CNS-neuropeptide interactions and obesity

314A

ASH XV ABSTRACTS

studies in resistant hypertensive subjects underscore the predictive value of clinical markers, i.e. high cholesterol, rising creatinine, abdominal bruits, smoking and peripheral vascular occlusion. Recent studies with aortography added to conventional coronary angiography indicate that nearly 20% of hypertensive patients will have “incidental” RAS ⬎50%, some of which will exceed 70% lumen narrowing. Remarkably, blood pressures and kidney function are often satisfactory with only moderate antihypertensive regimens, 45% of which contained ACE inhibitors in 1998 –1999. With expanding indications for ACE inhibitors, including proteinuric renal disease and reduction of cardiovascular risk, it is likely that even more patients with unsuspected RAS will be treated with ACE inhibitors in the future. The risks of progressive vascular occlusion and clinical events, such as accelerating hypertension, declining renal function and/or accelerated cardiovascular events become para-mount in selecting patients for further evaluation and intervention. Overall, 31% of patients develop progressive vascular stenosis, but total occlusion occurs in 3–5%, less than reported even 10 years ago. Patients followed for more than 36 months after identification of incidental stenotic lesions ⬎70% progressed to clinical end-points regarding blood pressure or renal function in less than 10% of cases. Initial therapy in patients with atherosclerotic RAS therefore consists of vigorous blood pressure control, often including agents which block the renin-angiotensin system. Lipid reduction and smoking cessation are critical. Failure to respond with stable blood pressure and/or kidney function often defines those patients who may benefit from further diagnostic study and vascular reconstruction.

ANGIOPLASTY AND STENTING AS INITIAL TREATMENT FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE Peter W. de Leeuw. Dept. of Medicine, University Hospital Maastricht, Maastricht, The Netherlands Percutaneous transluminal renal angioplasty (PTRA) and renal stent placement (RSP) have largely replaced surgical approaches as first-line treatment of renal artery stenosis. Both PTRA and RSP are relatively safe, in most cases technically successful, and less costly than bypass grafting. Indications for PTRA and/or RSP are renovascular hypertension and ischemic nephropathy. However, several observational studies have shown that these techniques rarely cure the hypertension. In addition, at least three randomized trials indicate that angioplasty is no better than medical treatment in terms of blood pressure control. Although one cannot entirely rule out that this reflects a poor selection of patients, even refined measurements such as lateralization of renin secretion cannot predict outcome. In general, the results of angioplasty with respect to blood pressure are better at younger age and with less severe hypertension. Data on the renoprotective effect of PTRA with or without RSP are extremely scarce. Inasmuch as these are available, they suggest that late results of PTRA alone are disappointing as far as renal function is concerned. In part, this is related to a high percentage of restenosis, par-

AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2

ticularly in the presence of ostial lesions. PTRA combined with stenting probably carries a better long-term prognosis although there are no randomized trials to support this claim. Also, data are lacking on the effect of stenting relative to medical treatment. Key Words: Renal artery stenosis; angioplasty; stenting

Thursday, May 18, Astor Ballroom, 5:00 PM to 6:30 PM Theme I: The Obesity Epidemic OBESITY: THE RELATIVE ROLES OF GLUTTONY, SLOTH, AND GENETICS James O. Hill, Ph.D., Director. Center for Human Nutrition, University of Colorado Health Sciences Center, Denver, CO The United States is experiencing an epidemic of obesity. Obesity is a major threat to health (through increased risk of diabetes, dislipidemia and hypertension) and quality of life. Data from familial, twin, and adoption studies strongly suggest that genetic factors contribute to some of the variation in body weight and body fatness within a population. However, the prevalence of obesity in the entire population has increased dramatically over the past two decades. It is unlikely that substantial changes have occurred in the gene pool over this period, so that we must examine how changes in our environment have increased the susceptibility of obesity in many genetic phenotypes. The rapid increase in obesity in the U.S. has been caused largely by an environment that promotes excessive food intake and discourages physical activity. Although humans have evolved strong physiological mechanisms to defend against body weight loss, they appear to have only weak defense against body weight gain when food is abundant. Control of portion size, consumption of a diet low in fat and energy density, and regular physical activity are behaviors that protect against obesity. However, it is becoming difficult to adopt and maintain these behaviors in the current environment. If we are to succeed in combating the epidemic of obesity, we must direct efforts toward modifying the environment. Key Words: Obesity; portion size; low fat diets; physical activity CNS-NEUROPEPTIDE INTERACTIONS AND OBESITY Robert V. Considine, Ph.D. Indiana University School of Medicine, Indianapolis, IN Early work over half a century ago implicated the central nervous system, and in particular the hypothalamus, in the regulation of energy intake and energy expenditure. However it was not understood how the brain monitored energy stores in the body and adjusted intake and expenditure to maintain a relatively constant body weight. Leptin, a protein secreted by the adipose tissue, provides a signal to the hypothalamus of both the amount of energy stored in the adipose tissue and extremes in energy intake. In rodents leptin decreases the activity of neurotransmitters such as NPY and Agouti-Related Peptide (AGRP) which stimulate food intake, and increases expression of POMC (␣-MSH) which inhibits food intake. Leptin also regulates hypothalamic-pituitary activity and has centrally-mediated effects

AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2

FACULTY ABSTRACTS

315A

on insulin sensitivity. However, the relatively high serum leptin in obese subjects suggests that humans may be resistant to the weight-reducing actions of leptin. A basic understanding of the leptin signal pathway has been achieved; however the mechanisms that regulate leptin production are not understood. Hexosamine biosynthesis is a mechanism through which cells “sense” the influx of nutrients. Hexosamines appear to regulate leptin production in human adipocytes. In summary leptin provides a coordinating signal to the central mechanisms regulating body energy balance. The adipocyte utilizes the hexosamine biosynthetic pathway to determine the amount of leptin to release.

