Sustained influence of the renal nerves to attenuate sodium retention in angiotensin hypertension.

Recent studies indicate that baroreflex suppression of renal sympathetic nerve activity is sustained for up to 5 days of ANG II infusion; however, steady-state conditions are not associated with ANG II hypertension of this short duration. Thus the major goal of this study was to determine whether neurally induced increments in renal excretory function during chronic intravenous infusion of ANG II are sustained under more chronic conditions when hypertension is stable and sodium balance is achieved. Experiments were conducted in five conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (Den) and innervated (Inn) kidneys. ANG II was infused after control measurements for 10 days at a rate of 5 ng. kg(-1). min(-1). Twenty-four-hour control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from Den and Inn kidneys (Den/Inn) were 92 +/- 4 mmHg and 0.99 +/- 0.05, respectively. On days 8-10 of ANG II infusion, MAP was stable (+30 +/- 3 mmHg) and sodium balance was achieved. Whereas equal amounts of sodium were excreted from the kidneys during the control period, throughout ANG II infusion there was a greater rate of sodium excretion from Inn vs. Den kidneys (day 10 Den/Inn sodium = 0.56 +/- 0.05), indicating chronic suppression of renal sympathetic nerve activity. The greater rate of sodium excretion in Inn vs. Den kidneys during renal sympathoinhibition also revealed a latent impairment in sodium excretion from Den kidneys. Although the Den/Inn for sodium and the major metabolites of nitric oxide (NO) decreased in parallel during ANG II hypertension, the Den/Inn for cGMP, a second messenger of NO, remained at control levels throughout this study. This disparity fails to support the notion that a deficiency in NO production and action in Den kidneys accounts for the impaired sodium excretion. Most importantly, these results support the contention that baroreflex suppression of renal sympathetic nerve activity is sustained during chronic ANG II hypertension, a response that may play an important role in attenuating the rise in arterial pressure.

Obesity hypertension: role of leptin and sympathetic nervous system.

Obesity may account for as much as 65% to 75% of human essential hypertension in most industrialized countries. Excess renal sodium reabsorption and a hypertensive shift of renal-pressure natriuresis play a key role in mediating obesity hypertension. Sympathetic activation contributes to obesity-induced sodium retention and hypertension because adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with other neurochemical pathways in the hypothalamus may be a partial link between excess weight gain and increased sympathetic activity. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term intravenous leptin infusions in nonobese rodents at rates that raise plasma concentrations to the levels found in severe obesity increase arterial pressure and heart rate through adrenergic activation. Also, transgenic mice that overexpress leptin develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including melanocortin-4 receptors. However, it is unclear whether this pathway or others, such as neuropeptide Y, mediate the long-term effects of leptin on blood pressure. In addition, leptin has other actions, such as stimulation of nitric oxide formation and enhancement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the precise role of these complex interactions in human obesity has not been elucidated, this is an important area for further investigation, especially considering the current epidemic of obesity in most industrialized countries.

Baroreflexes prevent neurally induced sodium retention in angiotensin hypertension.

Recent studies indicate that renal sympathetic nerve activity is chronically suppressed during ANG II hypertension. To determine whether cardiopulmonary reflexes and/or arterial baroreflexes mediate this chronic renal sympathoinhibition, experiments were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (Den) and innervated (Inn) kidneys. Dogs were studied 1) intact, 2) after thoracic vagal stripping to eliminate afferents from cardiopulmonary and aortic receptors [cardiopulmonary denervation (CPD)], and 3) after subsequent denervation of the carotid sinuses to achieve CPD plus complete sinoaortic denervation (CPD + SAD). After control measurements, ANG II was infused for 5 days at a rate of 5 ng. kg(-1). min(-1). In the intact state, 24-h control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from Den and Inn kidneys (Den/Inn) were 98 +/- 4 mmHg and 1.04 +/- 0.04, respectively. ANG II caused sodium retention and a sustained increase in MAP of 30-35 mmHg. Throughout ANG II infusion, there was a greater rate of sodium excretion from Inn vs. Den kidneys (day 5 Den/Inn sodium = 0.51 +/- 0.05), indicating chronic suppression of renal sympathetic nerve activity. CPD and CPD + SAD had little or no influence on baseline values for either MAP or the Den/Inn sodium, nor did they alter the severity of ANG II hypertension. However, CPD totally abolished the fall in the Den/Inn sodium in response to ANG II. Furthermore, after CPD + SAD, there was a lower, rather than a higher, rate of sodium excretion from Inn vs. Den kidneys during ANG II infusion (day 5 Den/Inn sodium = 2.02 +/- 0.14). These data suggest that cardiac and/or arterial baroreflexes chronically inhibit renal sympathetic nerve activity during ANG II hypertension and that in the absence of these reflexes, ANG II has sustained renal sympathoexcitatory effects.

