Role of TRPV1 channels in renal haemodynamics and function in Dahl salt-sensitive hypertensive rats

This study tests the hypothesis that dysfunction of transient receptor potential vanilloid type 1 (TRPV1) channels occurs and contributes to the decrease in the glomerular filtration rate (GFR) and sodium/water excretion in Dahl salt-sensitive hypertensive rats. Recirculating Krebs-Henseleit buffer added with inulin was perfused at a constant flow in the isolated kidneys of Dahl salt-sensitive (DS) or Dahl salt-resistant (DR) rats fed a high-salt (HS) or low-salt (LS) diet for 3 weeks. Perfusion pressures (PP) were pre-adjusted to three levels ( approximately 100, approximately 150 or approximately 190 mmHg) with or without phenylephrine. Capsaicin, a selective TRPV1 agonist, in the presence or absence of capsazepine, a selective TRPV1 antagonist, was perfused. Basal GFR, urine flow rate (UFR) and Na(+) excretion (U(Na)V) were significantly lower in DS-HS than in DR-HS, DS-LS and DR-LS rats. Capsaicin caused pressure-dependent decreases in PP and increases in GFR, UFR and U(Na)V in all groups, with less magnitude of decreases in PP and increases in GFR, UFR and U(Na)V in DS-HS than in DR-HS, DS-LS and DR-LS rats. Capsazepine completely blocked the effect of capsaicin on PP, GFR, UFR and U(Na)V in all groups. Thus, these results show that TRPV1 function is impaired in the kidney of DS rats fed a high-salt diet, which may contribute to the decrease in GFR and renal excretory function in DS rats in the face of salt challenge.     

Effect of KCl infusion on renin secretory rates and aldosterone excretion in dogs.

The effects of unilateral intrarenal arterial KCl infusion in dogs (12 mueq/kg per min) on bilateral renal function, renin secretory rates, and aldosterone excretion were studied. During KCl infusion, infused-side renal arterial plasma [K+] increased by 2.2 +/- 0.6 meq/liter. Systemic plasma [K+] simultaneously rose by 0.6 +/- 0.1 meq/liter. Plasma renin activity decreased 29 +/- 9%, and the decrease correlated with the increases in plasma [K+]. Renin secretory rate decreased bilaterally, the decrease being greater in each experiment on the infused side. Aldosterone excretion increased during KCl infusion by 72 +/- 17%, despite a decrease in plasma renin activity. With KCl infusion there was a bilateral increase in K+ excretion, and a positive correlation was observed between the net alterations in K+ and Na+ excretion. No significant alterations in systemic blood pressure, glomerular filtration rate, total renal blood flow, or intracortical renal blood flow distribution were observed. These studies suggest that K+ inhibits the release of renin by an intrarenal mechanism, which may be related to a K+-induced alteration in Na+ absorption.     

Role of prostaglandin cyclooxygenase and cytochrome P450 pathways in the mechanism of natriuresis which follows hypertonic saline infusion in the rat

AIM: The prostaglandin cyclooxygenase (COX) and P450 cytochrome (CYP450) pathways of arachidonic acid metabolism are functionally interrelated and both engaged in control of sodium excretion; the study focused on their contribution to the natriuresis which follows hypertonic saline infusion in the rat. METHODS: In anaesthetized rats, clearance studies were conducted, supplemented with laser-Doppler measurements of the cortical and medullary blood flow (CBF, MBF), and measurement of medullary tissue admittance (Y), an index of interstitial ion concentration. RESULTS: Indomethacin (Indo), 5 mg kg(-1) i.v. paradoxically enhanced the natriuresis secondary to intra-aortic suprarenal 5% saline load, further increasing sodium excretion by 385 +/- 73% (P < 0.01). After acute clotrimazole, 10 mg kg(-1) i.v. an inhibitor of CYP450 epoxygenase, the increase in natriuresis was smaller and did not differ from that observed after the drug's ethanol solvent. In rats pre-treated with clotrimazole for 3 days, hypertonic saline loading increased sodium excretion (U(Na)V) to 0.94 +/- 0.22 micromol min(-1) , compared with a significantly greater (P < 0.05) increase to 2.76 +/- 0.48 micromol min(-1) measured in untreated controls. Indo increased U(Na)V twofold, similarly in the clotrimazole and in the control group; in the absence or presence of clotrimazole treatment, COX blockade significantly decreased MBF and increased Y. CONCLUSION: The data indicate that blockade of the CYP450 epoxygenase significantly impairs excretion of sodium in rats acutely loaded with hypertonic NaCl solution. The paradoxical post-Indo natriuresis is preserved in clotrimazole treated rats, which speaks against the role of CYP450 pathway in the response.     

