Michael W. Brands

Chronic Leptin Infusion Increases Arterial Pressure

Plasma leptin concentration is increased in hypertensive obese humans, but whether leptin contributes to the increased arterial pressure in obesity is not known. In this study, we tested whether chronic increases in leptin, to levels comparable to those in obesity, could cause a sustained increase in arterial pressure and also the importance of central nervous system (CNS) versus systemic mechanisms. Five male Sprague-Dawley rats were implanted with chronic nonoccluding catheters in the abdominal aorta and both carotid arteries for CNS infusion, and five other rats were implanted with an abdominal aorta catheter and femoral vein catheter for intravenous (I.V.) infusion. After 7 days of control, leptin was infused into the carotid arteries or femoral vein at 0.1 microg/kg/min for 5 days and 1.0 microg/kg/min for 7 days, followed by a 7-day recovery period. The carotid artery and i.v. infusions of leptin at 1 microg/kg/min significantly increased plasma leptin levels, from 1.2+/-0.4 ng/mL to 91+/-5 ng/mL and from 0.9+/-0.1 ng/mL to 94+/-9 ng/mL, respectively, but there was no significant increase in either group at the low dose. Food intake also did not change at the low dose but decreased by approximately 65% in the carotid group and 69% in the i.v. group after 7 days of the 1 microg/kg/min infusion. Mean arterial pressure (MAP) increased slightly at the low dose only in the carotid group, but this was not statistically significant. At the higher dose, however, MAP increased significantly from 86+/-1 mm Hg to 94+/-1 mm Hg in the carotid group and from 87+/-1 mm Hg to 93+/-1 mm Hg in the i.v. group. Heart rate also increased significantly in both groups at 1 microg/kg/min leptin infusion. Fasting blood glucose and insulin levels decreased significantly at 1 microg/kg/min in both the carotid artery group (-10.5% and -82.5%, respectively) and the i.v. group (-13.6% and -80.4%, respectively). All variables returned to control levels after leptin infusion was stopped. These results indicate that chronic increases in circulating leptin cause sustained increases in arterial pressure and heart rate and are consistent with a possible role for leptin in obesity hypertension.

Obesity-induced hypertension. Renal function and systemic hemodynamics.

This study examined the control of renal hemodynamics and tubular function, as well as systemic hemodynamics, during obesity-induced hypertension in chronically instrumented conscious dogs. Mean arterial pressure, cardiac output, and heart rate were monitored 24 hours a day using computerized methods, water and electrolyte balances were measured daily, and renal hemodynamics were measured each week during the control period and 5 weeks of a high-fat diet. After 7 to 10 days of control measurements, 0.5 to 0.9 kg of cooked beef fat was added to the regular diet, and sodium intake was maintained constant at 76 mmol/d throughout the study. After 5 weeks of the high-fat diet, body weight increased from 24.0 +/- 1.0 to 35.9 +/- 4.9 kg, mean arterial pressure increased from 83 +/- 5 to 100 +/- 4 mm Hg, cardiac output increased from 2.86 +/- 0.27 to 4.45 +/- 0.55 L/min, and heart rate rose from 68 +/- 5 to 107 +/- 9 beats per minute. Associated with the hypertension was an increase in cumulative sodium balance to 507 +/- 107 mmol after 35 days and a rise in sodium iothalamate space, an index of extracellular fluid volume, to 131 +/- 4% of control. Sodium retention was due to increased tubular reabsorption, because glomerular filtration rate and effective renal plasma flow increased throughout the 5 weeks of the high-fat diet, averaging 135 +/- 4% and 149 +/- 19% of control, respectively, during the fifth week of the high-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension in Obese Zucker Rats: Role of Angiotensin II and Adrenergic Activity

We designed our studies to determine whether blood pressure is elevated in obese Zucker rats compared with lean control rats and to test the importance of the renin-angiotensin and adrenergic nervous systems in long-term blood pressure control in this genetic model of obesity. We monitored mean arterial pressure 24 hours per day using computerized methods in 13- to 14-week-old lean and obese Zucker rats maintained on a fixed, normal sodium intake (3.3 mmol/d). Mean arterial pressure (average of 5 days) was higher in obese (100 +/- 1 mm Hg) than in lean (86 +/- 1) rats. Although control plasma renin activity was lower in obese than in lean rats (3.66 +/- 0.15 versus 5.48 +/- 0.11 ng angiotensin I/mL per hour), blood pressure sensitivity to exogenous angiotensin II was greater in obese than in lean rats. Blockade of endogenous angiotensin II receptors with losartan (10 mg/kg per day) for 7 days also caused a greater decrease in blood pressure in obese (36 +/- 2 mm Hg, n = 6) than in lean (25 +/- 1, n = 5) rats. However, combined alpha- and beta-adrenergic blockade with terazosin (10 mg/kg per day) and propranolol (10 mg/kg per day), respectively, for 8 days caused only modest decreases in blood pressure in obese (9 +/- 3 mm Hg, n = 8) and lean (4 +/- 2, n = 6) rats, despite effective alpha- and beta-adrenergic blockade. These results suggest that increased arterial pressure in obese Zucker rats depends in part on angiotensin II. However, additional mechanisms may also contribute to increased blood pressure in obese Zucker rats.