Role of sympathetic nervous system and neuropeptides in obesity hypertension.

Obesity is the most common cause of human essential hypertension in most industrialized countries. Although the precise mechanisms of obesity hypertension are not fully understood, considerable evidence suggests that excess renal sodium reabsorption and a hypertensive shift of pressure natriuresis play a major role. Sympathetic activation appears to mediate at least part of the obesity-induced sodium retention and hypertension since adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with neuropeptides in the hypothalamus may link excess weight gain with increased sympathetic activity. Leptin is produced mainly in adipocytes and is believed to regulate energy balance by acting on the hypothalamus to reduce food intake and to increase energy expenditure via sympathetic activation. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term leptin infusion at rates that mimic plasma concentrations found in obesity raises arterial pressure and heart rate via adrenergic activation in non-obese rodents. Transgenic mice overexpressing leptin also develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including the melanocortin-4 receptor (MC4-R). However, the role of this pathway in mediating the long-term effects of leptin on blood pressure is unclear. Also, it is uncertain whether there is resistance to the chronic renal sympathetic and blood pressure effects of leptin in obese subjects. In addition, leptin also has other cardiovascular and renal actions, such as stimulation of nitric oxide formation and improvement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the role of these mechanisms in human obesity has not been elucidated, this remains a fruitful area for further investigation, especially in view of the current "epidemic" of obesity in most industrialized countries.

Cardiovascular regulation during insulin infusion into the carotid or vertebral artery in dogs.

OBJECTIVE: To test the hypothesis that insulin increases heart rate and arterial pressure via direct effects on the central nervous system. METHODS AND DESIGN: Insulin was infused into the cerebral circulation of conscious dogs (n = 8) chronically instrumented for continuous infusions and measurement of arterial pressure, cardiac output, heart rate and other hemodynamic variables. In acute experiments, insulin was infused for 30 min into either a carotid or vertebral artery at several rates calculated to increase cerebral circulation insulin concentrations to levels in the physiological or pathophysiological range. It was infused with and without a simultaneous glucose infusion. During long-term experiments, insulin was infused into either a carotid or a vertebral artery for 4 days at 0.4 or 0.2 mU/kg per min, respectively. RESULTS: Insulin infusion alone into the cerebral circulation produced no changes in any measured cardiovascular variable. A simultaneous glucose infusion also produced no changes in cardiovascular dynamics, except at the highest rate of infusion into the carotid artery. The changes seen at the highest rate of infusion are unlikely to be insulin-induced, since similar changes occurred when either glucose or saline was infused in the absence of any insulin infusion. Long-term insulin infusion (4 days) into carotid or vertebral arteries also produced no changes in any measured cardiovascular or renal variable. CONCLUSIONS: These results provide no evidence that insulin, at physiological or pathophysiological concentrations, increases heart rate or arterial pressure by acting directly on the central nervous system, and suggest that sympathetic activation and tachycardia previously observed with systemic hyperinsulinemia may be secondary to peripheral actions of insulin.

Renal nerves promote sodium excretion during long-term increases in salt intake.

