetic rats exhibited reduced responsiveness to the beta-adrenergic agonist isoproterenol. Over a concentration range of 3 x 10(-9) to 10(-7) M, isoproterenol-mediated stimulation in the rate of left ventricular pressure decline, a measure of myocardial relaxation, and the rate of left ventricular pressure rise, a measure of myocardial contractility, were significantly depressed in the diabetic hearts. To clarify the basis for this defect, individual steps involved in the actions of the beta-adrenergic agonists were examined. Dihydroalprenolol binding assays revealed that neither beta-adrenergic receptor number nor binding affinity was affected by the diabetic condition. Also unaffected by diabetes was isoproterenol-mediated stimulation of adenylate cyclase activity, myocyte accumulation of adenosine 3',5'-cyclic monophosphate (cAMP), or the increase in cAMP-dependent protein kinase activity ratio. However, it was found that both in the presence and absence of cAMP-dependent protein kinase, activity of the sarcolemmal calcium transporter was significantly depressed in the diabetic heart. Also attenuated was protein kinase-induced enhancement of sarcoplasmic reticular calcium transport. The likelihood that these abnormalities contribute to alterations in calcium homeostasis and myocardial contractile function is discussed.

Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation.

Non-insulin-dependent diabetic (NIDD) male Wistar rats develop a cardiomyopathy approximately 9 mo after the onset of the diabetic condition. This cardiomyopathy is characterized by reduced contractility, relaxation, cardiac work, and diastolic compliance. Although the basis for these defects is not completely understood, altered cellular Ca2+ regulation appears to play a major role in their development. In both isolated sarcolemmal membrane and cardiomyocytes, significant diabetes-linked defects in Ca2+ metabolism were observed. A small, but significant, decrease in the rate of sarcolemmal ATP-dependent Ca2+ transport of the diabetic heart was observed. Also evident was a major defect in sarcolemmal Na(+)-Ca2+ exchange as determined by reduced Na(+)-dependent Ca2+ transport into vesicles and Na(+)-dependent Ca2+ efflux from 45Ca(2+)-loaded cardiomyocytes from diabetic rats. In isolated cardiomyocytes, it was observed that the relative fluorescence of fura-2 at 502 nm was higher in cells from NIDD hearts, suggestive of a higher cytosolic free Ca2+. Consistent with diabetes-linked defects in Ca(2+)-transporter activities, the accumulation of Ca2+ after depolarization with KCl was greater in the diabetic. This study demonstrates that diabetes-induced defects in Ca2+ movement by the various Ca2+ transporters lead to abnormal cytosolic Ca2+ regulation by the diabetic cardiomyocytes. This observation supports the notion that abnormal Ca2+ regulation contributes to the development of the NIDD cardiomyopathy.

Transcriptional regulation of ribosomal RNA synthesis during growth of cardiac myocytes in culture.

The mechanism(s) by which rRNA accumulates during the growth of cardiac myocytes was investigated. The rates of rDNA transcription were measured in contracting myocytes and compared with nonbeating myocytes depolarized with 50 mM KCl. After 3 days of contraction the absolute rate of rDNA transcription was accelerated by 2-fold as measured by incorporation of [3H]UTP into the external transcribed spacer of preribosomal RNA. Corresponding increases in transcription were observed in isolated nuclei of contracting myocytes as measured by either hybridization of run-on transcripts of preribosomal RNA or activity of RNA polymerase I. The extent to which transcription was stimulated in contracting myocytes accounted for the previously observed acceleration of rRNA synthesis rates. The steady-state levels of preribosomal RNA relative to rRNA were unchanged in contracting myocytes, but the total amount of preribosomal RNA was 1.3-fold greater as a result of increased rRNA content. The increase of preribosomal RNA in proportion to rRNA in contracting myocytes demonstrated that the rate of preribosomal RNA processing was unchanged and that rRNA synthesis is regulated by an accelerated rate of rDNA transcription.

Defective sarcolemmal phosphorylation associated with noninsulin-dependent diabetes.

Noninsulin-dependent diabetes is associated with a decrease in the activity of sarcolemmal phosphatase 1, but no change in the activities of phosphatase 2A, 2B, or 2C. Also unaffected by diabetes were the activities of protein kinase C, cAMP-dependent protein kinase and calcium-calmodulin protein kinase. Because of the decrease in phosphatase 1 activity, 32P incorporation into sarcolemmal phosphoproteins catalyzed by either intrinsic protein kinases or extrinsic cAMP-dependent protein kinase was elevated in the diabetic. Among the proteins whose phosphorylation was elevated in diabetes was the phospholamban-like protein, which has been implicated in the regulation of ATP-dependent calcium transport. The phosphate-linked increase could be prevented by exposing the membranes to a phosphatase inhibitor and either extrinsic cAMP-dependent protein kinase or alamethicin. In addition to the phosphatase-linked effects, analysis of individual sarcolemmal phosphoproteins by SDS-polyacrylamide gel electrophoresis indicated that diabetes caused a specific elevation in membrane phosphorylation of some proteins (43 kDa and 78 kDa), but a decrease in the phosphorylation state of other phosphoproteins (31 kDa and 49 kDa). The data indicate that membrane phosphorylation is dramatically altered by diabetes. The possibility that this contributes to altered myocardial function is discussed.

The effect of sulfonylurea therapy on defective calcium movement associated with diabetic cardiomyopathy.

Adult rats exposed to 70 mg/kg streptozocin developed characteristic symptoms of overt diabetes, such as muscle wasting and severely elevated blood glucose levels. Chronic treatment of these rats with the sulfonylurea glyburide for a period of 5 weeks did not affect either the weight of the animal or the degree of hyperglycemia. The drug also failed to influence myocardial glucose metabolism. Nevertheless, the decline in myocardial function associated with the diabetic cardiomyopathy was less in the glyburide-treated rats. At higher preload, myocardial work was significantly reduced in the untreated diabetic but was only moderately depressed in the glyburide-treated heart relative to the nondiabetic heart. The improvement in mechanical function was associated with partial recovery of sarcolemmal calcium pump activity. The drug did not alter the initial rate of Na+-Ca2+ exchange, but decreased the capacity of the transport system. The results indicate that glyburide benefits the diabetic heart by a mechanism independent of carbohydrate metabolism.

Regulation of calcium transport in drug-induced taurine-depleted hearts.

Drug-induced taurine depletion of rat heart led to the accumulation of free CoA, free carnitine and long-chain acylcarnitine, but a small decrease in long-chain fatty acyl-CoA. Although elevations in total tissue long-chain acylcarnitine levels have been linked to defective membrane function and the association of long-chain acylcarnitines with extramitochondrial membranes, these effects were absent in isolated sarcoplasmic reticulum prepared from taurine-depleted hearts. In contrast to the sarcoplasmic reticulum data, taurine depletion was associated with a significant decrease in ATP-dependent calcium uptake by isolated sarcolemmal vesicles. The major effect of taurine depletion on the sarcolemma was a 2-fold decrease in both the Vmax of calcium transport and the activity of the Ca2+ -stimulated ATPase. Sarcolemmal vesicles prepared from taurine-depleted hearts also exhibited a decreased capacity to transport calcium in exchange for sodium, although the initial rate of the process was unaffected by taurine depletion. Since incubation of sarcolemma from taurine-depleted hearts with taurine could not overcome the effects of taurine depletion, it was concluded that the effects of taurine were not caused by a direct interaction of it with the calcium pump. Possible mechanisms of taurine action are discussed.