The dopamine receptor antagonist haloperidol blocks natriuretic but not hypotensive effects of the atrial natriuretic factor

Studies were performed on anesthetized male Münich-Wistar rats to investigate the influence of the dopamine (DA) receptor antagonist haloperidol on the natriuretic response to infusion of a synthetic atrial natriuretic factor. The whole kidney glomerular filtration rate (GFR), urinary excretion of electrolytes, and arterial blood pressure (BP) were therefore measured in groups of animals pretreated with haloperidol or vehicle and given a continuous intravenous infusion of atrial natriuretic peptide (ANP; 28 amino acids). Forty-five minutes of ANP infusion at 10 micrograms h-1 kg-1 body wt did not increase GFR (change from 1.14 +/- 0.08 to 1.15 +/- 0.05 ml min-1 g-1 kidney wt). Sodium excretion (UNaV) increased more than four-fold from 0.037 +/- 0.008 to 0.165 +/- 0.070 mumol min-1 g-1 kidney wt (P less than 0.01). Potassium excretion (UKV) increased by 86% (P less than 0.001) and the urine flow rate (V) increased transiently by 63% (P less than 0.05) and did not differ from the control value during the last 15 min of ANP infusion. The urinary sodium concentration (UNa) increased almost three-fold, while BP decreased by 14%. There was no change in urine osmolality. In animals pretreated with haloperidol (1 mg kg-1 body wt), 45 min of ANP infusion did not significantly alter GFR (from 1.10 +/- 0.08 to 0.98 +/- 0.09 ml min-1 g-1 kidney wt). The UNaV did not increase significantly (change from 0.026 +/- 0.006 to 0.030 +/- 0.009 mumol min-1 g-1 kidney wt). The UKV was not elevated by ANP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of transcellular NaCl reabsorption in dog kidneys during hypercalcemia

Reduced concentrating and diluting capacity of the kidney in acute and chronic hypercalcemia may partly be due to inhibition of transcellular sodium reabsorption (RNa) in the thick ascending limb of Henle's loop. To examine this hypothesis, local heat production and RNa were measured during normo- and hypercalcemia at comparable glomerular filtration rate (GFR) in volume expanded, anesthetized dogs. Changes in proximal RNa which might occur during CaCl2 infusion, were minimized by infusing acetazolamide (75 mg/kg body wt iv). When ultrafiltrable calcium was increased from 1.12 +/- 0.09 to 2.95 +/- 0.10 mmol/l, cortical heat production was unchanged, whereas outer medullary heat production fell by 32 +/- 4%. RNa was reduced by 32 +/- 6%. Bicarbonate reabsorption did not change but calcium reabsorption and potassium excretion increased significantly. The potassium content of cortex and outer medulla increased during hypercalcemia, whereas ouabain, an inhibitor of Na+, K+-ATPase reduces the potassium content. We conclude that hypercalcemia does not inhibit transcellular RNa in the diluting segment by a direct effect on the Na+, K+-ATPase or the mitochondria, but by interfering with the coupled NaCl transport across the luminal cell membrane.     

The influence of Atriopeptins I and II on the relationship between glomerular filtration and natriuresis

The effects of two pure synthetic atrial natriuretic factors, Atriopeptin (AP) I and AP II, on the whole kidney glomerular filtration rate (GFR), sodium and potassium excretion (UNaV, UKV), urine flow rate (V) and arterial blood pressure (BP) were studied in adult male Sprague-Dawley rats. The variables were measured during a control period and during 70 min of continuous intravenous infusion of AP I or AP II at a rate of 10 micrograms h-1 kg-1 body wt. A time control group was studied in parallel to see whether the variables under study changed with time. The AP I infusion did not affect GFR (change from 1.34 +/- 0.10 to 1.24 +/- 0.04 ml min-1 g-1 kidney wt), but was clearly natriuretic (UNaV changed from 0.071 +/- 0.011 to 0.229 +/- 0.038 mumol min-1 g-1 kidney wt, P less than 0.01). The UKV increased from 0.504 +/- 0.073 to 1.138 +/- 0.121 mumol min-1 g-1 kidney wt, (P less than 0.001) and V from 1.88 +/- 0.10 to 2.94 +/- 0.15 microliter min-1 g-1 kidney wt, (P less than 0.001). Urine osmolality (Uosm) and BP were unaffected. During AP II infusion GFR remained unchanged but was slightly below the pre-infusion level during the last infusion period (1.05 +/- 0.07 as against 1.37 +/- 0.09 ml min-1 g-1 kidney wt, P less than 0.05). Despite this fact, UNaV was significantly elevated throughout the infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic portal vein infusion of glucose on sodium excretion in the rat.

