Effect of an angiotensin II antagonist on autoregulation in the isolated dog kidney.

The effect of the specific angiotensin II antagonist (AIIA), [1-sarcosine-8-alanine]angiotensin II, on autoregulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in an isolated dog kidney was examined. Infusing the AIIA into the renal artery at 1.9 mug/min inhibited the renal vasoconstrictor action of angiotension II infused simultaneously at 1.15 mug/min. Under conditions of constant renal arterial pressure the AIIA had no significant effect on sodium excretion, GFR, RBF, cortical blood flow distribution (microsphere method), or renin secretion in non-renin-depleted kidneys. Similarly, no agonist properties were observed when the AIIA was infused into renin-depleted kidneys. This dose of the AIIA did not impair the capacity of the isolated kidney to regulate GFR or RBF when renal arterial pressure was increased from 100 to 150 mmHg. Efficiency of autoregulation of GFR and RBF was 77 and 82% of that predicted for perfect autoregulation. These values are not significantly different from those of the isolated kidney not infused with the antagonist. It is concluded that the angiotensin II antagonist, [1-sarcosine-8-alanine]angiotensin II, has no significant agonist properties, that it antagonizes the renal vascular effects of exogenously administered angiotensin II, but does not impair renal autoregulation. These data provide no support for the hypothesis that the renin-angiotensin system mediates the autoregulation of GFR and RBF.     

Hormonal modulation of glomerular function

Glomeruli contain receptors for many hormones. Binding of angiotensin II (ANG II) or antidiuretic hormone (ADH) to glomerular mesangial cells elicits a contractile response. Other hormones induce synthesis of cyclic nucleotides (cAMP, cGMP). Glomeruli also synthesize several prostaglandins, renin, and ANG II. Micropuncture studies in Munich-Wistar rats have examined the effects of vasoactive drugs and hormones on the filtration process. Several vasodilators increase renal plasma flow in the dog and rat, but GFR remains relatively unchanged due to an offsetting fall in the ultrafiltration coefficient (Kf). Vasoconstrictor substances such as ANG II and norepinephrine cause declines in renal plasma flow and Kf, but GFR remains constant due to an increase in the transcapillary hydraulic pressure gradient. Antidiuretic peptides and parathyroid hormone also reduce Kf. Glomerular mesangial cells may regulate Kf by contracting and reducing glomerular capillary surface area. ANG II and ADH directly stimulate mesangial cell contraction in vitro. Other hormones appear to cause contraction by inducing local ANG II synthesis. These hormonal pathways are implicated in the pathogenesis of altered glomerular function in diverse forms of renal injury.     

A case of living-related kidney transplantation in Bartter's syndrome

Bartter's syndrome is a renal tubular disorder characterized by hypokalemia, metabolic alkalosis, increased urinary excretion of potassium and prostaglandins, a relative vascular resistance to the pressor effects of exogenous angiotensin II, and hyperplasia of the juxtaglomerular apparatus. In most patients, the glomerular filtration rate is normal and chronic renal failure does not develop. We report here on a case of living-related kidney transplantation in Bartter's syndrome, in which a non-steroidal anti-inflammatory drug is suspected to be the cause of the end-stage renal disease.     

Effects of antidiuretic hormone on electrolyte reabsorption and secretion in distal tubules of rat kidney

The effects of (1-desamino-8-d-arginine) vasopressin (dDAVP) on water and electrolyte transport in the distal tubule were investigated by micropuncture. Since, in addition to antidiuretic hormone, parathyroid hormone, calcitonin and glucagon stimulate the adenylate-cyclase system in this nephron segment, experiments were performed on hormone-deprived rats, i.e. homozygous DI Brattleboro rats with reduced levels of endogenous parathyroid hormone, calcitonin and glucagon. Along the distal tubule, dDAVP enhanced water, Cl, Na and Ca reabsorption and sharply increased net K secretion. Phosphate transport was left unchanged and Mg reabsorption was not significantly altered by dDAVP between the early and late distal tubule. Antidiuretic hormone also slightly increased water filtration rate in the superficial nephron, which rose in proportion to whole kidney glomerular filtration rate. It is concluded that, in rats: 1) antidiuretic hormone stimulates water, NaCl and Ca absorption and enhances K secretion along the distal tubule and 2) the tubular effects of dDAVP on electrolyte transport in the loop and distal tubule are responsible for decreasing Mg and Ca urinary excretion.     

Sympathetic modulation of renal hemodynamics,renin release and sodium excretion

Summary In anesthetized animals it has been shown previously, that the influence of electrical stimulation of efferent renal nerves on renal function with increasing stimulation frequencies can be graded; renin release is affected at low, sodium excretion at intermediate and vascular resistance at high stimulation frequencies.Experiments in conscious dogs are reviewed, which present evidence for a similar functional dissociation under physiological conditions.Moderate activations of the renal sympathetic nerves, which do not change renal blood flow 1) decrease sodium excretion independent of changes in angiotensin II, 2) interact with the pressure-dependent mechanism of renin release by resetting its threshold pressure and 3) modulate autoregulation by increasing the lower limits of glomerular filtration rate and renal blood flow-autoregulation.These findings may contribute to our understanding of the role of the renal nerves in the pathophysiology of congestive heart failure and hypertension.     

