Sodium-loaded Rats Research Articles

PS 14-14 24-HOUR URINARY SODIUM PREDICTS LEFT VENTRICULAR HYPERTROPHY REGRESSION TO SPIRONOLACTONE IN PATIENTS WITH RESISTANT HYPERTENSION

Objective: Patients with resistant hypertension (RHTN) commonly have primary aldosteronism (PA), which is associated with left ventricular hypertrophy (LVH). Aldosterone activates mineralocorticoid receptors (MR) and induces hypertrophy. Experimental studies indicate a paradoxical activation of the MR in sodium-loaded rats despite adequate suppression of aldosterone. MR antagonists slow down cardiac hypertrophy. We hypothesized that the MR antagonist spironolactone (SPL) would cause greater LVH reduction in patients on high sodium (Na) diet independent of aldosterone. Design and Method: Overall 34 patients with RHTN, defined as BP ≥ 140/90 mmHg despite ≥3 different medications, including a diuretic, were treated with SPL. Cardiac magnetic resonance imaging and biochemical evaluation was performed at baseline, 3 and 6 months in patients with PA and non-PA. PA was defined as renin activity (PRA) <1 ng/ml/h and urinary aldosterone ≥12 ug /24h. We dichotomized patients according to UNa level (UNa ≥200 mEq/24h: high Na diet) and PA status. LVH reduction was indexed by left ventricular mass (LVM) and interventricular septum thickness (IVS) regression. Results: LVM and IVS regression after treatment with SPL at 3 and 6 months was greater in patients with PA on a normal sodium diet and less pronounced in patients on a high sodium diet suggesting that Na blunts the effects of cardiac MR when treated with SPL. However, in patients with non-PA high Na intake did not blunt the effects of SPL. Conclusions: Contrary to our hypothesis, high dietary Na blunted LVH regression in patients with PA treated with SPL. Further studies are needed to elucidate mechanisms for sodium dependent MR activation in patients with PA and non-PA.

High dietary sodium blunts effects of mineralocorticoid receptor antagonism on left ventricular hypertrophy regression in patients with resistant hypertension

Purpose of Study: Patients with resistant hypertension (RHTN) commonly have primary aldosteronism (PA), which is associated with left ventricular hypertrophy (LVH). Aldosterone activates mineralocorticoid receptors (MR) and induces hypertrophy. Experimental studies indicate a paradoxical activation of the MR in sodium-loaded rats despite adequate suppression of aldosterone. MR antagonists slow down cardiac hypertrophy. We hypothesized that the MR anatagonist spironolactone (SPL) would cause greater LVH reduction in patients on high sodium (Na) diet independent of aldosterone. Methods Used: Overall 34 patients with RHTN, defined as BP 140/90 mmHg despite 3 different medications, including a diuretic, were treated with SPL. Cardiac magnetic resonance imaging and biochemical evaluation was performed at baseline, 3 and 6 months in patients with PA and non-PA. PA was defined as renin activity (PRA)<1 ng/ml/h and urinary aldosterone 12 ug /24h. We dichotomized patients according to UNa level (UNa 200 mEq/24h: high Na diet) and PA status. LVH reduction was indexed by left ventricular mass (LVM) and interventricular septum thickness (IVS) regression. Summary of Results: LVM and IVS regression after treatment with SPL at 3 and 6 months was greater in patients with PA on a normal sodium diet and less pronounced in patients on a high sodium diet suggesting that Na blunts the effects of cardiac MR when treated with SPL. However, in patients with non-PA high Na intake did not blunt the effects of SPL. Conclusions: Contrary to our hypothesis, high dietary Na blunted LVH regression in patients with PA treated with SPL. Further studies are needed to elucidate mechanisms for sodium dependent MR activation in patients with PA and non-PA.