To determine whether the renal nerves contribute to sodium homeostasis during long-term increments in sodium intake, studies were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. They were fed a low sodium diet and continuously infused with isotonic saline (350 mL/d) to provide a daily sodium intake of approximately 60 mmol. After control measurements, sodium intake was increased to 470 mmol/d by increasing the rate of isotonic saline infusion to 3000 mL/d for 5 days; this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure and ratios for urinary sodium, potassium, and creatinine excretion from denervated and innervated kidneys (DEN/INN) were 96+/-3, 1.06+/-0.04, 1.00+/-0.04, and 1.01+/-0.02 mm Hg, respectively. During the approximately 8-fold increase in sodium intake, there was no long-term change in mean arterial pressure, and daily sodium balance was achieved within 48 hours. Moreover, during the first day of high salt intake, there were significant reductions in the DEN/INN for sodium and potassium excretion, which persisted for the entire 5-day period of increased sodium intake; on day 5, the DEN/INN for sodium and potassium excretion was 0.86+/-0.03 and 0.86+/-0.04, respectively. In contrast, the DEN/INN for creatinine excretion remained at control levels during high salt intake. Furthermore, similar long-term reductions in the DEN/INN for sodium and potassium excretion occurred in a second group of dogs administered adrenergic receptor-blocking agents for 5 days to interrupt the functional effects of the renal nerves. These data indicate that sustained renal sympathoinhibition promotes sodium and potassium excretion during long-term increments in sodium intake by inhibiting tubular reabsorption of these electrolytes.

Renal nerves promote sodium excretion in angiotensin-induced hypertension.

To determine whether the sympathetic nervous system contributes to the hypertension induced by pathophysiological increments in plasma angiotensin II (Ang II) concentration, we determined the neurally induced changes in renal excretory function during chronic intravenous infusion of Ang II. Studies were carried out in five conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from the denervated and innervated kidneys. After control measurements, Ang II was infused for 5 days at a rate of 4.8 pmol/kg per minute (5 ng/kg per minute); this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure (MAP) and for the ratio of denervated to innervated kidneys (DEN/INN) for urinary sodium, potassium, and creatinine excretion were 93+/-5 mm Hg, 1.17+/-0.09, 1.10+/-0.10, and 1.00+/-0.02, respectively. As expected, Ang II infusion caused sodium retention for several days before sodium balance was achieved at an elevated MAP (day 5=124+/-4 mm Hg). Moreover, by day 2 of Ang II-induced hypertension, there were significant reductions in the DEN/INN for sodium and potassium, which persisted for the 5 days of Ang II infusion; on day 5, the DEN/INN values for sodium and potassium were 0.71+/-0.10 and 0.91+/-0.12, respectively. In contrast, the DEN/INN for creatinine was unchanged from control levels during Ang II infusion, and measurements of renal hemodynamics indicated comparable reductions in glomerular filtration rate (approximately 13%) and renal plasma flow (approximately 25%) during Ang II infusion. This indicates that the renal nerves promoted sodium and potassium excretion during Ang II-induced hypertension by inhibiting tubular reabsorption of these electrolytes. Thus, this study provides no support for the hypothesis that increased renal sympathetic nerve activity impairs sodium excretion and contributes to Ang II-induced hypertension.

Long-term dietary supplementation with L-arginine prevents age-related reduction in renal function.

Aging is associated with loss of nephron function and reductions in serum L-arginine and excretion of nitric oxide (NO) metabolites. The present study was performed to determine if long-term dietary treatment with L-arginine, the NO synthase substrate, could prevent age-related renal injury. Studies were performed in four groups of rats, aged 12-13 mo, for 8 mo: group 1 received L-arginine (2% in 2.5% corn syrup, n = 5); group 2 received sodium nitrite, an NO donor (0.1%, in 2.5% syrup, n = 7); group 3 was an untreated control group (n = 7); group 4 was treated with 2.5% corn syrup (n = 5). Urinary protein increased and urinary nitrate/nitrite decreased with age in controls, but, during L-arginine treatment, urinary protein decreased and nitrate/nitrite increased. Two weeks after L-arginine was stopped, urinary protein had increased and nitrate/nitrite had decreased to the same level as in controls. L-Arginine treatment increased glomerular filtration rate (GFR) by 50% compared with untreated controls. In contrast, nitrite had no effect on GFR. Morphologically, L-arginine protected against aging injury by reducing the number of sclerotic glomeruli. In summary, we found that L-arginine prevented the age-related glomerular injury and reduction in GFR. The mechanism of protection, however, may be independent of NO.

Influence of the renal nerves on sodium excretion during progressive reductions in cardiac output.