Anesthetized rats were prepared with catheters in the hepatic portal (HPV) and femoral (FEM) veins and in the bladder or ureters. In some experiments the left kidney was denervated. HPV infusion of 1 M glucose at 2 ml/h for 20 min increased Na excretion by the kidney when given as a second infusion. Bilateral cervical vagotomy eliminated the increase in Na excretion during glucose infusion and uncovered a delayed decrease in Na and K excretion. Renal denervation attenuated the increase in Na excretion to HPV glucose. FEM infusion of glucose had variable effects, increasing Na excretion only after vagotomy. The results are interpreted to suggest that central and vagal receptors tend to enhance Na excretionwhereas splanchnic nerve afferents and humoral mediator(s) have the opposite effect.     

Chronic blockade of angiotensin II formation during sodium deprivation.

The present study was designed to investigate the mechanisms by which the renin-angiotensin system (RAS) regulates arterial pressure (AP) and renal function during chronic sodium deprivation. Intravenous infusion of the converting enzyme inhibitor SQ 14225 (14 microgram.kg-1.mm-1) for 8 days in 12 sodium-deficient dogs caused a marked decrease in AP from 90 +/- 1 to 67 +/- 2 mmHg and a reduction in glomerular filtration rate (GFR), filtration fraction (FF), and plasma aldosterone concentration (PAC). Despite the fall in AP and GFR, urinary Na excretion and effective renal plasma flow (ERPF) increased above control levels. In four dogs, infusion of aldosterone (200 micrograms/day) for 8 days during continuous SQ 14225 infusion restored PAC to levels above control, but did not significantly change AP or renal function from the values observed during SQ 14225 infusion alone. However, infusion of angiotensin II (AII) (10 or 20 ng.kg-1.min-1) for 5--8 days during continuous SQ 14225 infusion almost completely restored AP and renal function to control levels. These data indicate that the RAS plays a major role in regulating AP, renal hemodynamics, and Na excretion during Na deprivation, probably through the direct effects of AII rather than through changes in PAC.     

Renal hydrogen ion secretion after release of unilateral ureteral obstruction.

The effect of 24 h of unilateral ureteral obstruction on HCO3 reabsroption and urinary acidification was studied in dogs. The postobstructed kidney (EK) had a significantly lower glomerular filtration rate and renal plasma flow than the contralateral kidney (CK). Urinary pH prior to HCO3 loading was significantly higher in the EK as was maximal HCO3 reabsorption. Saline loading depressed HCO3 reabsorption to the same degree in both kidneys. Urinary PCO2, during HCO3 loading, and during phosphate infusion, was significantly lower in the EK than the CK. Fractional Na excretion was significantly higher in the EK than the CK after deoxycorticosterone acetate administration. Na2SO4 administration enhanced acid excretion only in the CK. K excretion was significantly lower in the EK than the CK both during HCO3 loading and Na2SO4 administration. There was redistribution of cortical blood flow from the outer cortex toward the inner cortex in the EK as compared to the CK. There was no difference in plasma renin activity from both renal veins. These data demonstrate enhanced proximal H+ secretion (which is abolished by volume expansion) and impaired distal H+ secretion by the postobstructed kidney. The distal defect is likely an effect of a generalized disorder of distal transport in that both K secretion and steroid-responsive Na reabsorption were impaired in the postobstructed kidney.     