Effects of Testosterone on Renal Function in Salt-Loaded Rats

IntroductionThe objective of this study is to investigate the effects of androgen on renal sodium excretion and renal functional in sodium-loaded rats. MethodsSixty male Wistar rats aged 8 weeks were used, of which 48 underwent orchiectomy and the other 12 underwent a sham procedure. The 48 orchiectomized rats were randomly divided into 4 groups (12/group): castrated rats (Cas), testosterone-supplemented castrated rats (TC), flutamide (androgen receptor blocker)-treated castrated rats (FC) and flutamide-treated testosterone-supplemented castrated rats (FTC). The 12 sham-operated rats served as controls. All 60 rats were fed with 8% NaCl chow for 8 weeks. Systemic blood pressure (BP) was recorded at 0, 4 and 8 weeks. Sodium excretion, microalbuminuria and creatinine clearance were calculated before and at the end of the experiment. Circulating levels of testosterone and angiotensin II and plasma renin activity were measured by radioimmunological method at the end of the experiment. ResultsBP of controls and TC was higher at 8 weeks than at baseline; BP of Cas, FC or FTC was lower than that of controls. Plasma renin activity and angiotensin concentrations were lower in Cas, FC and FTC (groups with testosterone absent or blocked) than in controls and TC (groups with testosterone intact). Cas, FC and FTC displayed less microalbuminuria, higher sodium excretion and higher creatinine clearance than control and TC. ConclusionsIn salt-loaded rats, testosterone seems to activate the renin-angiotensin system, resulting in sodium retention, higher BP and renal injury.

Effects of Decreased Renal Cortical Expression of G Protein-Coupled Receptor Kinase 4 and Angiotensin Type 1 Receptors in Rats

Abnormalities in renal angiotensin type 1 receptor (AT1R), D1 dopamine receptor (D1R) and G protein-coupled receptor kinase 4 (GRK4) are present in polygenic hypertension. Selective renal reduction of AT1R expression by intrarenal cortical infusion of antisense oligodeoxynucleotides (As-Odns) in conscious, uninephrectomized, sodium-loaded rats decreases proteinuria, normalizes the glomerular sclerosis index (GSI), increases the sodium excretion (UNaV), and modestly increases blood pressure (BP) in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto rats (WKY). In contrast, selective renal reduction of GRK4 expression by infusion of GRK4 As-Odns increases UnaV, attenuates the increase in arterial BP with age, and modestly decreases protein excretion in SHR, but not in WKY. In this study, we report that intrarenal cortical infusion of both GRK4 and AT1R As-Odns decreased BP and increased UNaV in SHR; these effects were also noted in WKY to a lesser extent. Infusion of SHR with this combination of As-Odns resulted in a decrease in proteinuria and improvement of GSI similar to those by AT1R As-Odn only. In contrast to the increased circulating angiotensin II and aldosterone levels induced by AT1R As-Odn alone, the combination of As-Odns decreased both, contributing to greater natriuresis and amelioration of hypertension than by GRK4 or AT1R As-Odn only. Our results indicate an interaction between GRK4-regulated receptors and the renin-angiotensin system in the regulation of renal function and BP.

PRESSOR AND NON‐PRESSOR EFFECTS OF SODIUM LOADING ON STROKE IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS

1. Aetiological studies have shown that sodium loading increases both blood pressure and death from stroke. The present study was designed to investigate the pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Eighty-five female SHRSP were used. Forty-nine SHRSP, aged 5 months, were randomly divided into two groups with or without sodium loading and their survival times were recorded. Thirty-six SHRSP, aged 3 months, were randomly divided into two groups and were instrumented to determine blood pressure, heart period and baroreflex sensitivity (BRS) after 4 months of sodium loading or normal rat chow. After determination of BRS, blood samples were collected for the measurement of tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and angiotensin (Ang) II and brains were dissected for light microscopic examination. 3. Over the 15 month period, the mortality of control SHRSP was 37.5%, which reached 80.0% in the sodium loading group. Compared with the control group, blood pressure was increased but BRS was significantly decreased (P < 0.001) in sodium-loaded rats. Levels of IL-1beta, IL-6 and AngII were all significantly increased (P < 0.05) in the sodium-loaded rats. Sodium loading also markedly increased the number of cerebral aneurysms. Multivariate regression analysis showed that IL-6 was the most significant factor related to aneurysm formation. 4. Sodium loading increases death from stroke in SHRSP. The increased blood pressure, impaired BRS, inflammatory reaction and the formation of cerebral aneurysms may contribute to the development of stroke.

Blood flow of the submandibular gland in sodium-depleted and -loaded rats: effect of nitric oxide synthase inhibition.