As this abstract is being written before the abstracts have been reviewed, the specifics of their content cannot be discussed. Of substantial interest is the fact that early in this decade the conventional wisdom— both in many companies and in academea—was that antihypertensive therapy was now so good that there was little point in investing time and effort in further development. Many companies, some of them substantial, closed their hypertension research programs and turned elsewhere. At the moment, the development of antihypertensive treatments is more active than at any time in history. The abstracts will cover angiotensin II antagonists, aldosterone antagonists, and vasopeptidase inhibitors. Once again, conventional wisdom was incorrect.

Key Words: Leptin; neurotransmitters; hexosamines

Key Words: Antihypertensive therapy; vasopeptidase inhibitors; angiotensin II antagonists; eplerenone

ROLE OF NEUROPEPTIDES IN LINKING OBESITY, SYMPATHETIC ACTIVITY AND HYPERTENSION William G. Haynes, M.D. Leptin is almost exclusively produced by adipose tissue and acts in the central nervous system (CNS) to decrease appetite and increase energy expenditure. We have demonstrated that systemic or CNS administration of leptin markedly increases sympathetic nerve activity (SNA) to brown adipose tissue, kidney, skeletal muscle and adrenal glands. Acute administration of leptin does not increase arterial pressure, although chronic leptin infusion does have a modest pressor effect. Leptin also has actions that oppose sympathetically mediated vasoconstriction, including natriuresis, insulin sensitization and simulation of endothelial nitric oxide generation. These diverse actions have made it difficult to assess the overall role of leptin in control of arterial pressure. Recent studies from our laboratory have shown the obese leptin-deficient ob/ob mice have lower arterial pressure than lean littermates. These data suggest that endogenous leptin contributes to the physiological maintenance of arterial pressure. The hypothalamic melanocortin system, via activation of melanocortin-4 receptors, decreases appetite and weight. The leptin and melanocortin systems appear to have independent and additive actions on body fat content. The melanocortin system acts to increase SNA to thermogenic and other tissues. Interestingly, obesity in the agouti mouse strain, due to genetic antagonism of melanocortin receptors, is associated with elevated arterial pressure. This may represent a non-specific effect of obesity or a purative hypertensive effect of melanocortinergic underactivity. Altercations in leptin and melanocortin activity may contribute to the adverse cardiovascular consequences of obesity. Contrasting blood pressure responses to obesity in ob and agouti mice suggests that the cardiovascular response to obesity depends critically on the underlying genetic and neuroendocrine mechanisms.

Thursday, May 20, Broadway Ballroom South, 5:00 PM to 7:00 PM Theme II: New Drugs NEW DRUG ABSTRACTS: SUMMARY N.K. Hollenberg*. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

Friday, May 19, Broadway Ballroom North, 10:30 AM to 11:30 AM Theme I: Hypertension and Atherosclerosis MICROVASCULAR AND INFLAMMATORY RESPONSES TO HYPERCHOLESTEROLEMIA D. Neil Granger. Mol & Cellular Physiology, LSU Health Sciences Center, Shreveport While the inflammatory manifestations of hypercholesterolemia (Hch) are generally assumed to occur exclusively in major arterial vessels, recent studies suggest that the inflammatory cell-mediated pathology may also extend to the arterial and venous segments of the microcirculation. Hch is known to result in an impaired endothelium-dependent relaxation of arterioles and to produce responses in capillaries and venules that are characteristic of an acute inflammatory response, including leukocyte-endothelial cell adhesion and increased vascular permeability and capillary fluid filtration. The accompanying oxidant stress appears to initiate the recruitment of inflammatory cells in postcapillary venules. These inflammatory cells appear to amplify the microvascular alterations of Hch by releasing cytokines and lipid mediators. An important consequence of these microvascular and inflammatory responses to Hch is a greater vulnerability of tissues to the deleterious effects of ischemia and reperfusion. Key Words: Leukocytes; ischemia; endothelium

Friday, May 19, Broadway Ballroom North, 11:30 AM to 12:30 PM Theme I: Mechanisms of Diabetes Mediated Cardiovascular Disease ENDOTHELIAL DYSFUNCTION AND ARTERIAL PRESSURE CONTROL IN DIABETES Michael W. Brands. University of Mississippi Medical Center Endothelial dysfunction, defined as impaired endothelialdependent vasodilation, generally is ascribed to abnormalities in the synthesis or action of nitric oxide (NO). There is considerable evidence for endothelial dysfunction in diabe-