Mario L. R. Cesaretti

Modelos experimentais de resistência à insulina e obesidade: lições aprendidas

For better understanding the role of each element involved in the physiopathology of obesity and insulin resistance, researchers can use experimental models, which may in controlled manner evaluate the participation of each element on the obesity and insulin resistance and provide information for better understanding the physiopathology and treatment of obesity and insulin resistance. Experimental obesity and insulin resistance can be due to a deficient response to leptin, secondary to hypoleptinemia and/or mutations on leptin receptor, by modifications on insulin receptor, deletion or diminished insulin signal transduction, enhancement of the effects of orexigen peptides and/or diminution of anorexigen peptides actions on hypothalamus, as well as secondary to arterial hypertension, as in the spontaneously hypertension. Obesity and insulin resistance can also be induced by glucocorticoid excess, frutose enriched and cafeteria diet and due to hypothalamus lesions induced by neonatal administration of monossodium glutamate.

Role of Substance P in Blood Pressure Regulation in Salt-Dependent Experimental Hypertension

The participation of substance P in the pathogenesis of five models of experimental hypertension, ie, DOCA-salt, subtotal nephrectomy, one-kidney-one clip renovascular, two-kidney-one clip renovascular, and spontaneous hypertension, was evaluated via an acute infusion of a newly synthesized potent, specific nonpeptide antagonist of substance P at the NK-1 receptor, the agent CP 96,345. In conscious unrestrained rats, CP 96,345 induced significant and sustained increases in mean arterial pressure of DOCA-salt, subtotal nephrectomy, and one-kidney-one clip renovascular hypertensive rats but only small and nonsignificant changes in blood pressure of two-kidney-one clip renovascular and spontaneously hypertensive rats. CP 96,345 had no effect on the blood pressure of sham-treated controls and Wistar-Kyoto rats. This NK-1 receptor antagonist did not significantly affect the heart rate of any experimental model studied. The data suggest that endogenous substance P may act as a partial counterregulatory mechanism against vasoconstriction in models of salt-dependent hypertension.

Efeito da indução de obesidade neuroendócrina sobre a hemodinâmica sistêmica e a função ventricular esquerda de ratos normotensos

The aim of this study was to evaluate the effects of obesity induced by neonatal Monosodium Glutamate (MSG) administration upon body weight, tail blood pressure, systemic hemodynamics and left ventricular function of Wistar rats. Two groups of Wistar rats were prepared: a) 18 animals made obese through the administration of 2mg/Kg/SC of MSG during the first 11 days of the neonatal period and b)16 control animals (vehicle treated for the same period). Adults animals were followed from the 3rd up the 6th month of life with blood pressure and body weight being measured twice a week. At the end of this period, in part of animals from both groups, we evaluated the left ventricular function through the Langendorff isolated heart preparation whereas the remainders were used to evaluate the systemic hemodynamics through a termodilution method. Results: MSG animals showed significant increases in heart rate (WST = 235,0 ± 35,1; MSG = 312,0 ± 90,8 bpm), total peripheral resistance (WST = 0,312 ± 0,100; MSG = 0,535 ± 0,195 mmHg.ml-1.min) and in relative epididymal adipose tissue content (WST = 2,076 ± 0,622; MSG = 2,731 ± 0,722 g/100g) and a reduction of systolic volume (WST = 1,020 ± 0,364; MSG = 0,748 ± 0,455 ml/bat). An increase in mean arterial pressure was also detected in obese animals during the hemodynamic evaluation. The increases in HR and TPR and the reduction in SV suggest an augmentation in the sympathetic activation of those obese normotensive rats associated with an increased visceral fat deposition.

Efeitos da administração de metformina sobre a pressão arterial e o metabolismo glicídico de ratos espontaneamente hipertensos tornados obesos pela injeção neonatal de glutamato monossódico

OBJECTIVES: To make available experimental model for the metabolic syndrome (MS) and verify effects of chronic oral treatment with metformin upon blood pressure (BP), body weight (BW), glucose metabolism, epididimal fat content (EF). METHOD: Males SHR received monossodium glutamate (MSG, 2 mg/kg/day/sc) during first 11 days of life. Control animals received saline. After 12 weeks, animals were separated in two groups, treated either with metformin 500 mg/ kg/day or vehicle during 12 weeks. PA and BW were determined. At the end of the follow-up, animals underwent an oral glucose tolerance test (OGTT) and insulin sensitivity index was determined. Upon sacrifice EF was measured. RESULTS: MSG worsened insulin resistance and induced visceral obesity in SHR, without change BP. Treatment with metformin improved glucose metabolism and reduces EF and BP. CONCLUSIONS: These observations emphasize the role of hepatic insulin resistance on MS and point out for beneficial cardiovascular effects with improvement in the insulin sensitivity.

204 VASCULAR RESPONSIVENESS OF SPONTANEOUSLY HYPERTENSIVE RATS (SHR) MADE OBESE BY CAFETERIA DIET

Objective: To evaluate the vascular responsiveness of SHR made obese by hypercaloric diet. Material and Methods: SHRs were treated with standard diet (SHR, n=9) or cafeteria diet (peanut, chocolate, cookie and Nuvilab standard chow (SHR+Caf, n=10). All animals have blood pressure and body weight measured twice a week. At the end of 12 weeks, all animals were sacrificed and the aortas were analyzed. Acetylcholine (10−6, 10−5, 10−4 M), Noradrenalin (10−3 M) and sodium nitroprusside (10−7, 10−6, 10−5, 10−4 M, with and without the endothelium) dose-responses curves were made. Were also determined the relative ventricular and periepididimal fat weight. Results: No differences were observed between the body weight and tail blood pressure. However, the animals fed cafeteria diet showed significant increase of visceral fat (SHR= 0.98± 0.12; SHR+Caf = 2 .12 ± 0.15 g/100 g, p<0.05) and increased insulin resistance (SHR=4.9 ± 0.48; SHR+Caf= 6.1 ± 0.98, p<0 .05). The analysis of dose-response curve showed that SHRCaf showed a decreased endothelium-dependent vasodilation, but did not reach statistical significance (SHR -20.3 ± 3.25; SHRCAF -30.85 ± 5.15%, ns). Endothelium-independent vasodilation was similar between the 2 groups. No differences were observed in ventricular weight. Figure. No caption available. Conclusion: Despite the cafeteria diet worsened glucose metabolism and increased visceral fat content, we did not observed impairment in vascular relaxation. Despite the trend, the absence of response probably is due to the short time of diet or the small number of experiments. References:Catena C, Cavarape A, Novello M, Giacchetti G, Sechi LA. Insulin receptors and renal sodium handling in hypertensive fructose-fed rats. Kidney Int. 2003 Dec;64(6):2163-71.Cesaretti MLR, Kohlmann, O. Modelos experimentais de resistência à insulina e obesidade: lições aprendidas. 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