The purpose of this study was to elucidate the role of the renal nerves in promoting sodium retention during chronic reductions in cardiac output. In five dogs, the left kidney was denervated and the urinary bladder was surgically divided to allow separate 24-h urine collection from the innervated and denervated kidneys. Additionally, progressive reductions in cardiac output were achieved by employing an externally adjustable occluder around the pulmonary artery and by servo-controlling right atrial pressure (control = 0.9 +/- 0.2 mmHg) at 4.7 +/- 0.1, 7.5 +/- 0.1, and 9.8 +/- 0.2 mmHg for 3 days at each level. At the highest level of right atrial pressure, the 24-h values for mean arterial pressure (control = 97 +/- 3 mmHg) and cardiac output (control = 2,434 +/- 177 ml/min) were reduced approximately 25 and 55%, respectively; glomerular filtration rate fell by approximately 35% and renal plasma flow by approximately 65%. However, despite the sodium retention induced by these hemodynamic changes, there were no significant differences in renal hemodynamics or sodium excretion between the two kidneys during pulmonary artery constriction. In contrast, after release of the pulmonary artery occluder on day 9, sodium excretion increased more (approximately 28% during the initial 24 h) in innervated than in denervated kidneys. These results suggest that the renal nerves are relatively unimportant in promoting sodium retention in this model of low cardiac output but contribute significantly to the short-term elimination of sodium after partial restoration of cardiac output and mean arterial pressure.

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)

Chronic angiotensin-converting-enzyme inhibition improves cardiac output and fluid balance during heart failure.

The purpose of this study was to examine the sequential changes in renal and cardiovascular function produced by chronic Benazepril administration at different stages of heart failure in dogs. Heart failure was produced by rapid ventricular pacing in five dogs with a normally functioning renin-angiotensin system (angiotensin normal, AN) and six dogs chronically administered the angiotensin-converting-enzyme inhibitor (ACEI) Benazepril. After 7 days of pacing, cardiac output was significantly higher and total peripheral resistance (TPR) lower in the ACEI compared with the AN dogs. Cumulative sodium and water balance increased significantly in both groups, but after 7 days of pacing there were no significant differences between groups. However, the rate of increase in sodium and water balance was significantly less in the ACEI group. Effective renal plasma flow decreased in the AN and ACEI groups during pacing, but there were no between-group differences, and no significant changes in glomerular filtration rate (GFR) occurred in either group. In the AN dogs, pacing was continued for 7-21 days until the onset of decompensated heart failure. Urinary sodium excretion increased on the first day of ACEI infusion during this stage but returned to pre-ACEI levels during the next 2-3 days. No significant improvement in cardiac output was measured during ACEI in decompensated heart failure. These data suggest that chronic ACEI administration can improve renal and cardiac function in early heart failure without impairing GFR but is less chronic ACEI administration can improve renal and cardiac function in early heart failure without impairing GFR but is less effective in later, decompensated stages.

Comparison of renal actions of urodilatin and atrial natriuretic peptide.

A 32-amino acid atrial natriuretic peptide (ANP)-like peptide, putatively synthesized by the kidney, has recently been isolated from human urine. This peptide, urodilatin (Uro), is structurally similar to the 28-amino acid ANP, suggesting that they might have similar actions on renal fluid and electrolyte excretion. The purpose of this study was to characterize the direct renal actions of low doses of Uro infusion and to compare them with the effects of equimolar intrarenal infusions of either ANP or the 24-amino acid atriopeptin III (AP III). Synthetic Uro was infused into the renal artery of pentobarbital sodium-anesthetized mongrel dogs (n = 8) at 0.14, 0.28, and 1.43 pmol.kg-1.min-1 while renal perfusion pressure was servo-controlled at 100 mmHg. Uro infusion at 1.43 pmol.kg-1.min-1 increased sodium excretion from an average control of 57.4 +/- 10.1 to 159.0 +/- 24.4 mueq/min. Uro infusion at the highest dose also increased potassium excretion (28.0 +/- 4.5 vs. 40.4 +/- 7.4 mueq/min), chloride excretion (56 +/- 11 vs. 155 +/- 22 mueq/min), and urine volume (0.54 +/- 0.12 vs. 1.22 +/- 0.25 ml/min). Fractional lithium excretion, a marker for proximal tubular sodium reabsorption, was not altered by Uro infusion, nor were urinary guanosine 3',5'-cyclic monophosphate excretion, glomerular filtration rate, or effective renal plasma flow changed. Equimolar infusions of these low doses of either alpha human ANP (n = 6) or AP III (n = 8) had no effect on any of the measured variables. Thus, within the range of doses used in this study, Uro was a more effective natriuretic and diuretic agent than either ANP or AP III.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure natriuresis and angiotensin II in reduced kidney mass, salt-induced hypertension.

