Abstract-Plasma leptm concentration IS increased m hypertensive obese humans, but whether leptm contributes to the increased arterial pressure m obesity 1s not knownIn this study, we tested whether chronic increases m leptm, to levels comparable to those m obesity, could cause a sustained increase m arterial pressure and also the importance of central nervous system (CNS) versus systemic mechanisms Five male Sprague-Dawley rats were implanted with chronic nonoccludmg catheters m the abdominal aorta and both carotid arteries for CNS mfunon, and five other rats were implanted with an abdominal aorta catheter and femoral vem catheter for intravenous (IV) mfuslon After 7 days of control, leptm was infused mto the carotid arteries or femoral vem at 0 1 pg/kg/mm for 5 days and 1 0 pg/kg/mm for 7 days, followed by a 7-day recovery period. The carotid artery and IV mfuslons of leptm at 1 pg/kg/mm slgmficantly increased plasma leptm levels, from 1.2?0 4 ng/mL to 91f5 ng/mL and from 0 9+-O 1 ng/mL to 9429 ng/mL, respectively, but there was no slgmficant increase m either group at the low dose Food intake also did not change at the low dose but decreased by approximately 65% m the carotid group and 69% m the IV group after 7 days of the 1 pg/kg/mm mfuslon Mean arterial pressure (MAP) Increased slightly at the low dose only m the carotid group, but this was not statlstlcally slgmficant At the higher dose, however, MAP increased significantly from 862 1 mm Hg to 942 1 mm Hg m the carotid group and from 87?1 mm Hg to 9321 mm Hg m the IV group. Heart rate also increased algmficantly m both groups at 1 pg/kg/mm leptm mfuslon Fasting blood glucose and msuhn levels decreased significantly at 1 pg/kg/mm m both the carotid artery group (-10 5% and -82 5%, respectively) and the IV group (-13 6% and -80 4%, respectively) All variables returned to control levels after leptm mfuslon was stopped. These results Indicate that chronic increases m clrculatmg leptm cause sustained increases m arterial pressure and heart rate and are consistent with a possible role for leptm m obesity hypertension.(Hypertension. 1998;31[part 2]:409-414.)Key Words: leptm n hypertension H sympathetic nervous system n blood pressure n heart rate n food intake

Adiponectin (Acrp30) is a physiologically active polypeptide hormone secreted by adipose tissue that shows insulin-sensitizing, antiinflammatory, and antiatherogenic properties. In humans, Acrp30 levels are inversely related to the degree of adiposity. In the current study, we tested the long-term weight-reducing and insulin-enhancing effects of

Abstract-The mechanisms of sodium-induced myocardial hypertrophy and vascular hypertrophy are poorly understood.We tested the hypothesis that a high sodium concentration can directly induce cellular hypertrophy. Neonatal rat myocardial myoblasts (MMbs) and vascular smooth muscle cells (VSMCs) were cultured in a 50:50 mixture of DMEM and M199 supplemented with 10% fetal bovine serum. Key Words: sodium Ⅲ hypertrophy Ⅲ myocardial myoblasts Ⅲ muscle, smooth, vascular S odium homeostasis profoundly influences the cardiovascular system in normotensive and hypertensive subjects and is a major risk factor for cardiovascular morbidity and mortality independent of other cardiovascular risk factors (for review, see Reference 1). Mounting evidence from animal, epidemiological, and clinical studies suggests that a high dietary salt intake is associated with myocardial hypertrophy. [2][3][4][5][6] Although the mechanism of salt-induced myocardial hypertrophy is poorly understood, dietary salt intake is thought to modify the process of myocardial hypertrophy by hemodynamic and/or nonhemodynamic mechanisms. 7The development of cardiac hypertrophy in response to pressure and/or volume overload is generally considered to be an adaptive mechanism to normalize ventricular wall stress. High blood pressure is one of the most powerful determinants of LVH, 8 and several studies 5,9 -11 have shown that a high dietary salt intake is associated with increased blood pressure. Therefore, many investigators consider an increased pressure load on the myocardium to be a major cause of LVH in subjects with salt-induced hypertension.More recent evidence points to a close relationship between the development and persistence of LVH and sodium intake, which may be independent of blood pressure. 2,4,6,[12][13][14] Frohlich and associates 12 reported that a high sodium diet not only caused further cardiac enlargement in spontaneously hypertensive rats but also increased cardiac mass in normotensive Wistar-Kyoto rats in the absence of increased blood pressure. Studies in humans have shown that the intracellular sodium concentration of red blood cells is positively correlated with the degree of LVH. 15 Together these results suggest that sodium-induced cardiac hypertrophy may be partially mediated by a direct action of sodium on the myocardium, independent of hemodynamic factors.The present study sought to determine whether sodium can directly induce hypertrophy of individual cells that are not exposed to many of the in vivo factors, such as high blood pressure or increased cardiac output, commonly associated with a high salt diet. The results indicate that increasing the concentration of sodium in cell culture medium can induce hypertrophy of neonatal rat MMbs and VSMCs. The hypertrophy