Effects of atrial natriuretic peptide (ANP) during converting enzyme inhibition

Studies were performed on anesthetized adult Münich-Wistar rats to investigate the role of angiotensin II in the natriuretic response to synthetic atrial natriuretic peptide (ANP, 28 amino acids). For this purpose the whole kidney glomerular filtration rate (GFR) and urinary excretion of electrolytes were measured in groups of animals pretreated with the converting enzyme inhibitor captopril (3 mg h-1 kg-1 body wt) or vehicle and then given a continuous intravenous infusion of ANP at 10 micrograms h-1 kg-1 body wt. In the vehicle-pretreated animals, 45 min of ANP infusion did not change GFR (control value 1.17 +/- 0.11, experimental value 1.17 +/- 0.06 ml min-1 g-1 kidney wt). Sodium excretion (UNaV) increased more than three-fold from 0.036 +/- 0.010 to 0.134 +/- 0.058 mumol min-1 g-1 kidney wt (p less than 0.05) and potassium excretion (UKV) increased from 0.481 +/- 0.055 to 0.946 +/- 0.068 mumol min-1 g-1 kidney wt (P less than 0.05). Urine osmolality (UOsm) remained unchanged, while the blood pressure (BP) decreased by 15%. In animals pretreated with captopril, ANP infusion led to a decrease in GFR from 1.27 +/- 0.11 to 1.05 +/- 0.09 ml min-1 g-1 kidney wt (P less than 0.05). Despite this effect, UNaV increased more than two-fold from 0.076 +/- 0.020 to 0.193 +/- 0.087 mumol min-1 g-1 kidney wt (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Abnormal relationship between sodium excretion and hypertension in spontaneously hypertensive rats

Summary Inulin clearance, single nephron glomerular filtration rate (SNGFR), Na and K excretion were studied following an acute saline infusion in spontaneously hypertensive (Okamoto strain) rats (SH). 1. Hypertonic saline load: experiments were performed in adult and young SH rats. As compared to control normotensive Wistar rats (NT), the sodium excretion rose much less following the load in SH. During the 75 min following the beginning of the load, adult SH excreted 15% (NT: 58%) and young SH 9% (NT=38%) of the sodium load (P<0.01 in both cases). Cin were similar in SH and NT during control period, and a similar increase was observed following the load. The superficial to juxtamedullary SNGFR ratio was 0.80±0.05 in 5 non diuretic adult SH, a value not different from that found in normal rats, and 0.87±0.07 in 3 salt loaded SH, indicating that no significant intrarenal GFR redistribution occurs in SH following an acute hypertonic saline load. 2. Following an isotonic saline load, the results were not different: the percentage of the sodium load excreted was 44±5% and 10±2% in NT and SH adult rats respectively.The possibility that the observed defect in sodium excretion of SH rats involves distal tubular function is suggested by the pattern of evolution in Na and K excretion.This work was partially presented at the Symposium on Current problems of Hypertension, 1973, Mainz (Germany).Maître de Recherches INSERM.     

Renal vascular effects of frusemide in the rat: influence of salt loading and the role of angiotensin II

We showed recently that post-frusemide (furosemide) natriuresis was associated with a major depression of medullary circulation. In the present study, prior to administration of frusemide the tubular transport of NaCl was modified by loading the animals with 5% saline to elucidate a possible interrelation between the tubular and vascular effects of the drug. Moreover, a possible involvement of the renin-angiotensin system was examined by pharmacological blockade using captopril, an inhibitor of angiotensin converting enzyme (1 mg x kg(-1), I.V.), or losartan, a selective inhibitor of angiotensin AT1 receptor (10 mg x kg(-1), I.V.). The effects of frusemide (0.25 mg x kg(-1) I.V., then the same dose given over 1 h) on renal medullary and cortical circulation (using laser-Doppler flowmetry) and renal excretion of sodium (U(Na)V), water and total solutes were measured in anaesthetised rats. With no pre-treatment, frusemide decreased the medullary flow (36.6 +/- 6.0%) significantly more than the cortical flow (10.1 +/- 1.0%; P < 0.001). The difference between the medulla and cortex was not significant in rats which showed high U(Na)V after hypertonic saline loading (2.0 +/- 0.4 vs. 0.4 +/- 0.1 micromol x min(-1) in non-loaded rats): 21.1 +/- 3.9% and 15.8 +/- 1.5%, respectively. At very high U(Na)V (9.5 +/- 1.1 micromol x min(-1)) the post-frusemide decrease in blood flow tended to be smaller in the medulla (7.6 +/- 7.7%) than in the cortex (16.2 +/- 2.6%). The fall in medullary blood flow was attenuated by pre-treatment with captopril (22.0 +/- 3.3%) and abolished by pre-treatment with losartan (2.8 +/- 11.8%). The decrease in cortical blood flow was not changed by hypertonic saline or angiotensin II blockers. The abolition of the post-frusemide depression of medullary blood flow by previous salt loading confirms the proposed link between tubular transport status and vasoconstriction. A similar modification of the response by blockade of the renin-angiotensin system suggests that the system is involved in the mechanism of medullary vasoconstriction.     

