Antinatriuretic Actions Research Articles

Central effects of atrial natriuretic factor on renal salt excretion

Atrial natriuretic factor (ANF) has been localized in periventricular brain areas involved in cardiovascular and fluid control. We investigated the effect of intracerebroventricular (icv) ANF (alpha-rat atriopeptin III) on renal sodium excretion in unilaterally nephrectomized, conscious unrestrained rats fitted with a chronic ureteral catheter. Isotonic NaCl (1 ml/h) was infused intravenously. ANF injected at doses (icv) of 1 ng (n = 6), 100 ng (n = 7), and 1 microgram (n = 7) reduced urinary sodium excretion (all values mumol/45 min, means +/- SE) from 111.6 +/- 24.4 to 83 +/- 20 (P less than 0.05), from 96.9 +/- 25.2 to 55 +/- 14 (P less than 0.01), and from 90.8 +/- 14.2 to 51 +/- 9 (P less than 0.01), respectively, whereas urinary flow rate did not change. The antinatriuretic effect was immediate in onset and lasted for greater than or equal to 60 min. Blood pressure remained unaltered. ANF (100 ng icv) increased efferent sympathetic renal nerve activity (+36%; n = 6, P less than 0.05), plasma renin activity (4.6 +/- 0.6 to 7.5 +/- 0.5 pmol angiotensin I.ml-1.h-1; n = 9, P less than 0.01), plasma angiotensin II (68.7 +/- 2.5 to 84.7 +/- 3.4 fmol/ml; n = 8, P less than 0.01), and aldosterone (22.3 +/- 3.6 to 37.2 +/- 4.0 ng/ml; n = 9, P less than 0.02). Renal denervation reduced the antinatriuretic effect of ANF by 37%. We conclude that brain ANF has antinatriuretic actions, which may be partly explained by activation of renal nerves.

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.

Endothelin in experimental congestive heart failure in the anesthetized dog

Studies were performed in anesthetized dogs to determine plasma endothelin (ET) concentrations in the presence and absence of experimental congestive heart failure (CHF) produced by rapid ventricular pacing for 8 days. These studies were also designed to determine the effect of exogenous low-dose ET upon integrated cardiorenal and endocrine function in the presence and absence of CHF. In these studies, plasma ET was significantly elevated in CHF (3.25 +/- 0.39 pg/ml) compared with normal (1.03 +/- 0.21 pg/ml) or sham-operated (1.08 +/- 0.27 pg/ml) groups. Compared with the control group, which was characterized by a significant cardiorenal vasoconstrictor response to low-dose ET, a significant attenuation of the vasoconstrictor and antinatriuretic actions of ET was observed in the CHF group. Despite these differential responses, exogenous ET suppressed plasma renin activity (PRA) and activated aldosterone in both control and CHF groups. Thus these studies demonstrate for the first time that experimental CHF is characterized by elevated plasma ET in association with an attenuated cardiorenal response to exogenous ET. In contrast, low-dose ET inhibited PRC and activated aldosterone in the presence and absence of experimental CHF.

The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system

Previous studies using human pituitary extracts have not resolved whether the sodium retaining effects of human growth hormone (hGH) are mediated in part by increased aldosterone secretion. We have studied the effects of an authentic biosynthetic GH (bio-hGH) preparation on sodium metabolism and on the activity of the renin-angiotensin system. Six young men were administered this preparation at 0.2 U/kg/d subcutaneously for five consecutive days. Twenty-four-hour urine collections were obtained for measurement of sodium excretion and osmolality and blood collected for quantitating changes in sodium, osmolality, plasma renin activity (PRA), aldosterone, and arginine vasopressin (AVP) concentrations. Bio-hGH administration resulted in a fall in 24-hour urinary sodium excretion (197 ± 38 to 42 ± 20 mmol, mean ± SD, P < .005), a reduction in urine volume (1,652 ± 182 to 848 ± 348 mL, P < .05) but not osmolality. PRA increased significantly from 1,118 ± 73 to 3,608 ± 1,841 fmol angiotensin 1 L/s ( P < .005), which was associated with a sevenfold increase in plasma aldosterone concentration (52 ± 12 to 402 ± 99 pg/mL, P < .001). Plasma osmolality and AVP concentrations did not change significantly. The results show that Bio-GH-induced retention of sodium involves the activation of the renin-angiotensin system. This mechanism may explain in part the occurrence of plasma volume expansion and hypertension in acromegaly and suggests a risk of fluid retention and possibly hypertension in subjects receiving supraphysiological doses of bio-hGH for treatment of short stature.