The present investigations were designed to study the hemodynamic effects of different sodium diets in the submandibular gland of rats with or without nitric oxide (NO) synthesis inhibition. Experimental animals were kept on: (1) standard chow and tap water ad libitum (normal group, N), or (2) wheat and distilled water ad libitum for 4 weeks (sodium-depleted animals, SD), or (3) standard chow and saline ad libitum for 4 weeks (sodium-loaded animals, SL). NO synthase was inhibited by N omega-nitro-L-arginine-methyl-ester (L-NAME, 10 mg/kg per day) in the last week. The rats were anesthetized, and blood pressure, cardiac output (Stewart-Hamilton's principle) and blood flow (BF) of the submandibular gland (Sapirstein's technique) were determined. High sodium intake resulted in a 47% increase of glandular BF as compared to BF measured in the control group. In all groups L-NAME decreased BF (ml/min per 100 g gland) as compared to those of rats with no L-NAME treatment (N: 76.4 +/- 15.4 vs. 56.0 +/- 11.6, P < 0.05; SD: 71.0 +/- 17.7 vs. 56.2 +/- 15.1, n.s.; SL: 112 +/- 29.4 vs. 66.9 +/- 18.4, P < 0.001), whereas the vascular resistance (VR, mm Hg x ml-1 x s x kg-1) increased (N: 11.0 +/- 2.3 vs. 17.5 +/- 4.1, P < 0.001; SD: 11.0 +/- 2.7 vs. 17.0 +/- 4.2, P < 0.01; SL: 8.5 +/- 2.4 vs. 14.9 +/- 4.6, P < 0.001). The increase in VR after L-NAME treatment was 64% in normal, 55% in sodium-depleted and 75% in sodium-loaded rats. Our results suggest that NO takes part in the regulation of vascular resistance and BF in the submandibular gland. Sodium load itself increases BF of the submandibular gland and this phenomenon may partly be mediated by NO.

Bradykinin B2-receptor blockade facilitates deoxycorticosterone-salt hypertension.

The contribution of endogenous kinins to the regulation of blood pressure, urinary volume, and renal sodium excretion was evaluated in Wistar rats on high sodium intake by using the new bradykinin receptor antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Neither Hoe 140 (3 nmol/hr s.c. for 4 weeks) nor its vehicle altered systolic blood pressure (tail-cuff plethysmography) or renal function in rats given saline solution (0.15 mol/L NaCl) to drink ad libitum. Four-week administration of deoxycorticosterone (DOC), combined with high sodium intake and uninephrectomy, increased systolic blood pressure from 127 +/- 3 to 160 +/- 3 mm Hg (p < 0.01). When long-term infusion of Hoe 140 was combined with DOC, high sodium intake, and uninephrectomy, systolic blood pressure rose from 127 +/- 3 to 175 +/- 3 mm Hg (p < 0.01). The hypertensive effect was greater in the Hoe 140 group (48 +/- 4 versus 33 +/- 3 mm Hg in controls, p < 0.05). This difference was confirmed by direct measurement of mean blood pressure (Hoe 140 group, 154 +/- 4 mm Hg; vehicle group, 139 +/- 4 mm Hg; p < 0.05). The antagonist blunted the increase in urinary volume induced by salt load and DOC in uninephrectomized rats, whereas it did not alter the increase in urinary sodium excretion. These results suggest that endogenous kinins do not play a major role in the regulation of normal blood pressure in sodium-loaded rats, whereas they may attenuate the hypertensive effect induced by long-term administration of mineralocorticoids and salt in uninephrectomized rats.

Effect of antidiuretic hormone on lithium as a marker for proximal tubule delivery.

To determine whether acute changes in antidiuretic hormone (ADH) alter the ability of lithium to quantitatively reflect proximal delivery, fractional lithium excretion (CLi/CIn) and late proximal (TF/P)In determined by micropuncture were measured in sodium-loaded rats following administration of desamino-8-D-arginine vasopressin (dDAVP) at rates equivalent to approximately half-maximal (20 pg/min) and maximal (40 pg/min) plasma levels of endogenous hormone. dDAVP dissociated the linear correlation between CLi/CIn and 1/(TF/P)In (r = 0.05) usually observed in sodium-loaded rats. Proximal delivery determined by lithium clearance underestimated (P less than 0.001) values obtained by micropuncture. Amiloride restored the linear correlation between CLi/CIn and 1/(TF/P)In in sodium-loaded dDAVP-treated rats (r = 0.70) and quantitative estimates of proximal delivery by each technique became equivalent. Indomethacin also reduced (P less than 0.001) estimates of proximal delivery obtained by lithium techniques in sodium-loaded rats. Water loading in hydropenic rats restored concordance between estimates of proximal delivery obtained by lithium clearance and micropuncture methods. Thus changes in ADH markedly alter the ability of lithium to function as a quantitative marker for proximal delivery. Furthermore, ADH may increase lithium uptake at distal nephron sites by an amiloride-sensitive pathway.