The functional state of the isolated rabbit kidney perfused with autologous blood

This report describes the technique and procedure for perfusing an isolated rabbit kidney with 25 ml heparinized autologous blood in a closed circuit including a pump and an oxygenator. The duration of the operative ischaemia was 5-8 min; the perfusion lasted 2.5 hours. An additional infusion was made to compensate for urinary losses. Renal blood flow increased progressively from 2.01+/-0.1 to 2.65+/-0.22* ml/g kidney weight (kw) per min (*P<0.05). Between the first (P1) and the last (P4) urine collection period the glomerular filtration rate (GFR) fell from 288+/-25 to 217+/-38* microl/g kw per min, urine flow from 5.58+/-1.13 to 4.91+/-0.75 microl/g kw per min, Na+ excretion from 1.07+/-0.19 to 0.63+/-0.12* micromol/g kw per min, K+ excretion from 0.46+/-0.03 to 0.28+/-0.05* micromol/g kw per min, P excretion from 2.5+/-0.2 to 2.0+/-0.5 microg/g kw per min, Ca excretion from 0.4+/-0.1 to 0.12+/-0.05* microg/g kw per min, creatinine excretion from 6.94+/-0.32 to 5.68+/-0.54 microg/g kw per min, glucose excretion from 18.2+/-3.2 to 1.6+/-0.5* microg/g kw per min, the free water clearance (CH2O) from -6.57+/-0.85 to -5.10+/-1.31 microl/g kw per min and urine osmolality from 600+/-52 to 590+/-105 mOsm/kg, urea excretion from 0.75+/-0.16 to 0.95+/-0.13 micromol/g kw per min. Excretion of glucose, P or Ca was observed only above a given plasma threshold value, and no transport maximum was found for glucose or P. Ca reabsorption paralleled the Na reabsorption. The proximal tubule pressure, measured within the 1st h of perfusion, was 12.5+/-1.1 mm Hg. Histological examination at the end of the perfusion showed dilatation of the tubules as in the non-perfused kidneys, and the presence of numerous bacteria. Hypertonic urine (380-1110 mOsm/kg) was observed in the presence of vasopressin, in the latter's absence the urine was hypotonic urine (206-278 mOsm/kg). There was no correlation between renal plasma flow and the GFR. CH2O increased with increasing filtered Na+ load. In conclusion, the blood-perfused, isolated rabbit kidney has a fairly constant functional capacity for approximately 2 h.     

The effect of AVP-V receptor stimulation on local GFR in the rat kidney

AIM: Arginine vasopressin (AVP) might influence urinary concentration ability by altering the intrarenal distribution of glomerular filtration rate (GFR). METHODS: To study this possibility we have measured the intracortical distribution of GFR following acute AVP-V1 receptor stimulation in anaesthetized female Sprague-Dawley (SPD) rats during euvolemia and water diuresis by the aprotinin method, allowing two consecutive measurements of zonal GFR in the same kidney. RESULTS: Acute i.v. bolus injection of 50 ng V1 receptor agonist ([Phe2, Ile3, Orn8]-vasopressin) followed by a continuous infusion of 5 ng min(-1) in euvolemic rats reduced GFR by 25% in outer cortex (OC), 20% in middle cortex (MC) and 19% in inner cortex (IC) relative to vehicle infusion (all P < 0.05). In water diuretic rats V1 receptor agonist reduced GFR by 22% in OC, 10% in MC and 11% in IC relative to vehicle infusion (P < 0.05). GFR decreased slightly more in OC than in MC and IC in both euvolemic and water diuretic rats (P < 0.05) indicating a distribution of GFR towards MC and IC. Acute infusion of the selective non-peptide V1 receptor antagonist OPC-21268 in euvolemic rats reduced GFR by 14% in OC, 13% in MC and 11% in IC relative to vehicle infusion (P < 0.05), with no significant difference between the layers. CONCLUSIONS: The change in distribution of GFR not only between OC and IC, but also between OC and MC suggests that the afferent/efferent arterioles and not the medullary vasa recta is the main site of resistance change. We conclude that acute i.v. infusion of V1 receptor agonist in high doses reduces GFR more in superficial than in deep cortex in both euvolemic and water diuretic rats and that this may be of some importance for water conservation, adding to the V2- receptor effect on water permeability of the collecting ducts.     