Mechanisms of Hypertension and Kidney Disease in Obesity

ABSTRACT: Abnormal kidney function is an important cause as well as a consequence of obesity. Excess renal sodium reabsorption, probably in the loop of Henle, and a hypertensive shift of pressure natriuresis play a major role in initiating increased blood pressure associated with weight gain. The mechanisms responsible for increased sodium reabsorption and altered pressure natriuresis in obesity include activation of the renin‐angiotension and sympathetic nervous systems, and physical compression of the kidneys due to accumulation of intrarenal fat and extracellular matrix. Sympathetic activation may be mediated, in part, by elevated circulating leptin and interactions with neuropeptides in the hypothalamus. Renal remodeling and extracellular matrix proliferation likely involve complex interactions between intrarenal physical forces, neurohumoral factors, and local growth factors and cytokines. Although glomerular hyperfiltration and increased arterial pressure help to compensate for increased renal tubular reabsorption in the early phases of obesity, these changes also increase glomerular capillary wall stress which, along with activation of neurohumoral systems and increased lipids and glucose intolerance, cause glomerular cell proliferation, matrix accumulation, and eventually glomerulosclerosis and loss of nephron function in the early phases of obesity. This creates a slowly developing vicious cycle that requires additional increases in arterial pressure to maintain sodium balance and therefore makes effective antihypertensive therapy more difficult. Because obesity is the main cause of Type 2 diabetes and an important cause of human essential hypertension, it seems likely that obesity is also one of the most important risk factors for end‐stage renal disease.

Abnormal pressure natriuresis : a cause or a consequence of hypertension ?

In all forms of chronic hypertension, the renal-pressure natriuresis mechanism is abnormal because sodium excretion is the same as in normotension despite the increased blood pressure. However, the importance of this resetting of pressure natriuresis as a cause of hypertension is controversial. Theoretically, a resetting of pressure natriuresis could necessitate increased blood pressure to maintain sodium balance or it could occur secondarily to hypertension. Recent studies indicate that, in several models of experimental hypertension (including angiotensin II, aldosterone, adrenocorticotrophic hormone, and norepinephrine hypertension), a primary shift of renal-pressure natriuresis necessitates increased arterial pressure to maintain sodium and water balance. In genetic animal models of hypertension, there also appears to be a resetting of pressure natriuresis before the development of hypertension. Likewise, essential hypertensive patients exhibit abnormal pressure natriuresis, although the precise cause of this defect is not clear. It is likely that multiple renal defects contribute to resetting of pressure natriuresis in essential hypertensive patients. With long-standing hypertension, pathological changes that occur secondary to hypertension must also be considered. By analyzing the characteristics of pressure natriuresis in hypertensive patients and by comparing these curves to those observed in various forms of experimental hypertension of known origin, it is possible to gain insight into the etiology of this disease.

ABNORMAL KIDNEY FUNCTION AS A CAUSE AND A CONSEQUENCE OF OBESITY HYPERTENSION

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.

Chronic hyperinsulinemia and blood pressure. Interaction with catecholamines

Although hyperinsulinemia and increased adrenergic activity have been postulated to be important factors in obesity-associated hypertension, a cause and effect relation between insulin, catecholamines, and hypertension has not been established. The aim of this study was to determine whether chronic hyperinsulinemia, comparable with that found in obese hypertensive patients, causes hypertension in normal dogs, increases plasma catecholamines, or potentiates the blood pressure effects of norepinephrine. In six normal dogs, insulin infusion (1.0 milliunits/kg/min) for 7 days, with euglycemia maintained, increased fasting insulin fourfold to sixfold. However, mean arterial pressure did not increase, averaging 99 +/- 2 mm Hg during the control period and 91 +/- 3 mm Hg during the 7 days of insulin infusion. Insulin did not alter plasma norepinephrine or epinephrine, which averaged 171 +/- 27 and 71 +/- 14 pg/ml, respectively, during the control period and 188 +/- 29 and 45 +/- 12 pg/ml during the 7 days of insulin infusion. In six dogs, norepinephrine was infused (0.2 microgram/kg/min) for 7 days to raise plasma norepinephrine to 2,940 +/- 103 pg/ml. Insulin infusion (1.0 milliunits/kg/min) for 7 days during simultaneous infusion of norepinephrine did not further increase mean arterial pressure, which averaged 101 +/- 3 during norepinephrine and 98 +/- 2 mm Hg during insulin plus norepinephrine infusion. Thus, chronic hyperinsulinemia did not increase mean arterial pressure or plasma catecholamines and did not potentiate the blood pressure actions of norepinephrine. These observations provide no evidence that chronic hyperinsulinemia or interactions between insulin and plasma catecholamines cause hypertension in normal dogs.

Long-term cardiovascular role of nitric oxide in conscious rats.