Inhibitory roles of the hypothalamic atrial natriuretic polypeptide on the vasopressin release in the sodium-loaded rats

Implication of the brain atrial natriuretic polypeptide on the vasopressin release was investigated using rats fed with a high-sodium containing diet. Sodium loading increased not only the blood pressure but also the urinary output of vasopressin significantly. The plasma vasopressin concentration increased about 10 times after the intracerebroventricular injections of angiotensin II. Thereby, magnitude of the response was significantly smaller in the rat fed with a high sodium diet than in rats with the regular-diet. The hypothalamic content of both vasopressin and atrial natriuretic polypeptide was significantly larger in the high-salt group than the regular-salt. The intraventricular injections of atrial natriuretic polypeptide abolished the vasopressin release induced by the intraventricular injections of angiotensin II. These results indicate that the vasopressin production in the hypothalamus is increased, but the release is relatively suppressed in the sodium-loaded rats, and that increased hypothalamic atrial natriuretic polypeptide is involved in the suppression of the vasopressin release and in decreasing their sodium appetite to avoid the high sodium environment.

Modulation of brain angiotensin-converting enzyme by dietary sodium and chronic intravenous and intracerebroventricular fusion of angiotensin II.

Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics with the substrate Hip-His Leu, the inhibitors SQ 20,881 and SQ 14,225, and iun its Cl- activation profile. Modification of dietary NaCl intake was associated with marked changes in brain ACE activity. Sodium-loaded rats had lower activity of ACE in hypothalamus, striatum, and midbrain, and higher activity in spinal cord compared to controls. In sodium-restricted rats, ACE was elevated in pituitary and depressed in spinal cord. Chronic intravenous infusion of angiotensin (AII) was associated with a pattern of changes partly resembling sodium loading: ACE was depressed in hypothalamus and striatum but elevated in midbrain. After chronic intracerebroventricular infusion of AII, ACE was elevated in striatum and hippocampus, and depressed in spinal cord; a pattern of changes quite different from those associated with intravenous AII. These results show that ACE in several brain regions is sensitive to dietary sodium intake and support the hypothesis that angiotensin-containing neurons in these areas might be responsive to NaCl status of the animal. The observed changes in brain ACE do not seem to be explained in any simple manner by changes in circulating or central angiotensin II.

Partial Replacement of Sodium by Potassium in the Diet Restores Impaired Noradrenaline Inactivation and Lowers Blood Pressure in Stroke-Prone Spontaneously Hypertensive Rats

1. Partial replacement of sodium by potassium in the diet attenuates the rise in blood pressure in stroke-prone spontaneously hypertensive rats (SHR-SP). 2. The blood pressure-lowering effect of potassium cannot be ascribed to a reduction in intravascular volume. 3. The increased dietary intake of potassium leads to a reduced stimulation of the sympathoneuronal and sympathoadrenal system by cold compared with the response of sodium-loaded rats. 4. The impaired inactivation of noradrenaline observed in sodium-loaded SHR-SP is improved in SHR-SP on a potassium-substituted diet. 5. It is concluded that changes in dietary intake of sodium and potassium modulate sympathetic activity and the metabolism of noradrenaline, both of which are related to the development of hypertension in SHR-SP.

Altered PGE2 and PGF2 alpha production by glomeruli and papilla of sodium-depleted and sodium-loaded rats.

Prostaglandin (PG) E2 and F2 alpha synthesis by isolated glomeruli and papillary homogenates prepared from control, salt-loaded, and salt-depleted rats was measured in vitro with and without added arachidonic acid using specific radioimmunoassays. Glomeruli from salt-depleted rats synthesized less PGE2 and more PGF2 alpha than glomeruli from control rats under both conditions. The effect of sodium restriction could be attributed to stimulation of glomerular 9-keto-PGE2 reductase activity unrelated to a change in the concentration of this enzyme. High salt diet had no effect on PG synthesis by glomeruli. Papillary homogenates prepared from salt-loaded rats synthesized more PGE2 than those from control rats both with and without added arachidonic acid. This finding suggests an effect of high salt diet at a stage further than phospholipid deacylation. Low salt diet had no effect on PG synthesis by papillary homogenates. The physiological control of PG synthesis in response to changes in the NaCl content of the diet is, therefore, different for the glomeruli and the papilla.