Water and sodium excretion in unilaterally denervated normal and sodium depleted anesthetized rats before and after plasma volume repletion

The possible role of a reduction in plasma volume (PV) by surgery as well as the importance of dietary Na supply in denervation natriuresis have been investigated on Inactinanesthetized male rats subjected to acute unilateral renal sympathectomy. Four groups were studied: I. Normal Na diet (n=14); II. Low Na diet (boiled rice for 2 weeks)-isotonic glucose infusion (n=10); III. Low Na diet-isotonic saline infusion (n=5); IV. Normal and low Na diet rats served as conscious control (n=10). Surgery caused a 9–11% increase in hematocrit and a 15–18% decrease in PV in groups I–III. Plasma volume repletion (PVR) reverted these changes. In group I sodium excretion from both kidneys was only a fraction of that in conscious animals kept on the same diet (group IV) and marked denervation natriuresis was observed. After PVR sodium output of innervated (I) kidneys was not different from that of conscious rats but denervated (D) kidneys excreted twice that amount. In group II Na excretion was increased compared to conscious Na depleted controls, and PVR augmented further this difference. Surprisingly, the difference in urinary sodium excretion (U_NaV) between I and D kidneys was absent after surgery and was minimal after PVR in this group. In group III physiological saline infusion reverted the effect of Na depletion and denervation natriuresis was present both before and after PVR. It is concluded that PV reduction does not play a major role in denervation phenomenon. In Na depleted anesthetized rats denervation natriuresis is absent or minimal.     

Renal nerve blunts natriuretic and diuretic response to atrial natriuretic peptide in conscious rabbits

The contribution of the renal nerve to the natriuretic and diuretic responses to rat atrial natriuretic peptide (rAMP) was investigated in conscious rabbits with unilateral renal denervation. Renal nerve activity (RNA) was measured at the contralateral innervated kidney. Catheters were bilaterally implanted into the ureters. Urine samples were collected from each kidney by gravity drainage at 10-min clearance intervals. In rabbits with all baroreflexes intact, infusion of rANP at 0.3 micrograms/(kg.min) for 30 min decreased mean arterial pressure by 8 +/- 4 mmHg and increased RNA by 53 +/- 13%. After sinoaortic baroreceptor denervation (SAD), hypotensive response to infusion of rANP was greater than that in intact rabbits, while RNA did not change. After SAD plus vagotomy, infusion of rANP lowered mean arterial pressure by 21 +/- 4 mmHg and RNA by 19 +/- 6%. In the denervated kidney, infusion of rANP increased Na+ excretion by 16.1 +/- 4.5 from 3.5 +/- 1.0 muEq/min and water excretion by 0.17 +/- 0.05 from 0.08 +/- 0.02 ml/min. In the contralateral innervated kidney, infusion of rANP increased the amount of Na+ and water excretion by 4.5 +/- 3.2 muEq/min and 0.07 +/- 0.04 ml/min, which were significantly less than those in the denervated kidney. These results indicate that infusion of rANP increases RNA, due to baroreceptor reflexes, and that this increase in RNA blunts natriuretic and diuretic action of rANP.     

Redistribution of glomerular filtration and renal plasma flow in CNS-induced natriuresis

