Maternal renal dysfunction in sheep is associated with salt insensitivity in female offspring

To examine the programming effects of maternal renal dysfunction (created by subtotal nephrectomy in ewes prior to mating; STNx), renal and cardiovascular function were studied in 6-month-old male and female offspring of STNx and control pregnancies. After studies were conducted on a low salt diet (LSD) some female offspring underwent salt loading (0.17 m NaCl in the drinking water for 5–7 days; HSD). On LSD both male and female offspring of STNx had similar mean arterial pressures (MAP), heart rates, cardiac outputs and renal function to those measured in offspring of control ewes. In female STNx offspring on a HSD, plasma sodium levels increased and haematocrits fell, indicating volume expansion ( P < 0.05). Plasma renin levels were not suppressed despite the increases in plasma sodium concentrations, but aldosterone levels were reduced. In control animals plasma renin levels fell ( P < 0.05) but there was no change in plasma aldosterone concentrations. There was a positive relationship between GFR and MAP which was present only in female STNx offspring. In conclusion, in STNx offspring there was an impaired ability to regulate glomerular filtration independent of arterial pressure, renin release was insensitive to a high salt intake and control of aldosterone secretion was abnormal. This study provides evidence of abnormal programming of the renin–angiotensin system and glomerular function in offspring of pregnancies in which there is impaired maternal renal function.     

Effects of bradykinin and papaverine on renal autoregulation and renin release in the anaesthetized dog

The present study on six anaesthetized dogs investigates the influences of two different vasodilators, bradykinin and papaverine, on the relationship between autoregulation of renal blood flow and glomerular filtration rate, sodium excretion and renin release. At control conditions renal blood flow and glomerular filtration rate was autoregulated to the same levels of renal arterial pressure, 55 ± 3 and 58 ± 3 mmHg, respectively. Renin release increased from 0.3±0.1 to 22±4 μg AI min^-1, and sodium excretion decreased from 99 +29 to 4.6 ± 3.3 μmol min^-1 when renal arterial pressure was reduced from 122±6 to 44±2 mmHg. Infusion of bradykinin (50 ng kg^-1 min^-1) increased renal blood flow by 50% at control blood pressure without changing glomerular filtration rate, and both renal blood flow and glomerular filtration rate autoregulated to the same pressure levels as during control. Sodium excretion increased threefold at control renal arterial pressure, but was unchanged at low renal arterial pressure. Bradykinin did not change renin release neither at control nor low renal arterial pressure. Papaverine infusion at a rate of 4 mg min^-1 increased renal blood flow 50% without changing glomerular filtration rate. The lower pressure limits of renal blood flow and glomerular filtration rate autoregulation were increased to 94±6 and 93±6 mmHg, respectively. Sodium excretion increased sixfold at control renal arterial pressure and was still as high as the initial control values at low renal arterial pressure (97±27 μmol min^-1) accompanied by only a small increase in renin release (1.4±0.3 to 6±2 μg AI min^-1). We conclude that bradykinin does not influence autoregulatory pressure limits of renal blood flow and glomerular filtration rate nor the accompanying increase in renin release during reductions in renal arterial pressure. Papaverine on the other hand maintains high sodium chloride delivery to macula densa at low renal arterial ressure, suppressing renin release and impairing autoregulation through effects on the tubulo-glomerular feedback mechanism.     

The Glomerular Filterability of Inulin and of Different Molecular Weight Preparations of Polyethylene Glycol in the Rabbit