Glomerular Endothelial Cells in Uranyl Nitrate-induced Acute Renal Failure in Rats

In uranyl nitrate (UN)-induced acute renal failure (ARF) glomerular ultrafiltration coefficient (K(f)) decreases because of unknown reasons. Since transport of water across the glomerular capillary wall occurs predominantly extracellularly through the endothelial fenestrae (EF), a reduction in the diameter and/or the density of EF can reduce the extracellular filtration area and the glomerular K(f). To examine this possibility, ARF was induced in rats by intravenous administration of UN in low (15 mg/kg) and high doses (25 mg/kg). Fenestral density ( x+/-SEM) per 5 cm(2) from the scanning electron micrographs (x30,000) was 107+/-10, 103+/-9, and 101+/-11 at 2, 7, and 17 h after the intravenous administration of bicarbonate saline to the control rats. In the low-dose UN group the EF density was 91+/-2, 52+/-8, and 45+/-11 at 2, 7, and 17 h after the injection, whereas for the high-dose group at corresponding time intervals the EF density was 95+/-3, 54+/-9, and 44+/-10. Fenestral diameters, in Angstrom units ( x+/-SEM), were 751+/-53, 765+/-43, and 764+/-37 at 2, 7, and 17 h after the injection of bicarbonate saline to control rats. At corresponding intervals after the administration of UN, the fenestral diameters were 501+/-61, 472+/-28, and 438+/-98 for the low-dose group and 525+/-43, 470+/-39, and 440+/-56 for the high-dose group. 2, 7, and 17 h after the injection of UN, fenestral area of the low-dose group decreased to 52.1, 30.1, and 24.6% of the controls, whereas in the high-dose group, the fenestral area declined to 54.3, 30.2, and 23.6% of the controls. Administration of UN (15 mg/kg) to sodium-loaded rats did not alter renal function or endothelial cell morphology. It is suggested that in UN-induced ARF the morphological alterations in endothelial cells reduce the K(f) of glomerular capillaries by reducing the filtration area.

Sodium-chloride-induced protection in nephrotoxic acute renal failure: Independence from renin

It has been shown that the severity of experimentally induced acute renal failure (ARF) is inversely related to dietary sodium chloride intake, and the effects have been attributed to the concurrent changes in renal renin. In the current study, renal renin of rats was increased by chronic sodium deprivation and decreased by chronic sodium loading and DOCA administration. In two nephrotoxic models (mercuric chloride, uranyl nitrate), giving previously sodium-deprived rats 1% sodium chloride to drink for 48 hours prior to ARF induction greatly attenuated the severity without any reduction in their high renal renin. Conversely, giving previously sodium-loaded rats tap water to drink for 4 to 5 days prior to AFR induction greatly enhanced the severity without any increase in their subnormal renal renin. Therefore, the changes in severity of ARF resulting from changes in dietary sodium are not mediated by changes in renal renin. Significant inverse correlations were found between mean peak BUN values during the follow-up period (5 to 7 days) and the 24-hour urinary sodium excretions prior to ARF induction in both models, suggesting that sodium intake and/or excretion at the time of induction is a good predictor of the severity. The effects of sodium chloride in both models were predominantly expressed during the maintenance phase, and consisted of attenuation of the severity (both models) and hastening of the recovery (mercuric chloride model). Possible mechanisms by which dietary sodium produced its effects, independently of its effects on the renin-angiotensin system, are discussed.

Renal action of adenosine: effect on renin secretion in the rat.