Natriuretic Effects of Calcium Antagonists

An important characteristic which distinguishes calcium antagonists from traditional vasodilators is their natriuretic rather than antinatriuretic action. Evidence that all classes of calcium antagonists have a natriuretic effect has been provided by intravenous administration in animal experiments. After single oral doses, all calcium antagonists have some natriuretic effect, but its extent differs with different compounds; dihydropyridines have a greater immediate natriuretic response than verapamil or gallopamil. Recent experiments by our group using the newer dihydropyridine derivative, isradipine, indicate that the natriuretic response may occur at even lower doses than the antihypertensive effect. Indeed, doses of 2.5mg, 5.0mg and 7.5mg of this compound caused an increasingly larger fall in blood pressure, while the natriuretic and diuretic effects peaked with the 2.5mg dose. The natriuretic effect is associated with no or a very small change in glomerular filtration rate and with a more consistent increase in renal plasma flow. The duration of the natriuretic action of calcium antagonists is debated. Our studies have shown that this action is evident during the first 2 days of administration of a dihydropyridine, and then seems to disappear; however, a small negative sodium balance persists, an observation that accounts for the absence of any increase in bodyweight or fluid volumes with long term administration of calcium antagonists, despite their vasodilating action. Recent data have shown that under long term treatment with isradipine sodium clearance was still increased a few hours after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth Hormone and Body Composition

Through its anabolic, lipolytic and antinatriuretic actions, GH has profound effects on body composition. In untreated acromegaly, body weight, body cell mass and extracellular water are increased simultaneously with a decrease of body fat. After successful treatment, extracellular water and body fat normalize, but cell mass remains high. The changes in cell mass, body fat and extracellular water observed in acromegaly suggest different dose-response relationships between GH and these parameters. The relationship between GH concentration and the lipolytic actions of GH is more linear, while the relationship between GH and excess extracellular water is more curvilinear. The sodium-retaining effect of GH seems to be mediated by stimulation of the Na(+)-K+ pump. At higher GH levels, the pump activity is counteracted by an alleged sodium transport inhibitor. In GH-deficient children, GH treatment is followed by rapid loss of adipose tissue and muscular gain. The influence of GH on body composition in GH-deficient adults has recently received attention. Compared to normal subjects, these patients are overweight and have decreased cell mass. Replacement treatment with GH restores body composition towards normal.

The diuretic and natriuretic action of human atrial natriuretic peptide in humans: Lack of effect of exogenous insulin

The interaction of exogenous, synthetic human atrial natriuretic peptide [(hANP) (ANF 99–126)] and of exogenous insulin was investigated in six healthy men and in seven type I diabetic patients using the euglycemic clamp technique. A primed-continuous (1.0 mU/kg × min) infusion of biosynthetic human insulin was administered to acutely raise and maintain plasma insulin concentrations at approximately 75 to 100 μU/mL during four hours while plasma glucose concentrations were maintained constant at the fasting level by a variable infusion of glucose. In healthy men a decrease in natriuresis ( P < .01) was seen during a euglycemic clamp study without exogenous hANP. No changes in diuresis and natriuresis were seen during a control experiment without exogenous insulin and glucose. Both in healthy men and in the type I diabetics sequential IV bolus doses of hANP of 100, 200, and 400 μg induced an increase in urine flow ( P < .01) and in natriuresis ( P < .01). In healthy men these effects were comparable to those achieved by hANP in the absence of induced hyperinsulinemia. It is concluded that the antinatriuretic action of insulin is of no major relevance in counteracting the pharmacologic action of hANP in healthy men. The effects of pharmacologic doses of hANP on diuresis and natriuresis in patients with type I diabetes mellitus is comparable to that in healthy men.

Effects of insulin on kidney function and sodium excretion in healthy subjects.

Insulin action on kidney function was evaluated in 8 healthy subjects, (mean age 27 years) using the euglycaemic clamp technique. Insulin was infused at rates of 0, 20 and 40 mU.min-1.m-2 over consecutive periods of 120 min resulting in plasma insulin concentrations of 8 +/- 2, 29 +/- 7 and 66 +/- 14 mU/l. The renal clearance of 51Cr-EDTA, lithium, sodium and potassium was determined during the last 90 min of each period. Sodium clearance declined with increasing plasma insulin concentrations (1.3 +/- 0.4, 1.0 +/- 0.3 and 0.5 +/- 0.2 ml.min-1.1.73 m-2, p less than 0.001), while glomerular filtration rate (108 +/- 21, 104 +/- 21 and 108 +/- 20 ml.min-1. 1.73 m-2) and lithium clearance (a marker of fluid flow rate from the proximal tubules) 29 +/- 5, 29 +/- 4 and 30 +/- 4 ml.min-1.1.73 m-2) remained unchanged. Calculated proximal tubular reabsorption of sodium and water was unchanged, while calculated distal fractional sodium reabsorption increased (95.5 +/- 1.5, 96.4 +/- 1.2 and 98.1 +/- 0.7%, p less than 0.001). Potassium clearance and plasma potassium concentration declined, whereas plasma aldosterone and plasma renin concentrations were unchanged. In conclusion, elevation of plasma insulin concentration within the physiological range has a marked antinatriuretic action. This effect is located distally to the proximal renal tubules.