Jorgensen , K. E., J. V. Møller and M. I. Sheikh . The glomerular filterability of inulin and of different molecular weight preparations of polyethylene glycol in the rabbit. Acta physiol. scand. 1972. 84. 408–414. It has been claimed on the basis of clearance experiments that inulin is incompletely filterable through the glomerular membrane of the rat kidney (Berglund 1964, 1965). In the present study the renal excretion in the rabbit of inulin and different preparations of polyethylene glycol has been compared during constant infusion of these substances. Identical clearance values were obtained for inulin and polyethylene glycol, having molecular weights of 1500 (PEG–1500) and 4000 (PEG–4000). The ratio of the clearances between polyethylene glycol of a molecular weight of 6000 (PEG–6000) and inulin was smaller than unity (0.89±0.03). Gel filtration analysis of plasma and urine samples indicated unrestricted filtration of inulin through the glomerular membrane of this species. Furthermore, gel filtration and ultrafiltration experiments indicated that the molecular size of inulin and PEG–1500 is similar, while the molecular dimensions of PEG–6000 exceed that of the most high molecular weight fractions of inulin. It is concluded that the clearance of inulin, PEG–1500, and PEG–4000 may be used as a measure of the glomerular filtration rate in the rabbit, whereas the glomerular filtration of PEG–6000 is restricted to some extent. The incomplete filterability of PEG–6000 is attributed to the relatively larger molecular size.     

Effect of somatostatin on kidney function and vasoactive hormone systems in healthy subjects

Summary The acute effects of i.v. somatostatin (250 mcg bolus followed by 250 mcg/h continuous infusion for two hours) on renal hemodynamics, renal electrolyte and water handling, and urinary excretion of catecholamines and prostaglandins, as well as on plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, dopamine, glucagon, and plasma renin activity were studied in seven normal subjects. Somatostatin decreased effective renal plasma flow and glomerular filtration rate, osmotic and free water clearances, urine volume, and sodium and potassium excretion, while urinary osmolality, fractional excretion of sodium, and phosphate excretion increased significantly. Plasma concentrations of arginine vasopressin, atrial natriuretic factor, norepinephrine, epinephrine, and dopamine remained unchanged, while plasma renin activity (3.0±0.25 vs 2.4±0.2 ng AngI/ml/h;p}<0.01) and glucagon levels (40±11 vs 20±16 pg/ml;p}<0.01) decreased. Urinary excretion of norepinephrine, epinephrine, dopamine, PGE₂, and PGF_2alpha was suppressed under somatostatin. A significant positive correlation was found between urinary dopamine and sodium excretion (r=0.7;p}<0.001) and urinary postaglandin E₂ and glomerular filtration (r=0.52;p}<0.01). Without accompanying changes in plasma osmolality and vasopressin concentration significant antidiuresis occurred, suggesting a direct tubular effect of somatostatin. However, the hormone-induced changes are due mainly to the decrease in renal plasma flow. The results demonstrate that somatostatin at supraphysiological doses exerts significant effects on the kidney.Abbreviations PAH paraaminohippuric acid - ANF atrial natriuretic factor - AVP arginine vasopressin - PRA plasma renin activity - ERPF effective renal plasma flow - GFR glomerular filtration rate - TRP tubular reabsorption of phosphate - NE norepinephrine - E epinephrine - DA dopamine - GH growth hormone     

Renal endothelin system and excretory function in Wistar-Kyoto and Long-Evans rats