In normal subjects, high sodium intake causes little change in mean arterial pressure (MAP). However, MAP is sodium sensitive after reduction of kidney mass. The present study examined the role of increased renal artery pressure and decreased angiotensin II (ANG II) formation in maintaining sodium balance during high sodium intake in dogs with reduced kidney mass. In seven dogs with pressure natriuresis intact, increasing sodium intake from 36 to 466 meq/day for 7 days raised MAP from 91 +/- 2 to 106 +/- 2 mmHg. Sodium excretion increased promptly and cumulative sodium balance increased by only 80 +/- 26 meq after 7 days of high sodium intake. When renal perfusion pressure was servo-controlled to prevent pressure natriuresis, comparable increases in sodium intake raised MAP from 88 +/- 2 to 128 +/- 4 mmHg after 7 days. Sodium excretion rose to match intake, but cumulative sodium balance increased by 226 +/- 34 meq after 7 days. In dogs in which ANG II levels were held constant by converting enzyme inhibition and constant ANG II infusion (2 ng.kg-1.min-1 iv), raising sodium intake for 7 days elevated MAP from 126 +/- 2 to 146 +/- 4 mmHg after 7 days while increasing cumulative sodium balance by 212 +/- 29 meq. When renal perfusion pressure was servo-controlled and ANG II levels held constant, raising sodium intake elevated MAP from 125 +/- 3 to 166 +/- 11 mmHg and increased cumulative sodium balance by 399 +/- 128 meq. These data indicate that pressure natriuresis and decreased ANG II formation are important in minimizing sodium retention and hypertension during high sodium intake. However, other mechanisms can increase sodium excretion independent of pressure natriuresis and suppression of ANG II during salt-induced hypertension.

Obesity-associated hypertension. Hyperinsulinemia and renal mechanisms.

Hyperinsulinemia and insulin resistance have been postulated to link obesity and hypertension. Evidence supporting this concept derives mainly from epidemiological studies showing a correlation between insulin resistance, hyperinsulinemia, and blood pressure and from short-term studies suggesting that insulin has renal and cardiovascular actions that, if sustained, could elevate blood pressure. However, a cause-and-effect relation between insulin and hypertension has not been clearly established. Recent studies indicate that chronic hyperinsulinemia, similar to that found in obese hypertensive patients, did not raise blood pressure in normal dogs, even when renal excretory capability was reduced by prior removal of kidney mass. Chronic insulin infusion also failed to elevate blood pressure in dogs maintained on a high sodium intake and did not potentiate the long-term blood pressure responses to angiotensin II or norepinephrine. The presence or absence of insulin resistance may not be a major factor in determining the blood pressure response to hyperinsulinemia since chronic insulin infusion also failed to cause hypertension in obese, insulin-resistant dogs. Although hyperinsulinemia causes transient sodium retention, sustained decreases in renal excretory capability sufficient to cause chronic hypertension did not occur in dogs. In rats, insulin infusion causes small increases in blood pressure, although several characteristics of the hypertension (e.g., salt-sensitivity) differ from those observed in obese human hypertensive patients. Whether humans more closely resemble dogs or rats with respect to their long-term cardiovascular responses to insulin remains to be determined. However, very high insulin levels in humans with insulinoma do not cause hypertension, and several studies suggest that there is only a weak correlation between plasma insulin concentration and blood pressure in normal humans. Therefore, additional factors besides hyperinsulinemia per se may be responsible for a major component of obesity-associated hypertension.

Hypertension during chronic hyperinsulinemia in rats is not salt-sensitive.