κ‐Opioid‐induced changes in renal water and electrolyte management and endocrine secretion

1. Subcutaneous injection of the kappa-opioid agonist U50,488 into conscious, saline-loaded rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 3 h. Plasma renin activity and corticosterone levels were elevated but plasma vasopressin (AVP) and aldosterone levels were unaltered in similarly treated rats. 2. U50,488 administration to adrenal demeddulated rats was not associated with a diuresis but produced an antinatriuresis, though sodium excretion rates were higher in demedullated than in sham-operated animals. Plasma AVP and corticosterone levels were not affected by demeddulation or subsequent U50,488 treatment. Sham-operated, U50-488-treated rats showed the expected increase in plasma corticosterone levels. 3. U50,488 administration resulted in an antidiuresis and an antinatriuresis in AVP-deficient Brattleboro DI rats. 4. When coupled with fasting stress U50,488 administration resulted in similar but attenuated renal responses compared with those observed in unfasted rats. Basal plasma corticosterone levels were elevated in fasted animals and were further increased by U50,488. 5. Both water and electrolyte handling by the kidney are altered by U50,488. The diuretic effects of U50,488 were reversed by adrenal demedullation and in the absence of endogenous AVP, but the antinatriuretic actions were not altered, suggesting that the effects upon renal water and electrolyte excretion may be mediated by separate mechanisms.

Renal sensitivity to angiotensin II in the conscious dog.

Local formation of angiotensin II (AII) within the kidney has been demonstrated. Changes in renal function induced by inhibitors of the renin-angiotensin system have been the basis for the postulate that AII may act as a paracrine substance in the kidney. We studied the renal action of chronic intrarenal infusions of AII at doses between 2 and 2000 fmol/kg X min in uninephrectomized conscious dogs monitored on 80 meq daily sodium intake. Exogenous AII was confined to the kidney, as demonstrated by the absence of systemic pressor and adrenal cortical responses during the intrarenal infusion. After 2 control days, each dose of AII was infused intrarenally for a period of 3 days. The smallest intrarenal dose of AII that caused significant antinatriuresis and antidiuresis was 20 fmol/kg X min. A significant reduction in urinary volume and sodium excretion occurred during the first 24 h of the infusion period and was proportionate to the amount of peptide infused. Renal escape from the antinatriuretic and antidiuretic effects of the peptide ensued on the second and third days of infusion. There were no significant changes in urinary potassium excretion, plasma renin activity (PRA), plasma aldosterone concentration, or blood pressure throughout the period of intrarenal AII administration. These data demonstrate dose-dependent direct antinatriuretic and antidiuretic actions of low AII concentrations. Escape from the sodium-retaining action of intrarenal AII occurred by 48 h and was independent of suppression of endogenous renin-angiotensin. These results indicate that AII alters renal function by direct intrarenal mechanisms.

Complex physiological and biochemical action of aldosterone in toad urinary bladder and mammalian renal collecting duct cells.

Since the discovery of the steroid hormone aldosterone nearly 35 years ago, our knowledge on the cellular actions of aldosterone is still incomplete. Most of the present physiological and biochemical knowledge about the antinatriuretic action was revealed by investigations on amphibian tight epithelia, in particular the toad urinary bladder. Less biochemical information was obtained from mammalian tissue such as microdissected renal tubules and cultured cells. In our opinion, it is questionable whether de novo synthesis of cell proteins-induced by aldosterone-can explain all of the hormonal effects to increase the Na+ transport. In the present paper we try to analyze the wide and contradictory field of biochemical data about the action of aldosterone on the increase in Na+ transport in renal cells in an attempt to incorporate this information into an extended working hypothesis. We suggest distinguishing principally between an early and a late biochemical response phase. We speculate that aldosterone may act by a two-step mechanism: the early and late aldosterone-induced proteins.

Captopril attenuates diuretic and natriuretic actions of furosemide but not atrial natriuretic peptide.