Aim: The role of the kidney endothelin system in the renal regulation of fluid and electrolyte excretion was investigated in Wistar–Kyoto (WKY) and Long–Evans (LE) rats in which we found previously marked differences in the renal excretory responses to endothelin A receptor blockade. Methods: The selective endothelin A and B receptor antagonists BQ‐123 (16.4 nmol kg⁻¹ min⁻¹) and BQ‐788 (25 nmol kg⁻¹ min⁻¹) were infused i.v. for 50 min in conscious chronically instrumented WKY and LE rats and their renal function and renal endothelin system were studied. Results: Without effects on glomerular filtration rate or renal blood flow, BQ‐123 and BQ‐788 decreased by more than 50% (P < 0.01) both urine flow rate and electrolyte excretion in WKY rats but only urine flow rate (P < 0.05) in LE rats. Endothelin‐1 content, preproET‐1/GPDH mRNA ratio, B_max and K_d of total endothelin receptors in renal cortex did not differ between the two strains. In contrast, plasma endothelin‐1 concentration (0.58 ± 0.04 vs. 1.05 ± 0.01 femtomol mL⁻¹; P < 0.01), renal papillary ET‐1 concentration (68 ± 5 vs. 478 ± 62 fmol mg⁻¹ protein; P < 0.01) and preproET‐1/GPDH mRNA ratio (0.65 ± 0.09 vs. 0.88 ± 0.05; P < 0.05) as well as total endothelin receptor number in renal papilla (B_max 5.3 ± 0.4 vs. and 9.0 ± 1.2 pmol mg⁻¹ protein; P < 0.05) were markedly lower in LE than in WKY rats. In vitro studies showed that in both strains ET_B receptors on renal cortical membranes amounted between 65% and 67% and on papillary membranes between 85% and 88%. Conclusion: The present data show that the selective ET_A or ET_B receptor blockade differentially affects tubular water and salt handling, which becomes apparent in conditions of low renal papillary endothelin receptor number and tissue endothelin‐1 concentration.     

Effect on renin release of inhibiting renal nitric oxide synthesis in anaesthetized dogs

Nitric oxide plays an important role in the regulation of basal renal blood flow. This study was performed to examine whether selective inhibiti± of renal nitric oxide synthesis affects renin release in vivo. Accordingly, in six barbiturate-anaesthetized dogs renin release was examined before and after intrarenal infusion of the selective inhibitor of nitric oxide synthesis, N^G-nitro-l -arginine (NOARG). NOARG was infused into the renal artery to yield a renal arterial blood concentration of 0.4 μmol ml^-1. NOARG did not change systemic arterial blood pressure and glomerular filtration rate, but reduced basal renal blood flow by 26 ± 2%. Urine flow, sodium and potassium excretion were reduced after inhibition of renal nitric oxide synthesis. Basal renin release (3 ± 2 μg AI min^-1) was not altered by NOARG infusion (1 ± 1 μg AI min^-1). To stimulate renin release the renal artery was constricted to a renal perfusion pressure of 50 mmHg. At this perfusion pressure infusion of NOARG reduced renin release significantly from 48 ± 11 μg AI min^-1to 14 ± 4 μg AI min^-1. In conclusion, inhibition of renal nitric oxide synthesis reduces basal renal blood flow and reduces renin release stimulated by renal arterial constriction. These findings indicate that renal nitric oxide modulates both renal blood flow and renin release in vivo.     

Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating ability in mice

Aim: Hypertension is a common disease in the industrialized world and approximately 5% of all cases are secondary to kidney malfunction. We have recently shown that hydronephrosis due to partial unilateral ureteral obstruction (PUUO) causes salt‐sensitive hypertension in rats. The mechanisms are still unclear, but appear to be intrarenal and primarily located to the diseased kidney. In the present study, we have developed a model for PUUO to study if hydronephrotic mice develop salt‐sensitive hypertension. Methods: PUUO was created in 3‐week‐old mice (C57bl/6J). Blood pressure and heart rate were measured telemetrically in adult animals on normal and high salt diets. Metabolism cages were used to study the renal excretion of electrolytes and water. Plasma samples for renin analysis were collected and renal histological changes were evaluated. Results: All hydronephrotic animals developed salt‐sensitive hypertension that correlated to the degree of hydronephrosis. In hydronephrotic animals, blood pressure increased from 114 ± 1 mmHg on normal salt diet to 120 ± 2 mmHg on high salt diet, compared with 103 ± 1 to 104 ± 1 in controls. Hydronephrotic animals showed increased diuresis and reduced ability to regulate electrolyte concentration. No differences in plasma renin concentration were found between the groups. The parenchymal weight and glomerular area of contralateral kidneys were significantly increased in the hydronephrotic animals. Histopathology of the hydronephrotic kidneys displayed areas with fibrosis, inflammation and glomerular changes. Conclusion: This study provides a model for PUUO in mice and demonstrates the presence of salt‐sensitive hypertension and an impaired renal concentrating ability in mice which has not been described before.     