The present study was undertaken to further evaluate the interaction of adenosine and the renin angiotensin system. In 12 sodium-restricted (SR) Sprague-Dawley rats plasma renin activity in the arterial carotid (PRAa) and the renal venous (PRAv) blood was measured using a radioimmunoassay for angiotensin I (AI). Renin secretion rate (RS) was calculated from the arteriovenous difference of PRA and renal plasma flow obtained from the reading of an electromagnetic flowmeter and hematocrit. Adenosine infused into the thoracic aorta at a rate of 33 nmol/min·100g body weight, decreased RS from 250±29 ng AI/min in the control periods to 115±17 ng AI/min (P<0.001, n=9). After cessation of the adenosine infusion RS recovered incompletely to 167±21 ng/AI/min. Adenosine reduced glomerular filtration rate (GFR) by 56% (P<0.001) but renal blood flow (RBF) by only 20%. The effects of adenosine were also studied in a group of sodium loaded (SL) rats. In 6 non-laparotomized SL rats (PRAa=16±5 ng AI/ml·h) GFR was not significantly changed following adenosine infusion (1.54±0.16 vs 1.42±0.09 ml/min). In additional 7 SL rats (PRAa=39±4 ng AI/ml·h) in which RBF was measured with an electromagnetic flow probe, adenosine reduced GFR by 20% (P<0.01), whereas RBF increased from 13.7±1.2 to 16.5±2.2 ml/min (P<0.05). RS in SL rats was not affected by adenosine infusion (59±16 vs 62±26 ng AI/min). There was a close correlation between the adenosine induced decrease of GFR and PRAa (r=0.91, n=25) suggesting a higher sensitivity of the renal vasculature to adenosine when the renin-angiotensin system was stimulated. Micropuncture experiments in 9 Sprague-Dawley rats on a normal sodium diet demonstrated that adenosine infused in the low dose of 5 nmol/min·100 g of body weight markedly decreased the superficial nephron GFR from 38.6±2.65 to 20.5±1.67 nl/min (P<0.001) whereas whole kidney GFR was not changed significantly. This disproportionate response of superficial nephron compared to whole kidney GFR indicates that adenosine affects preferentially the superficial nephrons. It is concluded that adenosine depresses the renin secretion in SR rats. This depression was accompanied by a marked fall of the GFR. The renal response to adenosine was nearly abolished in SL rats suggesting that the renal action of adenosine is functionally related to the reninangiotensin system.

Decreased plasma renin activity and renin release in rats with phaeochromocytoma.

1. We have examined the response of renin to chronic low and high sodium chloride intake in rats with transplanted phaeochromocytoma. 2. Phaeochromocytoma suppressed the usual elevated plasma renin activity observed during sodium deprivation. 3. Studies in isolated perfused kidneys indicated that sodium-deprived phaeochromocytoma rats released substantially less renin than sodium-deprived control rats despite an almost identical renal renin content in both sets of animals. In addition, low perfusion pressure (50 mmHg) failed to stimulate renin release in kidneys from these phaeochromocytoma rats. 4. Additional experiments demonstrated that chronic sodium chloride loading suppressed plasma renin activity, renin content and renin release in both phaeochromocytoma and control rats. Both sodium-loaded phaeochromocytoma and sodium-loaded control rats were unresponsive to low perfusion pressure. 5. We conclude that noradrenaline-secreting phaeochromocytoma impairs the response of plasma renin activity in the rat by inhibiting renin release. We also conclude that chronic sodium chloride loading has a similar effect, but the mechanisms remain to be determined.

Stimulation of renin release in perfused kidney by low calcium and high magnesium.

These experiments were designed to test whether changing perfusate calcium or magnesium concentrations affected renin release in the isolated perfused rat kidney, and whether kidneys removed from sodium-loaded or sodium-deprived rats released the same amount of renin in response to identical stimuli. Kidneys were perfused with Kreb-Henseleit solution containing albumin. Renin release was inversely related to perfusate calcium concentration, whereas renin release was directly related to perfusate magnesium. Although a low calcium medium or low perfusion pressure (50 mmHg) stimulated renin release, the release was substantially greater in the sodium-deprived rats. Increasing the perfusate sodium concentration from 85 to 206 mM increased excretion, but did not alter renin release. It is concluded that a) low perfusate calcium and high magnesium concentrations stimulate renin release, b) kidneys removed from sodium-deprived rats released substantially more renin thatn those from sodium-loaded rats, and c) changing perfusate sodium concentration alters sodium excretion, but does not affect renin release.

