Osvaldo Kohlmann

Treatment of Obesity Hypertension and Diabetes Syndrome

Obesity has been shown to be an independent risk factor for coronary heart disease. The insulin resistance associated with obesity contributes to the development of other cardiovascular risk factors, including dyslipidemia, hypertension, and type 2 diabetes. The coexistence of hypertension and diabetes increases the risk for macrovascular and microvascular complications, thus predisposing patients to cardiac death, congestive heart failure, coronary heart disease, cerebral and peripheral vascular diseases, nephropathy, and retinopathy. Body weight reduction increases insulin sensitivity and improves both blood glucose and blood pressure control. Metformin therapy also improves insulin sensitivity and has been associated with decreases in cardiovascular events in obese diabetic patients. Antihypertensive treatment in diabetics decreases cardiovascular mortality and slows the decline in glomerular function. However, pharmacological treatment should take into account the effects of the antihypertensive agents on insulin sensitivity and lipid profile. Diuretics and beta-blockers are reported to reduce insulin sensitivity and increase triglyceride levels, whereas calcium channel blockers are metabolically neutral and ACE inhibitors increase insulin sensitivity. For the high-risk hypertensive diabetic patients, ACE inhibition has proven to confer additional renal and vascular protection. Because hypertension and glycemic control are very important determinants of cardiovascular outcome in obese diabetic hypertensive patients, weight reduction, physical exercise, and a combination of antihypertensive and insulin sensitizers agents are strongly recommended to achieve target blood pressure and glucose levels.

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.

Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive patients with type 2 diabetes and microalbuminuria

IntroductionPatients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria.MethodsPatients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85–105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56).ResultsBlood pressure was significantly reduced at 1 year in both groups (−22.2/−14.6 mmHg and −19.5/−14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of −3.9 mg/mmol creatinine (95% CI −5.3, −2.5) for manidipine/delapril (P<0.001 vs. baseline) and −2.7 mg/mmol creatinine (95% CI −4.0, −1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change −0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group.ConclusionsA fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

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.

Left Ventricular Hypertrophy Evaluation in Obese Hypertensive Patients: Effect of Left Ventricular Mass Index Criteria

PURPOSE To evaluate left ventricular mass (LVM) index in hypertensive and normotensive obese individuals. METHODS Using M mode echocardiography, 544 essential hypertensive and 106 normotensive patients were evaluated, and LVM was indexed for body surface area (LVM/BSA) and for height2 (LVM/h2). The 2 indexes were then compared in both populations, in subgroups stratified according to body mass index (BMI): <27; 27-30; >/= 30kg/m2. RESULTS The BSA index does not allow identification of significant differences between BMI subgroups. Indexing by height2 provides significantly increased values for high BMI subgroups in normotensive and hypertensive populations. CONCLUSION Left ventricular hypertrophy (LVH) has been underestimated in the obese with the use of LVM/BSA because this index considers obesity as a physiological variable. Indexing by height2 allows differences between BMI subgroups to become apparent and seems to be more appropriate for detecting LVH in obese populations.

Left Ventricular Diastolic Function in Essential Hypertensive Patients. Influence of Age and Left Ventricular Geometry

PURPOSE To evaluate diastolic dysfunction (DD) in essential hypertension and the influence of age and cardiac geometry on this parameter. METHODS Four hundred sixty essential hypertensive patients (HT) underwent Doppler echocardiography to obtain E/A wave ratio (E/A), atrial deceleration time (ADT), and isovolumetric relaxation time (IRT). All patients were grouped according to cardiac geometric patterns (NG - normal geometry; CR - concentric remodeling; CH- concentric hypertrophy; EH - eccentric hypertrophy) and to age (<40; 40 - 60; >60 years). One hundred six normotensives (NT) persons were also evaluated. RESULTS A worsening of diastolic function in the HT compared with the NT, including HT with NG (E/A: NT - 1.38+/-0.03 vs HT - 1.27+/-0.02, p<0.01), was observed. A higher prevalence of DD occurred parallel to age and cardiac geometry also in the prehypertrophic groups (CR). Multiple regression analysis identified age as the most important predictor of DD (r2=0.30, p<0.01). CONCLUSION DD was prevalent in this hypertensive population, being highly affected by age and less by heart structural parameters. DD is observed in incipient stages of hypertensive heart disease, and thus its early detection may help in the risk stratification of hypertensive patients.

Effects of different degrees of insulin sensitivity on endothelial function in obese patients.