Upregulation of the brain renin-angiotensin system in rats with chronic renal failure

Aim: We investigated how the brain renin–angiotensin system is involved in regulation of the sympathetic activity and arterial pressure in rats with chronic renal failure. Methods: Systolic arterial pressure, heart rate and diurnal urinary noradrenaline excretion were measured for 12 weeks in spontaneously hypertensive rats (SHR) with or without subtotal nephrectomy. Expression of mRNAs related to the brain renin–angiotensin system was measured using polymerase chain reaction. Effects of a 6‐day intracerebroventricular infusion of a type 1 angiotensin II receptor antagonist (candesartan) or bilateral dorsal rhizotomy on these variables were also investigated. Results: Systolic arterial pressure and urinary excretion of noradrenaline were consistently higher in subtotally nephrectomized SHR than in sham‐operated SHR (262 ± 5 vs. 220 ± 3 mmHg, P < 0.001; 2.71 ± 0.22 vs. 1.69 ±0.19 ng g^?1 body weight day^?1, P < 0.001). Expression of renin, angiotensin‐converting enzyme and type 1 angiotensin II receptor mRNAs in the hypothalamus and lower brainstem was greater in subtotally nephrectomized SHR than in sham‐operated SHR. Continuous intracerebroventricular infusion of candesartan attenuated hypertension and the increase in urinary noradrenaline excretion in subtotally nephrectomized SHR. Dorsal rhizotomy decreased arterial pressure, urinary excretion of noradrenaline and expression of renin–angiotensin system‐related mRNAs in brains of subtotally nephrectomized SHR. Conclusion: The brain renin–angiotensin system in subtotally nephrectomized SHR appears to be activated via afferent nerves from the remnant kidney, resulting in sympathetic overactivity and hypertension in this chronic renal failure model.     

The role of antidiuretic hormone in cold-induced diuresis in the anaesthetized rat

The aim of this study was to investigate whether the increased diuresis in consequence of hypothermia is due to a depression of the hypothalamic release of antidiuretic hormone (ADH). The plasma concentration of antidiuretic hormone and the effect of intravenous (i.v.) administration of 65 ng kg^?1 desmopressin (selective V₂-receptor agonist) were determined in the anaesthetized rat. In spite of a 50% (P < 0.001) decrease in glomerular filtration rate, urine flow increased sixfold (P < 0.01) and urine sodium excretion increased sevenfold (P < 0.05), whereas urine osmolality decreased (P < 0.001). At the same time plasma antidiuretic hormone decreased from 7.5 ± 1.1 to 3.8 ± 0.4 pg mL^?1 (P = 0.01). After injection of desmopressin urine flow was completely restored, whereas urine osmolality and sodium excretion were only partially normalized. Since tubular conservation of water and fractional water reabsorption decreased during hypothermia, the diuresis must have resulted from an augmented loss of water. This is further supported by the fact that osmolal excretion was not influenced either by hypothermia or by desmopressin. It is concluded that the diuresis in consequence to hypothermia is due both to a decrease in the release of ADH and to a reduction of renal medullary hypertonicity.     

The effect of prostaglandin inhibition on renal function in the developing anesthetized lamb

The importance of prostaglandin (PG) compounds for renal function in the developing kidney was studied by comparing renal blood flow (RBF), glomerular filtration rate (GFR) and fractional sodium (Na) excretion in control lambs and lambs treated with a PG synthesis inhibitor, indomethacin. The lambs were 1–2 and 4–6 weeks old and they were studied either during hydropenia (HP) or volume expansion (VE). lndomethacin significantly decreased Na excretion in both groups of hydropenic lambs. lndomethacin also completely blunted the natriuretic response to VE in the older lambs but had no effect on Na excretion in the volume expanded younger lambs. It is concluded that partial lack of PG inhibiting action on tubular Na transport will contribute to the poor natriuretic response to VE in neonatal lambs. Since PG will act locally rather than being blood-borne messengers, the divergent PG action in younger and older lambs might be explained by local differences in maturation of PG metabolism as well as by local differences ir the maturation of PG sensitivity.     