Angiotensin II binding to renal glomeruli from sodium-loaded and sodium-depleted rats

125I-labeled angiotensin II (125I-labeled AII) and [3H]angiotensin II ([3H]AII) bind specifically to isolated rat glomeruli. Three groups of receptor sites could be defined by the KD value (7.1 +/- 0.3 X 10(-11, 3.4 +/- 0.2 X 10(-10), and 1.6 X 10(-9) M, respectively) and the number of receptor sites (11.6 +/- 1.2, 29.4 +/- 3.9, and 113.8 +/- 3.8 fmol/mg glomerular protein, respectively). Both association and dissociation constants for 125I-labeled AII were greater than those for [3H]AII, but their ratio (KD) remained unchanged. Specificity of binding to these three groups of receptor sites was demonstrated by the following: 1) inhibition of binding of labeled AII by unlabeled hormone or by antagonists; and 2) reversibility of binding, independent of either hormone or receptor degradation. Binding was increased in glomerular preparations from acutely and chronically sodium-loaded rats, compared with glomerular preparations from acutely and chronically sodium-depleted rats. This change in binding resulted from both a change in the number of receptor sites and modification of the affinity of AII for its receptors. KD was higher in preparations from sodium-depleted rats (12.9 +/- 3.3 and 14.6 +/- 3.9 X 10(-11) M in chronically and acutely depleted rats, respectively) than in those from sodium-loaded rats (2.7 +/- 0.2 and 3.9 +/- 1 X 10(-11) M in chronically and acutely sodium-loaded rats, respectively). Changes in the binding of AII to its glomerular receptors could play a role in the adaptation of glomerular filtration rate to the sodium balance.

Adenosine response of the rat kidney after saline loading, sodium restriction and hemorrhagia.

Experiments were performed on three groups of rats. The first group consisted of sodium loaded (SL) rats (high sodium diet, 10 meq Na/day, the second group consisted of sodium restricted (SR) rats (low sodium diet, 0.7 meq Na/day) and the third group consisted of hemorrhagic rats (HR), which were bled with 1-1,5% of the body weight. Blood pressure, glomerular filtration rate (GFR) and sodium excretion were measured. In some animals renal blood flow (RBF) was recorded with an electromagnetic flow meter. Adenosine was injected or infused into the thoracic aorta. Bolus injection of 10 nmoles adenosine resulted in a rapid and marked decrease of RBF (40%) in SR rats whereas in SL rats only a very small decrease of RBF (2%) was observed. Continuous infusion of adenosine (10(-7) moles/min) decreased GFR by 54% in SR rats and by 33% in HR rats, whereas GFR in SL rats did not change significantly. 5'-AMP decreased GFR in SR rats by 18% and in HR rats by 32%. Adenosine and 5'-AMP caused a slight fall in the systemic blood pressure, but this decrease could not account for the decrease of GFR. The sensitivity of kidney vasculature to adenosine parallelled high plasma renin activity (162 ng ang/ml-h in SR and 76 ng ang/ml-h in HR), elevated renal vascular resistance and low GFR. Simultaneous infusion of angiotensin (Hypertensin), 250 ng/min, in SL rats resulted in an increase of sensivity to adenosine infusion: GFR decreased by 21%. Our experiments demonstrated that a marked renal vasoconstriction caused by adenosine only occurs in rats in which renin-angiotensin system was stimulated.

Prior receptor occupancy as a determinant of the pressor activity of infused angiotensin II in the rat.

The pressor responsiveness to angiotensin II and norepinephrine was examined in rats before and during blockade of coverting enzyme activity with the nonapeptide SQ 20881. Responses to angiotensin II were impaired by sodium deprivation but enhanced by sodium loading or bilateral nephrectomy. During the period of converting enzyme blockade, a twofold increase in the angiotensin II pressor response was observed in the salt-restricted rats, whereas only a small change occurred in the salt-loaded rats. Infusion of the inhibitor produced a profound fall in the blood pressure of the salt-depleted rats with a relatively minor fall in the sodium-loaded rats. Norepinephrine pressor responses were slightly potentiated in the salt-restricted rats after administration of SQ 20881, but no change occurred in the salt-loaded or the nephrectomized rats. These observations support the view that the decreased angiotensin II pressor activity during salt deprivation is the result of a prior occupancy of receptor sites by endogenous hormone. Therefore, a change in the number or the affinity of receptors consequent to changes in sodium balance need not be postulated to explain the phenomenon.