Diabetes and arteriosclerosis. The role of antagonists of PPAR-gamma

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POSTERS: Obesity, Insulin Resistance, Diabetes

P-429 TRANSFORMING GROWTH FACTOR ␤1 AND COLLAGEN TYPE 1 AND III IN MYOCARDIAL TISSUE IN OBESE AND LEAN ZUCKER RATS Jorge E. Toblli, Graciela DeRosa, Gabriel Cao, Pablo Piorno. Lab. Exp. Medicine, Hospital Alema´ n & Hospital de Clı´nicas, Buenos Aires, Argentina. High glucose concentration and insulin resistance states are both associated with a number of metabolic abnormalities in various tissues including myocardium. This study was to determine differences between obese (OZR) and lean (LZR) Zucker rats, which are a model of obesity and mild NIDDM, regarding morphological changes including immunostaining with TGF␤1 and two different types of collagen (Col I and Col III) in myocardium. 8-month-old male OZR (n⫽ 8) G1 (fa/fa) and LZR (n⫽ 8) G2 (Fa/fa) were used for this experiment. Hearts were processed for immunohistochemistry and LM.OZR presented a significant higher heart weight with lower myocyte and capillary density when compared with LZR. In addition, OZR showed an increase in either cardiac TGF␤1 in interstitium as well as in vessel wall and both Col I and Col III, when compared with LZR. In conclusion, OZR present important morphological changes in myocardium, which could explain why congestive heart failure is highly prevalent in obesity and NIDDM. Mean ⴞ SD

G1 OZR

G2 LZR

P

Body Weight (g) BW Fasting Glucose (mg/dl) Insulin/Glucose ratio SBP (mmHg) Heart Weight (g)/100g BW Myocyte density Myocyte diameter (␮) Capillary density Myocyte/Capillary ratio TGF␤1 in Interstitium (%) TGF␤1 in vessel wall (%) Col 1 (%) Col III (%)

551.5 ⫾ 81.3 267.7 ⫾ 14 0.38 ⫾ 0.07 150.3 ⫾ 3.6 0.38 ⫾ 0.06 20 ⫾ 2.5 32.0 ⫾ 3.1 9.5 ⫾ 1.6 2.19 ⫾ 0.3 3.3 ⫾ 0.6 7.5 ⫾ 0.5 11.9 ⫾ 0.3 9.3 ⫾ 0.5

390.1 ⫾ 43.3 95.1 ⫾ 8.9 0.07 ⫾ 0.02 125.1 ⫾ 2 0.25 ⫾ 0.02 47 ⫾ 0.5 21.3 ⫾ 0.4 31.5 ⫾ 3.7 1.52 ⫾ 0.1 0.4 ⫾ 0.1 1.4 ⫾ 0.5 3.2 ⫾ 0.4 6.9 ⫾ 0.8

⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01

Key Words: Myocardial Fibrosis, Obesity, Zucker Rats

P-430 THE RELATIONSHIP BETWEEN BLOOD PRESSURE AND INDICES OF OBESITY Bernard M.Y. Cheung, Tai-Chung Lam, Fefe C.Y. Law, Cyrus R. Kumana, Chu-Pak Lau. Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong. Introduction: Obesity predisposes to the development of hypertension. The present investigation explores further indices of obesity as predictors of blood pressure. Method: 209 subjects (98 men, 111 women; age 48⫾13 yrs) were studied. 137 of them were hypertensive (systolic blood pressure ⱖ 140mmHg and/or diastolic blood pressure ⱖ 90 mmHg) and the other 72 were normotensive. The medical history was obtained and the subjects were examined with special attention to blood pressure and indices of obesity. Body fat was assessed using bioelectrical impedence (Body Fat analyzer, Tanita). Results: Diastolic blood pressure (DBP) was related to age (r⫽0.21, p⬍0.001) and indices of obesity including body mass index (r⫽0.36, p⬍0.001), body fat (r⫽0.18, p⫽0.01), waist circumference (WC) (r⫽0.46, p⬍0.001) and waist-to-hip ratio (r⫽0.41, p⬍0.001). Systolic blood pressure (SBP) was also related to age (r⫽0.41, p⫽0.003), WC (r⫽0.34, p⬍0.001) and the other indices of obesity. Multiple regression analysis suggested that WC (␤⫽0.44, p⬍0.001) and age (␤⫽0.14, p⫽0.04) were independent predictors of DBP (R2⫽0.23, p⬍0.001). Similarly, WC (␤⫽0.28, p⬍0.001) and age (␤⫽0.35, p⬍0.001) were independent predictors of SBP (R2⫽0.24, p⬍0.001). DBP correlated with WC in both men (r⫽0.36, p⫽0.001) and women (r⫽0.43,