The goal of this study was to examine the chronic blood pressure and renal actions of insulin in conscious rats and to determine whether the blood pressure response to insulin is salt-sensitive. The effects of chronic hyperinsulinemia were examined in three groups of Sprague-Dawley rats given low sodium (LS rats, 0.6 meq/day), normal sodium (NS rats, 3.0 meq/day), or high sodium (HS rats, 11.4 meq/day) intakes. After 5-7 days of acclimation and 4 days of control measurements, insulin was infused 24 hr/day (1.5 milliunit/kg/min i.v.) for 7 days, and euglycemia was maintained by infusion of glucose (22 mg/kg/min i.v.). Mean arterial pressure was recorded continuously 19 hr/day, using computerized techniques, from chronically implanted aortic catheters. Chronic insulin infusion increased arterial pressure similarly in the three groups of rats, from 91 +/- 2 to 104 +/- 4 mm Hg in LS rats (n = 6), from 86 +/- 2 to 104 +/- 4 mm Hg in NS rats (n = 5), and from 91 +/- 2 to 105 +/- 8 mm Hg in HS rats (n = 5). There were no significant changes in plasma renin activity or glucose concentration in any group during insulin infusion. Control sodium excretions were 0.5 +/- 0.1, 2.3 +/- 0.1, and 9.3 +/- 0.6 meq/day in LS, NS, and HS rats, respectively, and there were no significant changes in urinary sodium excretion or cumulative sodium balance during 7 days of insulin infusion in any of the groups. These observations indicate that chronic hyperinsulinemia in rats produced hypertension that was not salt-sensitive and not dependent on sodium retention or increased renin secretion. Moreover, insulin-induced hypertension was associated with a shift of renal pressure natriuresis, since sodium balance was maintained at elevated arterial pressures.

Chronic intrarenal hyperinsulinemia does not cause hypertension.

Hyperinsulinemia has been postulated to link obesity and hypertension via the antinatriuretic actions of insulin. The main goal of this study was to quantitate the importance of the direct intrarenal actions of insulin, independent of systemic effects, in altering blood pressure and renal function. This was accomplished by determining the responses to chronic intrarenal insulin infusion in uninephrectomized, chronically instrumented conscious dogs maintained on a 74 meq/day sodium intake. Insulin was infused at rates calculated to raise intrarenal, but not systemic, insulin to levels similar to those observed in obese hypertensive dogs. Intrarenal insulin infusion (0.6 mU.kg-1.min-1) for 7 days caused transient decreases in sodium excretion but no significant changes in potassium excretion. Mean arterial pressure did not change during 7 days of insulin infusion, averaging 93 +/- 4 mmHg during control and 93 +/- 3 mmHg during insulin infusion. Intrarenal insulin caused small increases in GFR but no significant changes in effective renal plasma flow or renal vascular resistance. These results demonstrate that insulin causes transient decreases in sodium excretion, but chronic intrarenal hyperinsulinemia does not elevate blood pressure in normal dogs. Additional factors other than the direct sodium-retaining effects of insulin may be important in raising blood pressure in obesity-associated hypertension.

Sustained hyperinsulinemia increases arterial pressure in conscious rats.

A large body of correlational evidence relating plasma insulin levels and arterial pressure in obese hypertensives suggests that hyperinsulinemia may play a causal role in the development of hypertension in these subjects. However, experimental evidence supporting the ability of increased plasma insulin per se to increase blood pressure is lacking. The goal of this study was to determine the effect of hyperinsulinemia on mean arterial pressure and renal electrolyte excretion in eight conscious rats. Arterial pressure was determined by sampling the signal from an abdominal aortic catheter once per minute, 19 h/day by computer. A 5-day intravenous insulin and glucose infusion that increased plasma insulin concentration 43% significantly increased mean arterial pressure from 93 +/- 1 mmHg to an average of 101 +/- 2 mmHg for the 5-day experimental period. Heart rate increased from 369 +/- 8 to 406 +/- 3 beats/min. Urinary sodium excretion transiently decreased on day 1 of insulin, but no significant sodium retention was measured after 5 days of insulin infusion, suggesting that the blood pressure increase was not volume mediated. There were no changes in any of these variables in eight vehicle-infused rats. These results suggest that hyperinsulinemia can increase mean arterial pressure in conscious rats, but the underlying mechanism remains to be elucidated.