Atrial Natriuretic Peptide (ANP) exerts a potent diuretic and natriuretic action in rat, dog and man. To test whether these actions of ANP are due to antagonism of the antinatriuretic actions of endogenous angiotensin II, an examination was made of the renal actions of ANP in anesthetized rats with and without captopril pretreatment. Captopril treatment did not alter the diuretic and natriuretic action of a single, intravenous bolus injection of ANP (1000 ng of the 8-33 ANP). Captopril treatment did significantly attenuate the diuretic and natriuretic actions of Furosemide (20 mg/kg ip). This attenuation was not reversed by concomitant, exogenous angiotensin II infusion. These results suggest that while ANP exerts its renal actions independently of the circulating renin-angiotensin system the diuretic and natriuretic action of Furosemide is modulated by a substrate of angiotensin converting enzyme.

Effect of intrarenal angiotensin II infusion on the renal escape from mineralocorticoid.

This study examined the hypothesis that suppression of the antinatriuretic action of angiotensin II (ANG II) is an important determinant of the escape from the sodium-retaining effects of mineralocorticoid. In five uninephrectomized dogs aldosterone (ALDO) infusion (10 ng X kg-1 X min-1) produced a fall in sodium excretion (UNaV) on the first day that returned to control on the fourth day of ALDO infusion. Mean arterial pressure (MAP) increased from 89 +/- 1 to 100 +/- 1 mmHg, and glomerular filtration rate (GFR) increased from 38 +/- 3 to 45 +/- 3 ml/min during ALDO infusion. After recovery, intrarenal infusion of ANG II (1.5 ng X kg-1 X min-1) was initiated to maintain a constant level of ANG II during the subsequent aldosterone administration. The intrarenal ANG II infusion produced a sustained increase in MAP (12 +/- 4 mmHg) and a sustained decrease in GFR (11 +/- 5 ml/min) and effective renal plasma flow (42 +/- 17 ml/min). With intrarenal ANG II levels fixed, ALDO infusion again produced a marked decrease in UNaV on the first day followed by a return to control levels on the third day. Again, MAP and GFR increased significantly during ALDO infusion (from 101 +/- 2 to 119 +/- 2 mmHg and from 27 +/- 6 to 35 +/- 4 ml/min, respectively). The absolute increase in MAP was significantly greater during ALDO infusion with intrarenal ANG II infusion as compared with ALDO infusion with intrarenal vehicle infusion alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal adaptation and gut hormone release during sodium restriction in ileostomized man.

The renal excretion of water, electrolytes, aldosterone and kallikrein was monitored in 12 ileostomized patients before and during sodium deprivation. Changes in plasma renin activity (PRA), plasma aldosterone and plasma arginine vasopressin (AVP) concentrations were measured, together with aldosterone in ileal fluid. The pattern of gut peptide release in response to a test meal was also examined to assess whether a circulating gut peptide might be involved in the renal adaptation to sodium restriction, and compared with healthy normal subjects who were under no dietary constraint. In each patient renal sodium excretion fell within 8-12 h of sodium deprivation and was associated with a prompt and significant rise in PRA; much later increases in plasma aldosterone concentration and renal aldosterone excretion occurred, and were established by day 2 of sodium restriction. No consistent change in renal kallikrein excretion was found. Ileal sodium loss was little changed by sodium deprivation, but ileal potassium concentration rose steadily and became significantly correlated with PRA, and to a lesser extent with renal aldosterone excretion. Of the gut peptides measured in plasma, only the insulin profile was altered by sodium deprivation, with an increase in the test meal response; insulin has previously been shown to have a significant antinatriuretic action at physiological concentrations. Plasma levels of pancreatic polypeptide and motilin were increased in ileostomized patients when compared with normal subjects, but were unaffected by the change to a low sodium diet. An early increase in urine flow and water diuresis occurred during sodium deprivation, following a cyclical pattern with peaks each evening.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of angiotensin II natriuresis and antinatriuresis.

The aim of this study was to determine the role of changes in renal arterial pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (ANG II). In seven anesthetized dogs, endogenous ANG II formation was blocked with captopril, and ANG II was infused intravenously at rates of 5-1,215 ng X kg-1 X min-1 while RAP was either servo-controlled at the preinfusion level or permitted to increase. When RAP was servo-controlled, ANG II infusion at all rates from 5-1,215 ng X kg-1 X min-1 decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) while increasing fractional reabsorption of lithium (FRLi) (an index of proximal tubular fractional sodium reabsorption) and causing no change in calculated distal tubule fractional sodium reabsorption (FRDNa). When RAP was permitted to increase, ANG II infusion rates up to 45 ng X kg-1. min-1 also decreased UNaV and FENa while increasing FRLi and causing no change in FRDNa. However, at 135 ng X kg-1 X min-1 and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though renal blood flow and filtration fraction were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during ANG II infusion compared with when RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of ANG II cause antinatriuresis when RAP is prevented from increasing.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II natriuresis and antinatriuresis: role of renal artery pressure, renal hemodynamics, and tubular reabsorption.