The goal of this study was to determine the arterial pressure and renal excretory responses to a continuous intravenous infusion of 7.4 nmol/kg per minute of the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in conscious rats. Studies were conducted in six groups of Sprague-Dawley rats with indwelling arterial and venous catheters over periods lasting 12 to 26 days. In the first group of rats, L-NAME infusion for 9 days caused a sustained increase in arterial pressure, and on the ninth day arterial pressure was increased 29 mm Hg. Infusion of L-NAME at the higher dose of 37 nmol/kg per minute for 9 days caused no greater increase in arterial pressure than the lower dose. Sodium and volume balances and phenylephrine pressor sensitivity were unchanged during L-NAME administration at 7.4 nmol/kg per minute; plasma renin activity increased 2.5-fold, but the vasodepressor and vasodilator responses to acetylcholine and bradykinin were unchanged. Arterial pressure remained significantly increased 7 days after L-NAME was stopped, but in another group of rats, intravenous L-arginine infusion caused arterial pressure to return to control within 1 day. This same dose of L-arginine was administered for 7 days intravenously, and neither arterial pressure nor sodium balance changed. In other groups of rats, L-arginine was administered in conjunction with L-NAME; this prevented any change in arterial pressure, whereas D-arginine did not. In conclusion, the data suggest that continuous intravenous infusion of L-NAME causes sustained increases in arterial pressure in conscious rats without any sodium or water retention. The hypertension is accompanied by increases in plasma renin activity and can be prevented with intravenous L-arginine administration.

Insulin Resistance, Hyperinsulinemia, and Hypertension: Causes, Consequences, or Merely Correlations?

Abstract Resistance to the metabolic effects of insulin and compensatory hyperinsulinemia have been postulated to mediate human essential hypertension, especially when associated with obesity. Evidence supporting this hypothesis has come mainly from epidemiological studies showing correlations between insulin resistance, hyper-insulinemia, and blood pressure, and from short-term studies suggesting that insulin has renal and sympathetic effects that could raise blood pressure if the effects were sustained. However, there have been no studies demonstrating a direct causal relationship between chronic hypertension and insulin resistance or hyperinsulinemia in humans. The few long-term studies that have been conducted in dogs and humans do not support the hypothesis that hyperinsulinemia causes hypertension or potentiates the hypertensive effects of other pressor agents such as angiotensin II or increased adrenergic tone. To the contrary, multiple studies in dogs and in humans suggest that the vasodilator action of insulin tends to reduce blood pressure. Although resistance to insulins metabolic effects has been suggested to be essential for hyperinsulinemia to cause hypertension, chronic increases in plasma insulin concentrations do not cause hypertension in dogs or humans even in the presence of insulin resistance. Also, recent studies have also shown that the blood pressure-lowering effects of antihyperglycemic agents, initially believed to lower blood pressure by decreasing insulin resistance, may be unrelated to their effects on insulin sensitivity. Obesity appears to be a key factor in accounting for correlations between insulin resistance, hyperinsulinemia, and hypertension, but increased blood pressure in obesity does not appear to be mediated by insulin resistance and hyperinsulinemia. Although insulin resistance and hyperinsulinemia may not be directly linked to hypertension, there is increasing evidence that metabolic abnormalities associated with insulin resistance may increase the risk of cardiovascular disease (e.g., coronary artery disease) associated with hypertension and Type II diabetes. For this reason, further studies of the long-term effects of insulin resistance on cardiovascular, renal, and metabolic functions are needed.

Hemodynamic and Renal Responses to Chronic Hyperinsulinemia in Obese, Insulin-Resistant Dogs

We previously reported that chronic hyperinsulinemia does not cause hypertension in normal insulin-sensitive dogs. However, resistance to the metabolic and vasodilator effects of insulin may be a prerequisite for hyperinsulinemia to elevate blood pressure. The present study tested this hypothesis by comparing the control of systemic hemodynamics and renal function during chronic hyperinsulinemia in instrumented normal conscious dogs (n = 6) and in dogs made obese and insulin resistant by feeding them a high-fat diet for 6 weeks (n = 6). After 6 weeks of the high-fat diet, body weight increased from 24.0 +/- 1.2 to 40.9 +/- 1.2 kg, arterial pressure rose from 83 +/- 5 to 106 +/- 4 mm Hg, and cardiac output rose from 2.98 +/- 0.29 to 5.27 +/- 0.54 L/min. Insulin sensitivity, assessed by fasting hyperinsulinemia and by the hyperinsulinemic euglycemic clamp technique, was markedly reduced in obese dogs. Insulin infusion (1.0 mU/kg per minute for 7 days) in obese dogs elevated plasma insulin from 42 +/- 12 microU/mL to 95 to 219 microU/mL but failed to increase arterial pressure, which averaged 106 +/- 4 mm Hg during control and 102 +/- 4 mm Hg during 7 days of insulin infusion. Hyperinsulinemia for 7 days in obese dogs elevated heart rate from 116 +/- 8 to 135 +/- 7 beats per minute but caused no significant changes in cardiac output, in contrast to normal dogs (n = 6), in which marked increases in cardiac output (31 +/- 5% after 7 days) and decreases in total peripheral resistance occurred during chronic insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)