Nitric oxide and the role of blood pressure variability to the kidney

Blood pressure variability is buffered by at least two mechanisms: the arterial baroreceptor reflex and nitric oxide (NO). Only recently is the importance of blood pressure variations on cardiovascular control being investigated. Here we report of a study performed in conscious dogs, in which renovascular hypertension was induced. Reduction of renal arterial pressure (RAP) to 85 mmHg for 24 h elicited profound hypertension by 60 mmHg (vs. control: 110 ± 3 mmHg; P < 0.01). This was accompanied by reduced volume and sodium excretion (–48% of control, P < 0.01 and –80% of control, P < 0.01, respectively) and augmented renin release by more than two‐fold (P < 0.01). This intervention was compared with a protocol in which RAP was reduced to the same mean value, however, RAP oscillated by ±10 mmHg at 0.1 Hz. This manoeuvre led to a transient increase in NO₃ excretion in urine (P < 0.01), blunted antidiuresis (–14% of control) as well as antinatriuresis (–40% of control) and attenuated the increased renin release by 30% (P < 0.05). In consequence, the magnitude of blood pressure increase was only half as high as that observed during static reduction of RAP (P < 0.01). It is concluded that blood pressure oscillations to the kidney have a profound influence on water and electrolyte balance and on renin release, which alleviates the onset of Goldblatt hypertension.     

Saline‐induced natriuresis and renal blood flow in conscious dogs: effects of sodium infusion rate and concentration

Aim: This study focused on static and dynamic changes in total renal blood flow (RBF) during volume expansion and tested whether a change in RBF characteristics is a necessary effector mechanism in saline‐induced natriuresis. Methods: The aortic flow subtraction technique was used to measure RBF continuously. Identical amounts of NaCl (2.4 mmol kg^?1) were given as slow isotonic (Iso, 120 min), slow hypertonic (Hyper, 120 min), and rapid isotonic loads (IsoRapid, 30 min). Results: During Iso and IsoRapid, arterial blood pressure increased slightly (6–7 mmHg), and during Hyper it remained unchanged. Iso and Hyper increased sodium excretion (4 ± 1 to 57 ± 27 and 10 ± 4 to 79 ± 28 μmol min^?1, respectively) and decreased plasma renin activity (by 38% and 29%), angiotensin II (by 56% and 58%) and aldosterone (by 47% and 65%), while RBF remained unchanged. IsoRapid caused a similar increase in sodium excretion (to 72 ± 19 μmol min^?1), a similar decrease in renin system activity, but a 15% elevation of RBF (282 ± 22 to 324 ± 35 mL min^?1). Selected frequency domain parameters of RBF autoregulation did not change in response to any load. Conclusions: In response to slow saline loading simulating daily sodium intake, the rate of sodium excretion may increase 10–20‐fold without any change in mean arterial blood pressure or in RBF. Regulatory responses to changes in total body NaCl levels appears, therefore, to be mediated primarily by neurohumoral mechanisms and may occur independent of changes in arterial pressure or RBF.     

The effect of isoprenaline infusion on renal renin and angiotensinogen gene expression in the anaesthetised rat