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p⬍0.001). However, the correlation between SBP and WC in men was weak (r⫽0.19, p⫽0.073). Conclusions: Our findings confirm that blood pressure is related to obesity. WC is a simple measurement and is a good predictor of blood pressure, especially in women. Key Words: Obesity, Waist Circumference, Hypertension

P-431 ROSIGLITAZONE TREATMENT RESTORES RENAL DOPAMINE RECEPTOR FUNCTION AND LOWERS BLOOD PRESSURE IN OBESE ZUCKER RATS Dhananjay N. Umrani, Tahir Hussain, Mustafa F. Lokhandwala. Institute for Cardiovascular Studies, College of Pharmacy, University of Houston, Houston, TX, United States. We have recently reported that a defective dopamine D1-receptor function leading to the failure of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules may cause sodium retention and contribute to hypertension observed in obese Zucker rats (Hypertension 34:1091-1096, 1999). The present study was designed to test the hypothesis that the defect in D1-receptor function is a result of hyperinsulinemia seen in obese Zucker rats. We designed experiments to study D1-receptor function in obese Zucker rats treated with rosiglitazone as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese Zucker rats served as control. We found that rosiglitazone treatment (10 mg/kg, p.o. for 4 weeks) caused significant decreases in plasma insulin, blood glucose and blood pressure while increasing 24 hour renal sodium excretion in obese-treated in comparison with obeseuntreated Zucker rats. In the isolated renal proximal tubules obtained from untreated lean Zucker rats, dopamine caused concentration-dependent inhibition of Na,K-ATPase and Na,H-exchanger activities but this inhibitory effect was almost blunted in untreated obese Zucker rats. Interestingly, in rosiglitazone-treated obese Zucker rats, the inhibitory effect of dopamine on Na,K-ATPase and Na,H-exchanger activities was similar to that observed in lean Zucker rats. This was accompanied by a similar restoration in renal D1-receptor numbers in treated obese Zucker rats. We propose that there exists an interaction between increased plasma insulin and renal D1-receptors in obese Zucker rats. The restoration of renal D1-receptor function by lowering plasma insulin levels with rosiglitazone may have contributed to the increase in sodium excretion and lowering of blood pressure in obese Zucker rats. Key Words: Renal Dopamine Receptor, Hyperinsulinemia, Obesity

P-432 DIABETES AND ARTERIOSCLEROSIS. THE ROLE OF ANTAGONISTS OF PPAR-GAMMA Carlos Calvo, Jose E. Lopez, Manuel Covelo, Maria J. Dominguez, Carmen Martinez, Vicente Lorenzo, Diana E. Ayala, Ramon C. Hermida. Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago, Spain; Bioengineering & Chronobiology Labs.,University of Vigo, Vigo, Spain. Rosiglitazone is an oral anti-diabetic, antagonist of PPAR-gamma, that improves the glucemic metabolism and regulates the components of hypertensive metabolic syndrome. The purpose of this study was to evaluate the efficacy of Rosiglitazone in the treatment of type 2 diabetes mellitus (DM-2) and to analyze the impact of treatment on blood pressure (BP) and on the lipid-fibrinolytic profile. We studied 18 untreated patients with DM-2 (10 men), 56.4⫾7.4 years of age and body mass index of 29.0⫾0.9 kg/m2, with HbA1c below 7.2%. Patients received 4-8 mg/day of Rosiglitazone for 16 weeks. Both clinic and biochemistry comparative evaluations as well as 24-hour ambulatory BP monitoring were performed in each patient before and after treatment. After 16 weeks of treatment, there was an improvement in the metabolic control of patients with DM-2, with a 1% reduction in the HbA1c levels