Infusion of hypertonic sodium chloride solution into the third cerebral ventricle results in a marked increase in renal sodium output, indicating an important regulator of extracellular volume homeostasis. The intrarenal events governing the enhanced excretion have not been thoroughly studied previously. In 12 anaesthetized male rats a stainless steel cannula was introduced stereotaxically into the right lateral cerebral ventricle. Urine volume and excretion rates, Na, K, and osmotically active particles were measured during control infusion of artificial cerebrospinal fluid and during stimulation of central mechanisms with I M NaCl (520 nl min-1). At the end of the stimulation period, regional renal plasma flow (86RbCl) and glomerular filtration rate (51Cr-EDTA) were measured with single injection techniques. A second group of 12 non-stimulated rats served as controls. During ICV stimulation, the urine flow rate increased from 1.8 +/- 0.19 to 6.4 +/- 1.01 microliter min-1 (P less than 0.001). The urinary concentrations of Na and K increased, leading to a rise in the excretion rates of these ions from 0.12 +/- 0.025 to 0.96 +/- 0.352 mumol min-1 (P less than 0.001) and 0.40 +/- 0.083 to 1.70 +/- 0.196 (P less than 0.001), respectively. The osmolar excretion rate was 2.9 +/- 0.35 mu Osm min-1 before stimulation and 9.6 +/- 1.09 higher (P less than 0.001) during stimulation. Simultaneously the inner medullary plasma flow rose two-fold from 0.7 +/- 0.06 to 1.4 +/- 0.12 microliter min-1 tissue (P less than 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal response to low and high phosphate intake in weanling, adolescent and adult rats

The renal response to low and high phosphate intake was studied in weanling, young and adult rats. Weanling rats were started on experimental diets containing 0.37%, 0.7%, or 1.7% phosphate at 24 days and adult rats at 60 days of age. After 21 days, clearance studies were done in anaesthetized animals. Urine was collected during basal conditions and following a phosphate infusion. Urinary excretion of calcium, phosphate and creatinine, and plasma levels of phosphate and creatinine were determined. Plasma phosphate was slightly higher in the younger rats in all dietary groups but was not influenced by phosphate intake in either age group. Urinary phosphate excretion and fractional phosphate excretion increased significantly in both age groups with increasing phosphate intake. After high phosphate intake, both net and fractional phosphate excretions were significantly higher in younger rats (0.97 +/- 0.08 and 0.24 +/- 0.06 mumol min-1 100 g-1, P less than 0.01, and 47.5 +/- 3.84 and 18.15 +/- 5.59%, P less than 0.01, respectively). The urinary excretion of calcium related to creatinine was higher in younger rats in all dietary groups with the highest value found after low phosphate intake. During an acute phosphate infusion, fractional phosphate excretion increased significantly in both age groups after normal phosphate intake but remained unchanged after low or high phosphate intake. Plasma phosphate increased significantly only in younger rats with high phosphate intake (2.9 +/- 0.18, 3.88 +/- 0.43, P less than 0.05). It is suggested that hypercalciuria reflects early stages of phosphate depletion and that in young rats stabilized on a high phosphate intake, phosphate retention may occur during an acute phosphate load.     

Local opiate withdrawal in locus coeruleus neurons in vitro

Noradrenergic neurons of the brain nucleus locus coeruleus (LC) become hyperactive during opiate withdrawal. It has been uncertain to what extent such hyperactivity reflects changes in intrinsic properties of these cells. The effects of withdrawal from chronic morphine on the activity of LC neurons were studied using intracellular recordings in rat brain slices. LC neurons in slices from chronically morphine-treated rats exhibited more than twice the frequency of spontaneous action potentials after naloxone compared with LC neurons from control rats. However, after naloxone treatment, the resting membrane potential (MP) of LC neurons from dependent rats was not significantly different from that in control rats. Neither resting MP nor spontaneous discharge rate (SDR) was altered by naloxone in LC neurons from control rats. Neither kynurenic acid nor a cocktail of glutamate and GABA antagonists (6-cyano-7-nitroquinoxalene-2,3-dione + 2-amino-5-phosphonopentanoic acid + bicuculline) blocked the hyperactivity of LC neurons precipitated by naloxone in slices from morphine-dependent rats. The effects of ouabain on MP and SDR were similar in LC neurons from control and morphine-dependent rats. These results indicate that an adaptive change in glutamatergic or GABAergic synaptic mechanisms or altered Na/K pump activity does not underlie the withdrawal-induced activation of LC neurons in vitro. Specific inhibitors of protein kinase A [Rp-cAMPS or N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H-89)] partially suppressed the withdrawal hyperactivity of LC neurons, and activators of cAMP (forskolin) or protein kinase A (Sp-cAMPS) increased the discharge rate of LC neurons from control rats. These results suggest that upregulation of cAMP-dependent protein kinase A during chronic morphine treatment is involved in the withdrawal-induced hyperactivity of LC neurons.