The aim of this study was to determine the role of changes in renal artery pressure (RAP), renal hemodynamics, and tubular reabsorption in mediating the natriuretic and antinatriuretic actions of angiotensin II (AII). In anesthetized dogs, endogenous AII formation was blocked with SQ-14225 and AII was infused i.v. at rates of 5-1215 ng/kg/min while RAP was either servo-controlled at the normal level or permitted to increase. When RAP was servo-controlled to prevent a rise i RAP, AII infusion at all rates from 5-1215 ng/kg/min decreased urinary sodium excretion (UNaV) and fractional sodium excretion (FENa), while increasing fractional reabsorption of lithium (FRLi), an index of proximal tubule fractional sodium reabsorption and distal fractional sodium reabsorption (FRDNa): When RAP was permitted to increase, AII infusion rates up to 45 ng/kg/min decreased UNaV, and FENa, while increasing FRLi and FRDNa. However, at 135 ng/kg/min and above, UNaV and FENa increased while FRLi and FRDNa decreased when RAP was allowed to rise, even though RBF and FF were not substantially different from the values observed when RAP was servo-controlled. Filtered sodium load was slightly higher when RAP was permitted to increase during AII infusion, compared to the dogs in which RAP was servo-controlled, although the differences were not statistically significant. Thus, even very large doses of AII cause antinatriuresis when RAP was prevented from increasing. The natriuretic effect of high dose of AII is caused by increased RAP which decreases fractional sodium reabsorption in proximal and distal tubules and causes slight increases in sodium delivery to the tubules.

Prostaglandins, kinins and the regulation of blood pressure.

Prostaglandins participate in the regulation of vascular reactivity and blood pressure by opposing the vasoconstrictor and antinatriuretic actions of pressor hormones, and by moderating the release of norepinephrine from vasoconstrictor nerves. Blood vessels synthesize prostaglandins intramurally, where their local release influences vascular reactivity. PGI2, unlike PGE2, may be a circulating hormone and may influence vascular resistance of organs remote from its site of synthesis. Prostaglandins not only attenuate the effects of vasoconstrictor hormones but also amplify the effects of the kallikrein-kinin system intrarenally and within the vasculature.

Inhibition of the anti-natriuretic action of aldosterone by thyroid hormone in the rat.

Urinary sodium excretion was measured in adrenalectomized, euthyroid rats, within 4 hours after injection of aldosterone and/or thyroid hormone (T3). Rats which received both hormones excreted significantly more Na than rats injected with aldosterone alone. Reverse-T3 did not affect the antinatriuretic action of aldosterone. Natriuresis following injection of T3 alone was similar to that measured in the absence of exogenous hormones. These observations suggest an interaction between aldosterone and T3 on renal Na excretion.

Characteristics of the antinatriuretic action of growth hormone.

SummaryThe antinatriuretic action of growth hormone (bovine) was studied in adrenalectomized rats. A dose-response relationship and a time sequence were determined for the antinatriuretic action of growth hormone. Actinomycin D was administered prior to the hormone to determine the effect of actinomycin D on growth hormone-induced antinatriuresis. The results indicated that the antinatriuretic response of growth hormone was dose related. It was found that a 2-hr delay in onset of action followed the administration of growth hormone. The duration of antinatriuresis was approximately 4 hr and this was observed between 2 and 6 hr after administration. The data show that actinomycin D administered prior to growth hormone completely blocked the antinatriuretic action of this agent. The blockade by actinomycin D suggests that RNA synthesis is involved in this action of growth hormone. The observed delay in onset of action of growth hormone is also consistent with the suggestion that growth hormone induced antin...

Mediation of aldosterone induced anti-natriuresis via RNA-synthesis de novo.

SummaryUsing the determination of the incorporation of orotic arid-6-C14 into mi-crosomal RNA-synthesis, de novo, it was found that aldosterone increased the mi-crosomal level of RNA at about the time it enhanced sodium reabsorption. The lack of an effect of aldosterone on sodium reabsorption before an increase in RNA-synthesis could be detected is consistent with the hypothesis that this hormone mediates its anti-natriuretic action, in vivo, via DNA directed synthesis of RNA.