In this study, we investigated the ability of acute infusions of isoprenaline to alter renin and angiotensinogen gene expression in the kidney of rats anaesthetised with chloralose-urethane. Groups of rats received I.V. infusions of either saline or the beta-adrenoceptor agonist isoprenaline at 400 ng x kg(-1) x min(-1) for 4 h. The isoprenaline infusion caused a sustained decrease in mean blood pressure of approximately 20 mmHg (P < 0.01), an increase in heart rate of 50 beats x min(-1) (P < 0.01) and reductions in urine flow and sodium excretion of 80-90 % (both P < 0.01). Renal blood flow and glomerular filtration rate were transiently reduced by 21 % (P < 0.01) and 61 % (P < 0.001), respectively, in the first hour, recovering to baseline levels after 4 h of infusion. At the end of the study, plasma renin activity was raised approximately 6-fold (P < 0.01) while renal renin and angiotensinogen mRNA levels were 1.8- and 1.5-fold higher (both P < 0.05) compared to the control group (saline infusion). The isoprenaline-induced renin secretion could have been mediated via the activation of beta-adrenoceptors resulting in the exocytosis of renin-containing granules, with a smaller contribution being due to reduced renal haemodynamics. The increase in renal renin gene expression in response to isoprenaline was probably due primarily to the intracellular signalling processes acting directly on nuclear mechanisms. Similarly, the increased renal angiotensinogen gene expression most probably reflected a direct action of the isoprenaline. These findings provide evidence that catecholamines are involved in mechanisms that rapidly alter the expression of the genes of the renin-angiotensin system within the kidney.     

Indomethacin Blockade of Renal PGE-Synthesis: Effect on Total Renal and Tubular Function and Plasma Renin Concentration in Hydropenic Rats and on Their Response to Isotonic Saline

The effects of indomethacin (I), a blocker of prostaglandin (PG)-synthetase, was studied in rats in an attempt to elucidate the physiological role of renal PGE. Plasma-I-concentrations of 13–14 μg/ml reduced renal venous plasma PGE-concentration significantly from 216 to 85 pg/ml within 45 min. Urine flow and solute excretion decreased by 42% and 20%, respectively, while urine osmolality increased 450 mOsm. Inulin clearance (C_IN) and proximal reabsorption rate was unaffected, while renal plasma flow (RPF) decreased by 18%. Plasma renin concentration decreased slightly but significantly. An i.v. saline load equal to 1% b.wt. given to I-treated rats failed to elevate significantly either urine flow, solute excretion, C_IN, RPF or proximal reabsorption rate, but plasma renin decreased further. The normal inverse relationship between plasma renin and proximal reabsorption rate was absent. The data are consistent with the concept that intrarenal PGE plays a role in adjustment of renal vascular resistance, and support the concept of a physiological role of intrarenal PGE in regulating salt and water excretion. The data do not support any major physiological role of PGE in regulating proximal tubular function.     

Effect of Arterial Blood Pressure Reduction on Renal Hemodynamics in the Developing Lamb

Aperia , A. and P. Herin . Effect of arterial blood pressure reduction on renal hernodynamics in the developing lamb. Acta physiol. scand. 1976. 98. 387–394. The relationship between pressure and flow in the kidney has been examined in 2–9 and 31–48 day old lambs. Renal blood flow (RBF), determined by the microsphere technique, and glomerular filtration rate (GFR) were first studied under control conditions. The abdominal aorta was then constricted above the renal arteries until the pressure ranged between 60 and 70 mmHg, i.e. just below the normal auto-regulatory range, and the hemodynamic recordings were repeated. During control conditions the arterial pressure was lower in the younger (93 mmHg) than in the older lambs (107 mmHg). During aortic constriction total RBF and GFR were reduced. In both age groups GFR was reduced out of proportion to RBF. The sodium excretion fell around 60% in both age groups. The fall in perfusion pressure resulted in a more pronounced blood flow reduction to the outer than to the inner cortical glomerular capillaries. This pressure-induced blood flow redistribution was found in both age groups. The consequences of the pronounced effect of reducing the perfusion pressure to 60–65 mmHg for the young lambs with their basally low arterial blood pressure are discussed.     