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Hyperhomocyst(e)inemia has been associated with the development of hypertension, stroke, and cardiovascular, cerebral/neuronal, renal, and liver diseases. To test the hypothesis that homocyst(e)ine plays an integrated role in multiorgan injury in hypertension, we employed: (1) spontaneously hypertensive rats (SHR) in which endogenous homocyst(e)ine levels are moderately high (18.1 +/- ().5 microM); (2) control age- and sex-matched Wistar Kyoto (WKY) rats in which homocyst(e)ine levels are normal (3.7 +/- 0.3 microM). To create the pathophysiological condition of hyperhomocyst(e)inemia, 20 mg/day homocyst(e)ine was administered for 12 weeks in (3) SHR (SHR-H) and in (4) WKY (WKY-H) rats. (5) Endogenous homocyst(e)ine levels were reduced slightly but not significantly from 18.1 +/- 0.5 microM to 12.5 +/- 0.7 microM in SHR by folic acid administration (SHR-F). Plasma and tissue levels of homocyst(e)ine were determined by HPLC and spectrophotometric methods. Plasma and sympathetic ganglion (neuronal) matrix metalloproteinase (MMP) activity was measured by zymography. Activity of neuronal MMP was increased in hyperhomocyst(e)inemic rats as compared with controls. Mean arterial pressure (mmHg) was 95 +/- 5, 126 +/- 8,157 +/- 10, 188 +/- 5, and 165 +/- 12 in WKY, WKY-H, SHR, SHR-H, and SHR-F, respectively. Urinary protein (mg/day) was 0.11 +/- 0.03, 0.88 +/- 0.22, 0.47 +/- 0.10, 0.89 +/- 0.21, and 0.81 +/- 0.21 in WKY, WKY-H. SHR, SHR-H, and SHR-F, respectively, as measured by the Bio-Rad dye binding assay. The relationships between increased arterial pressure, plasma homocyst(e)ine, and urinary protein were delineated. Plasma and neuronal creatinine phosphokinase (CK) isoenzymes were measured by agarose gel electrophoresis. All three CK isoenzymes, i.e., MM, MB, and BB, specific for skeletal, cardiac, and nerve tissue, respectively, were induced following 12 weeks' hyperhomocyst(e)inemia, suggesting multiorgan injury by homocyst(e)ine. Homocyst(e)ine induces endocardial endothelial cell (capillary) apoptosis and may reduce capillary cell density. Structural damage to aorta, myocardium, kidney, and renalureter was analyzed by histology. Results suggested an integrated physiological role of homocyst(e)ine in injury to the endothelial/epithelial cell lining in the respective organs.

1. Obesity is the most common nutritional disorder in the US and is a major cause of human essential hypertension. Although the precise mechanisms by which obesity raises blood pressure (BP) are not fully understood, there is clear evidence that abnormal kidney function plays a key role in obesity hypertension. 2. Obesity increases tubular reabsorption and this shifts pressure natriuresis towards higher BP. The increased tubular reabsorption is not directly related to hyperinsulinaemia, but is closely linked to activation of the sympathetic and renin-angiotensin systems, and possible changes in intrarenal physical forces caused by medullary compression due to accumulation of adipose tissue around the kidney and increased extracellular matrix within the kidney. 3. Obesity is also associated with marked renal vasodilation and increased glomerular filtration rate, which are compensatory responses that help overcome the increased tubular reabsorption and maintain sodium balance. However, chronic renal vasodilation causes increased hydrostatic pressure and wall stress in the glomeruli which, along with increased lipids and glucose intolerance, may cause glomerulosclerosis and loss of nephron function in obese subjects. Because obesity is a primary cause of essential hypertension as well as type II diabetes, there is good reason to believe that obesity may also be the most frequent cause of end-stage renal disease. 4. Future research is needed to determine the mechanisms by which excess weight gain activates the neurohumoral systems and alters renal structure and function. Because of the high prevalence of obesity in most industrialized countries, unravelling these mechanisms will likely provide a better understanding of the pathophysiology of human essential hypertension and chronic renal failure.

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