BACKGROUND Obesity derived from intra-abdominal fat deposition tends to increase hormonal and cytokine production, thus worsening insulin sensitivity and leading to endothelial dysfunction. Hyperinsulinemia is considered an independent risk factor for ischemic heart disease and cause of endothelial dysfunction in healthy individuals. OBJECTIVE To assess the impact of different degrees of insulin resistance, measured by HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), on endothelial function in obese, non-diabetic patients without prior history of cardiovascular events and different metabolic syndrome components. METHODS Forty obese individuals were submitted to anthropometric measurements, BP measurements at office and ABPM and laboratory tests, in addition to non-invasive ultrasound assessment of endothelial function. Patients were divided into 3 groups according to the level of insulin resistance: patients with HOMA-IR values from 0.590 to 1.082 were assigned to Group 1 (n=13), from 1.083 to 1.410 to Group 2 (n=14) and from 1.610 to 2.510 to Group 3 (n=13). RESULTS We found a significant difference in flow-mediated dilation in group 3 compared to group 1 (9.2 ± 7.0 vs 18.0 ± 7.5 %, p=0.006). There was a negative correlation between endothelial function and insulin, HOMA-IR and triglycerides. CONCLUSION Our data suggest that mild changes in insulin resistance levels assessed by HOMA-IR may have an impact on vasodilatatory endothelial function in uncomplicated obese individuals with different cardiovascular risk factors.FUNDAMENTO: A obesidade derivada da deposicao de gordura intra-abdominal tende a aumentar a producao de hormonios e citoquinas, piorando a sensibilidade a insulina e levando a disfuncao endotelial. A hiperinsulinemia e considerada um fator de risco independente para doenca isquemica cardiaca e e uma causa de disfuncao endotelial em individuos saudaveis. OBJETIVO: Avaliar o impacto de diferentes graus de resistencia a insulina, medida pelo HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), sobre a funcao endotelial de obesos, pacientes nao diabeticos, sem historia previa de eventos cardiovasculares e diversos componentes da sindrome metabolica. METODOS: Um total de 40 individuos obesos foi submetido a medidas antropometricas, pressao arterial de consultorio, MAPA e exames laboratoriais, alem de avaliacao ultrassonografica nao invasiva da funcao endotelial. Os pacientes foram divididos em tres grupos de acordo com o grau de resistencia a insulina: pacientes com valores de HOMA-IR entre 0,590 e 1,082 foram incluidos no Grupo 1 (n = 13); entre 1,083 e 1,410 no Grupo 2 (n = 14); e entre 1,610 e 2,510 no Grupo 3 (n = 13). RESULTADOS: Encontramos uma diferenca significativa na vasodilatacao mediada por fluxo no Grupo 3 em relacao ao Grupo 1 (9,2 ± 7,0 vs 18,0 ± 7,5 %, p = 0,006). Houve uma correlacao negativa entre a funcao endotelial e insulina, HOMA-IR e triglicerides. CONCLUSAO: Nosso estudo sugere que leves alteracoes nos niveis de resistencia a insulina avaliada pelo HOMA-IR podem causar algum impacto sobre a funcao vasodilatadora do endotelio em individuos obesos nao complicados com diferentes fatores de risco cardiovascular.

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.

GUIDELINES FOR TREATMENT OF HYPERTENSION IN LATIN AMERICA : THE BRAZILIAN EXPERIENCE

Treatment of hypertension in most countries of Latin America, in general, follows the recommendations of guidelines generated by both: the National Institute of Health of the United States of America (Joint National Committee) and the World Health Organization together with the International Society of Hypertension. Few countries of Latin America, as Brazil, in the last years have generated their own guidelines for detection, evaluation and treatment of hypertension. Its described the brazilian experience in generates and distributes a guideline for treatment of hypertensive. It is also discussed the difficulties and the needs to a successfully implement the recommendations of guideline for treatment of chronic diseases, such as hypertension.

Cardiovascular Effects of a Specific Nonpeptide Antagonist of Substance P (NK-1) Receptor in DOCA-Salt Hypertension

The neurotransmitter substance P acts also as a potent vasodilator. Its participation in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt hypertension was evaluated by 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 rats but only small, transient, and nonsignificant rises in blood pressure of sham-treated control rats. The rise in blood pressure was not accompanied by changes in heart rate. Maximal blood pressure increase in DOCA-salt rats was 31.7 +/- 14.8 mm Hg. In a second series of experiments, the hemodynamic effects of this antagonist were evaluated under anesthesia in both DOCA-salt and sham-treated control rats by the thermodilution method. During CP 96,345 infusion, sustained increases in cardiac index and stroke volume and decreases in total peripheral resistance were observed in both DOCA-salt and control rats. In DOCA-salt rats, cardiac index rose by 79.4%, while total peripheral resistance fell by 27.9% of the baseline values. In control rats, the changes were smaller (+27.2% and -22.5%, respectively). Stroke volume changed in parallel to cardiac output in both groups. The data suggest that acute blockade of NK-1 receptors increases blood pressure in DOCA-salt rats mainly by an increase in cardiac output. We conclude that endogenous substance P tends to counteract the DOCA-salt-induced elevation of blood pressure by modulating both cardiac output and peripheral resistance.