Maternal hypoxia developmentally programs low podocyte endowment in male,but not female offspring

Fetal hypoxia is a common complication of pregnancy. We have previously reported that maternal hypoxia in late gestation in mice gives rise to male offspring with reduced nephron number, while females have normal nephron number. Male offspring later develop proteinuria and renal pathology, including glomerular pathology, whereas female offspring are unaffected. Given the central role of podocyte depletion in glomerular and renal pathology, we examined whether maternal hypoxia resulted in low podocyte endowment in offspring. Pregnant CD1 mice were allocated at embryonic day 14.5 to normoxic (21% oxygen) or hypoxic (12% oxygen) conditions. At postnatal day 21, kidneys from mice were immersion fixed, and one mid-hilar slice per kidney was immunostained with antibodies directed against p57 and synaptopodin for podocyte identification. Slices were cleared and imaged with a multiphoton microscope for podometric analysis. Male hypoxic offspring had significantly lower birth weight, nephron number, and podocyte endowment than normoxic male offspring (podocyte number; normoxic 62.86 ± 2.26 podocytes per glomerulus, hypoxic 53.38 ± 2.25; p < .01, mean ± SEM). In contrast, hypoxic female offspring had low birth weight but their nephron and podocyte endowment was the same as normoxic female offspring (podocyte number; normoxic 62.38 ± 1.86 podocytes per glomerulus, hypoxic 61.81 ± 1.80; p = .88). To the best of our knowledge, this is the first report of developmentally programmed low podocyte endowment. Given the well-known association between podocyte depletion in adulthood and glomerular pathology, we postulate that podocyte endowment may place offspring at risk of renal disease in adulthood, and explain the greater vulnerability of male offspring.     

Renal function after myocardial infarction and cardiac arrest in rats: role of ANP-induced albuminuria?

Renal function was measured by clearance technique before and after acute myocardial infarction (MI) induced by left coronary artery ligation in male Sprague–Dawley rats. The animals were anaesthetized with halothane-nitrous oxide, paralysed with pancuronium and artificially ventilated. All parameters were stable throughout the experiment in sham-operated time control animals (n = 8). After MI, rats developed left ventricular dysfunction with increased left ventricular end-diastolic pressure and decreased mean arterial pressure. MI produced antidiuresis and antinatriuresis without changes in glomerular filtration rate (GFR), lithium clearance or renal albumin excretion (n = 8). The antidiuretic and antinatriuretic responses to MI were similar in rats with chronic bilateral renal denervation (n = 5). Three additional rats with chronic bilateral renal denervation had cardiac arrest and were resuscitated with cardiac massage, i.v. lidocaine and intracardiac adrenaline administration. These animals showed a transient increase in urine flow rate, sodium and albumin excretion with maximum 30–60 min after resuscitation, while GFR and lithium clearance were normal. Since cardiac ischaemia and sympathetic stimulation are strong stimuli for the release of atrial natriuretic peptide (ANP), we examined if ANP (0.25, 0.50, and 1.00 μg kg^?1 min^?1, n = 8 per dose) affects urinary albumin excretion. ANP increased dose-dependently the urine/plasma concentration ratio of albumin relative to inulin, which suggests that ANP increases the glomerular permeability for albumin. We conclude that MI causes stimulation of renal tubular sodium and water reabsorption by a mechanism which is independent of intact renal innervation. MI does not produce any change in renal albumin excretion in rats, but transient albuminuria may be observed in rats following cardiac arrest and/or manoeuvres used in cardiac resuscitation. Since ANP produces albuminuria, we speculate that ANP may be an important mediator of albuminuria in states with elevated plasma concentrations of ANP.     