The hemodynamic response to chronic hyperinsulinemia in conscious dogs.

This study describes the hemodynamic effects of chronic hyperinsulinemia in seven normal dogs. Insulin infused at 1 mU/kg/min together with glucose at 14 mg/kg/min for 7 days increased fasting plasma insulin concentration approximately six-fold. Plasma glucose concentration was unchanged on day 1 but was below control on day 6. Mean arterial pressure decreased from 81 +/- 4 mm Hg to 70 +/- 3 mm Hg, while cardiac output increased to 30 +/- 8% above control by day 7. Total peripheral resistance decreased to 69 +/- 5% of control. Urinary sodium excretion was significantly decreased and was accompanied by a 22% increase in extracellular fluid volume with no change in blood volume. All parameters returned to control levels during the recovery period. These data suggest that, in addition to promoting renal sodium retention, insulin may lower blood pressure and increase cardiac output through a peripheral vasodilatory effect.

Atrial natriuretic factor and blood pressure control: role of sodium and aldosterone.

This study examined the long-term actions of atrial natriuretic factor (ANF), at physiological levels, on renal function and mean arterial pressure (MAP) and the importance of Na intake and the renin-angiotensin-aldosterone system in modulating those effects. After a control period, ANF was infused intravenously at a rate of 10 ng.kg-1.min-1 for 7 days, followed by 7 days of 20 ng.kg-1.min-1 and 7 days of recovery. After 7 days of ANF at 10 ng.kg-1.min-1, MAP decreased from 87 +/- 3 to 80 +/- 2 mmHg in normal dogs on low sodium intake (LS, 7 meq Na/day) and from 89 +/- 2 to 79 +/- 2 mmHg in adrenalectomized dogs (ADX, 7 meq Na/day) given constant mineralocorticoid replacement. In both groups, no significant change in glomerular filtration rate (GFR) was observed, although sodium excretion increased transiently. ANF failed to cause significant changes in MAP, GFR, or sodium excretion in normal dogs on high sodium intake (HS, 269 meq Na/day). In LS and HS no long-term effects of ANF on plasma renin activity (PRA) and aldosterone were observed. In ADX, as expected, no change in aldosterone was observed. Thus, in normal and adrenalectomized dogs on LS, chronic ANF infusion caused sustained reductions in MAP. HS markedly attenuated the hypotensive effect of ANF. Our data suggest that the long-term effect of ANF is salt sensitive but that decreases in PRA and aldosterone are not essential for the long-term hypotensive effect of ANF.

Intrarenal atrial natriuretic peptide infusion lowers arterial pressure chronically.

Chronic intravenous infusions of atrial natriuretic peptide (ANP) have been shown to lower mean arterial pressure (MAP) in both normal and hypertensive animals. However, the importance of the renal actions of ANP in mediating this hypotension is unknown. This study was designed to determine whether physiological or pathophysiological increases in intrarenal ANP levels influence long-term control of arterial pressure. ANP was infused into the renal artery of seven conscious, uninephrectomized, chronically instrumented dogs at 1, 2, and 4 ng.kg-1.min-1 for 7 days at each dose, followed by a recovery period. Then ANP was infused intravenously following the same protocol. MAP decreased from 88 +/- 3 to 78 +/- 3 mmHg during intrarenal infusion of 1 ng.kg-1.min-1 ANP; increasing the ANP infusion rate did not result in a further reduction in MAP. Systemic arterial plasma ANP concentration did not change from control (15 +/- 5 pg/ml) during 1 or 2 ng.kg-1.min-1 intrarenal ANP infusion but increased slightly during 4 ng.kg-1.min-1 intrarenal ANP infusion, averaging 53 +/- 11 pg/ml. Renal arterial plasma ANP concentrations were calculated to increase to approximately 120 +/- 5, 248 +/- 11, and 484 +/- 22 pg/ml during 1, 2, and 4 ng.kg-1.min-1 intrarenal ANP infusion, respectively. Intravenous ANP infusion did not alter MAP at 1 ng.kg-1.min-1, but MAP was slightly lower than control during 2 and 4 ng.kg-1.min-1 ANP infusion and remained below control during the postinfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)