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(P⫽0.001), a mean decrease of 42 mg/dl in glucose (P⬍0.001), and a tendency to improve the lipid profile. With regard to the fibrinolytic profile, we found a 4.5 U/ml reduction (-21%; P⬍0.01) in plasminogen activator inhibitor, and a 2.4 ng/ml reduction (-25%; P⬍0.01) in tissue plasminogen activator. Results also indicate an antihypertensive effect of treatment with Rosiglitazone, with a significant average reduction in the 24-hour mean of systolic/diastolic BP (-11.6/-5.7 mm Hg; P⬍0.001), as well as in the diurnal (-12.0/-5.7 mm Hg; P⬍0.001) and the nocturnal (-11.8/-6.5 mm Hg; P⬍0.001) means of BP. Rosiglitazone is highly efficient for the metabolic control of DM-2 and, due to its mechanism of action, regulates and improves other components of the hypertensive metabolic syndrome, reducing BP and optimizing the cardiovascular risk of these patients. Key Words: Diabetes Mellitus, Rosiglitazone, Fibrinolytic Profile

P-433 INSULIN RESISTANCE AND PROLONGED ANTIHYPERTENSIVE THERAPY Mariya A. Orynchak, Evgen M. Neiko, Vitaliy N. Seredyuk, Evgen M. Gorban. Department of Therapy, Medical Academy, Ivano-Frankivsk, Ukraine; Department of Therapy, Medical Academy, Ivano-Frankivsk, Ukraine; Department of Therapy, Medical Academy, Ivano-Frankivsk, Ukraine; Department of Physiology, Institute of Gerontology, Kyiv, Ukraine. The purpose is to investigate the influence of the prolonged treatment by ACE inhibitor enalapril upon the blood immunoreactive insuline (IRI) levels and daily profile of blood pressure (DPBP), hemodynamics parameters in non-diabetic hypertensives. Studies were performed on 62 hypertensives with congestive heart failure (CHF) II-III (NYHA), aged 43-75 and 10 healthy people (control). Basal hyperinsulinemia was observed in 23 (37.10%) cases (I group), 2hr postloading hyperinsulinemia - in 27 (43.55%) cases (II group) with IRI levels higher in 2.7 and 3.1 times vs control (p⬍0.01). The normoinsulinemia was observed in 12 (19.30%) cases (III group). Basal hyperinsulinemia (I group) was associated with the increase of values of unfavorable DPBP night-peaker (43.50% vs 29.60% in II group) and eccentric hypertrophy of left ventricular with systolic dysfunction (60.90% vs 45.50% in II group). After one year of treatment with enalapril, basal and 2hr postloading hyperinsulinemia statistically significantly decreased in 39.13% cases in I group, only 2hr postloading hyperinsulinemia -in 37.03% cases in II group and without IRI levels changes - III group. The DPBP normalization, regression of pathological remodeling of left ventricular, the significant improvement of clinical course of arterial hypertension and CHF were greater in patients of III group and in patients with normalized IRI levels. Thus, the prolonged blockade of the renin-angiotensin system with ACE inhibitor enalapril promotes the decrease of insulin resistance in hypertensive patients with CHF. Key Words: Insulin resistance, Hypertension, Angiotensin-ConvertingEnzyme Inhibitor

P-434 URIC ACID LEVEL IS ONE OF THE PREDICTORS OF BP ELEVATION AND OBESITY Kazuko Masuo, Hiroshi Mikami, Toshio Ogihara, Michael L. Tuck. Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Endocrinology and Metabolism Division, Sepulveda VA Medical Center, Sepulveda, California, United States. Plasma uric acid level is well known as the predictor of renal injury and hypertension. In the present study, we tried to clarify whether plasma uric