Impaired glomerular permselectivity for albumin in chemically medullectomized WKY rats

Chemical renal medullectomy with 2-bromo-ethylamine hydrobromide (BEA) has been used to study the importance of the renal medulla in blood pressure regulation. However, conclusive evidence as to whether BEA treatment affects the glomerular barrier is lacking. In the present study, the effects of BEA upon glomerular permselectivity for albumin were studied using isolated kidneys (IPK) perfused at a low temperature (8 °C) to inhibit tubular reabsorption of proteins. Sixteen WKY rats (W_B) received an i.v. injection of BEA (150 mg kg^-1) while 10 rats served as controls (W_C). Volume balance, urinary osmolality and creatinine clearance (GFR) were measured in metabolic cages. Acute paired experiments (n=9) were performed 5–7 weeks after BEA. The rats were anaesthetized and the total in vivo albumin excretion was recorded. The kidneys were then isolated and perfused for measurements of inulin clearance (GFR) and fractional albumin clearance without tubular reabsorption of protein. The nine BEA treated rats showed polyuria and hypoosmotic urine. In vivo GFR was lower in the BEA treated groups when measured with creatinine clearance (459±22 vs. 213±41 μL min^-1 100 g^-1 body wt, P<0.001), while GFR was not significantly changed in the IPK (W_C=135±27, W_B=92±14 μL min^-1 100 g^-1 body wt, n.s.) when perfused at identical pressures. The fractional albumin clearance was increased three times in the BEA group (W_B=9.6±3.4J, P<0.05). Moreover, albumin excretion in vivo was similar in the two groups despite low GFR in the BEA group. We conclude that BEA treatment affects glomerular permselectivity for albumin.     

The effects of ureteral occlusion and renal venous constriction on kidney kallikrein-kinin and prostaglandin systems in dogs

Olsen , U. B. The effects of ureteral occlusion and venal cenous constriction on kidney kallikrein-kinin and prostaglandin systems in dogs. Acta physiol. scand. 1978. 104. 443–452. The intrarenal pressure was raised to 40–50 mmHg by ureteral occlusion or by renal venous constriction in anesthetized dogs loaded with 10% mannitol in saline and with a urine flow of approximately I ml/min/ kidney. Both manoeuvres produced vasodilation and decreased urine creatinine excretion (GFR). Ureteral occlusion was associated with a marked antinatriuresis, which contrasted the variable decrements in sodium excretion during renal venous constriction. Ureteral occlusion did not affect urine excretion of kallikrein or kinins, whilst renal venous constriction decreased urinary kallikrein excretion, yet markedly increased urinary kinin excretion. Ureteral occlusion and renal venous constriction comparably increased urine prostaglandin (E-like) excretion by a presumably pressure dependent mechanism. Inhibition of prostaglandin synthesis by indomethacin abolished the vasodilation during renal venous constriction and this was accompanied by marked reductions of urinary creatinine (GFR) and kallikrein excretions. whilst the kinin excretion was enhanced as observed before the administration of indomethacin.     

An isolated perfused rat kidney preparation designed for assessment of glomerular permeability characteristics

The aim of the present investigation was to modify the widely used isolated perfused rat kidney preparation to make it more suitable for studies of glomerular permeability to macromolecules. Both kidneys were perfused in situ using separate pumps in two of each other independent systems with Tyrode-solution containing human serum albumin (18.2 g 1^-1). Sodium nitroprusside was administered to induce dilatation and to maintain constant vascular resistance (PRU₁₀₀) during the experiments. The addition of sodium nitroprusside decreased vascular resistance from 0.17 ± 0.05 to 0.09 ± 0.02 mmHg min^-l 100 g^-1 ml^-1 and increased urine flow and glomerular filtration rate. The temperature of the perfusate was reduced from 37°C to 8°C to inhibit tubular reabsorption of protein and fluid, resulting in a urine to plasma concentration ratio of [⁵¹Cr]EDTA of 1.26 ± 0.07. Furosemide reduced the urine to plasma concentration ratio for [⁵¹Cr]EDTA further to 1.15 ± 0.02 and increased glomerular filtration rate. Moreover, by performing the studies at low temperatures (8°C) in the presence of sodium nitroprusside and furosemide it was possible to achieve low and stable albumin fractional clearance values close to those prevailing in vivo. Thus, the described technique, allowing simultaneous perfusions of both kidneys with different solutions, pressures and flows, seem to be well suited for studies of macromolecular transport across glomerular capillaries.