POSTERS: Obesity, Insulin Resistance, Diabetes

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acid level is one of the predictors of hypertension, obesity or obesityrelated hypertension in a longitudinal study of 5 years in a cohort. In 433 young, nonobese (BMI⬍26 kg/m2) normotensive Japanese men who were working in a factory, BMI, %fat accumulation (%FA), BP, pulse rate, plasma uric acid (UA), norepinephrine (NE), insulin, leptin (LEP), total cholesterol (Tch), triglyceride (TG), BUN and creatinine (Crn) were measured every 1 yr for 5 yrs. None had diabetes, medications for hyper-uric acidemia or hypertension during the study. BP elevation and weight gain (WG) for 5 years were defined as more than 10% increases in mean BP or BMI at entry. BP elevation and WG were noted in 13% and 17% in a cohort. WG induced BP elevation was 53% of subjects with WG. At entry, subjects with WG had higher levels of mean BP, pulse rate, UA and NE than subjects without WG (UA 5.6 mg/dl vs 4.1, P⬍0.01), although BMI, %FA, insulin, LEP, Tch, TG, BUN and Crn were similar. The absolute increases for 5 yrs in BMI, %FA, mean BP, UA, Tch, TG, plasma NE, insulin and LEP were greater in subjects with WG (UA 1.8 mg/dl vs 0.1, P⬍0.01). Subjects with BP elevation had higher levels of mean BP, pulse rate, UA, and plasma NE at entry (UA 6.1 mg/dl vs 4.1, P⬍0.01), although BMI, %FA, insulin and LEP, Tch, TG, BUN and Crn were similar. The absolute increases for 5 yrs in mean BP, BMI, %FA, plasma NE, UA and Crn were greater in subjects with BP elevation (UA 1.2 mg/dl vs 0.3, P⬍0.01). Subjects with WG induced BP elevation had higher level of UA at entry than subjects without WG induced BP elevation (UA 6.3 mg/dl vs 4.8, P⬍0.05). The absolute increases for 5 yrs in BMI, %FA, mean BP, pulse rate, UA, TG, NE, insulin and LEP were greater in subjects with WG induced BP elevation than subjects without significant BP elevation (UA 2.2 mg/dl vs 1.5, P⬍0.05). When analyzed the change in mean BP as a dependent factor in association with changes in BMI, plasma NE, insulin, LEP, UA, Tch and TG as determinant factors by multiple analysis, at 5 yrs, changes in BMI (P⫽0.007), plasma NE (P⫽0.019), and UA (P⫽0.007) were significant determinant factors in the changes in mean BP (R2⫽0.189, F⫽8.93, P⫽0.0001). In conclusion, these results demonstrated that plasma uric acid level is one of the predictors of weight gain, BP elevation and weight gain-induced BP elevation. Key Words: Uric Acid, Weight Gain, Blood Pressure Elevation

P-435 RENIN-ANGIOTENSIN SYSTEM POLYMORPHISMS INFLUENCE CARDIOVASCULAR RISK PROFILE OF OBESE ESSENTIAL HYPERTENSIVE PATIENTS Pedro Aranda, Francisco J. Aranda, Armando Reyes, Eduardo Lo´ pez de Novales. Hypertension Unit, Carlos Haya University Hospital, Malaga, Spain. Considering the role of RAS in the pathogenesis of obesity-hypertension, we studied possible contribution of RAS polymorphisms for defining cardiovascular risk profile of these patients. We studied 70(41-58.6%) obese (Mean BMI:32.5⫾2.2) essential hypertensives never treated with ACEIs or AIIRAs with a mean age: 58⫾8 y.o. 52(74.3%) patients were receiving other antihypertensive drugs. All patients were genotype for M235T polymorphism of AGT, the I/D of ACE and the a1166c of angiotensin II AT1R by PCR and restriction enzyme analysis. BP,HR,BMI were measured as well as determined fasten levels of glucose, insulin, uric acid, lipidic profile, creatinine, and 24 h microalbuminuria (UAE). Not statistically significant differences in BMI and rest parameters were found.Patients with the genotypes TT (AGT), DD (ACE) and cc(AT1R) showed worse cardiovascular profile. These results indicate that RAS polymorphisms contribute to define C-V risk profile of the obese hypertensives.