Glomerular microcirculation: Implications for diabetes,preeclampsia, and kidney injury

This review outlines the features of tandem regulation of glomerular microcirculation by autoregulatory mechanisms and intraglomerular redistribution of blood flow. Multiple points of cooperation exist between autoregulatory and distributional mechanisms. Mutual interactions between myogenic and tubuloglomerular feedback (TGF) mechanisms regulating the inflow are briefly discussed. In addition to this, TGF operation involving purinergic, autocoid, and NO signaling affects, however, not only afferent arteriolar tone, but mesangial cell tone as well. The latter reversibly reconfigures the distribution of blood flow between the shorter and longer pathways in the glomerular tuft. I advance a hypothesis that blood flow in these pathways spontaneously alternates, and mesangial cell tonicity serves as a rheostatic shift between them. Furthermore, humoral messengers from macula densa cells, themselves dependent on myogenic mechanisms, fine-tune the secretion of renin and, subsequently, the local, intrarenal generation of angiotensin II, which, in turn, provides additional vasomotor signaling to glomerular capillaries through changing the tone of mesangial cells. This complex regulatory network may partially explain the phenomenon of renal functional reserve, as well as suggest implications for changes in renal function during pregnancy, early diabetes mellitus, and acute kidney injury.     

Role of potassium channels in the control of renin secretion from isolated perfused rat kidneys

This study aimed to assess the relevance of specific potassium channels, such as inwardly or outwardly rectifying and calcium-regulated potassium channels, to the control of renin secretion. For this purpose we examined the effects of the K+ channel blockers 4-aminopyridine (1 mmol/l), barium (100 micromol/l), tetraethylammonium (2 mmol/l) and apamin (200 nmol/l) on basal renin secretion, on renin secretion stimulated by isoproterenol (10 nmol/l) and on the inhibition of renin secretion by angiotensin II (100-300 pmol/l) in the isolated rat kidney perfused at constant pressure. Whilst all four K+ channel blockers increased renal vascular resistance, only 4-aminopyridine and barium attenuated isoproterenol-stimulated renin secretion in an additive fashion and augmented the inhibitory effect of angiotensin II. These effects of K+ channel blockers were not changed by the L-type calcium channel blocker amlodipine (5 pmol/l), indicating that their effects on renin secretion are not due to voltage-operated calcium influx. Our data, moreover, suggest that potassium efflux from renal juxtaglomerular cells is not important for the inhibitory action of angiotensin II on renin secretion. As a consequence it appears that the membrane potential of renal juxtaglomerular cells per se is relevant to renin secretion such that membrane depolarization inhibits the exocytosis of renin whilst hyperpolarization favors renin secretion. By their activity, potassium channels can contribute to membrane hyperpolarization and thus facilitate renin secretion.     

Effect of [Sar1, Ala8]angiotensin II on renal vascular resistance.

Partial occlusion of the renal artery (RAO) was induced in dogs anesthetized with pentobarbital or morphine chloralose-urethan. The effect of [Sar1, Ala8]angiotensin II (P-113) was compared before and during RAO on blood flow and vascular resistance of the contralateral kidney. An increase in renin secretion rate was obtained in the ischemic kidney, which was accompanied by an increase in renal vascular resistance (RVR) in the contralateral kidney and a rise in systemic blood pressure. P-113 given intra-arterially to the contralateral kidney consistently increased renal blood flow and decreased RVR during RAO, but did not alter RVR significantly before RAO. The elevation in renin secretion rate decreased between 30 and 122 min after the initiation of RAO in the pentobarbital-anesthetized dogs but not in the chloralose-urethan-anesthetized dogs. These experiments indicate that during RAO release of renin causes, through formation of angiotensin, an increase in RVR in the contralateral kidney and intra-arterial administration of P-113 restores the vascular resistance to a near-normal level.     

The separation of renal activity from lung and from the venous effluent from perfused lungs

1. Antidiuretic and salt-retaining activity has been separated from cat and ox lung, and from the venous effluent of blood-perfused cat lungs, by acetone extraction, gel filtration, partition and thin-layer chromatography.2. The chromatographic properties of the renally active substance from lung and from pulmonary venous blood are similar.3. The renal actions of these substances, demonstrable in vivo and in the isolated organ, are characterized by reduction in the excretion of water and Na. Renal blood flow, glomerular filtration rate and the urinary Na/K are not significantly affected.4. Concentrations of the lung substance which equate with angiotensin II-val(5)-amide in reduction of urinary Na in rats during water diuresis and under alcohol sedation do not raise the mean arterial pressure of the anaesthetized rat nor contract the superfused rat colon. At these dose levels angiotensin II is markedly vasopressor and contracts the superfused rat colon.     

Glucose modulation of spike activity independently from changes in slow waves of membrane potential in mouse B-cells

Humoral vasoactive substances coming from portal blood have been considered as a possible cause of renal dysfunction in cirrhotic patients. We have thus investigated the effect of perfusion of portal blood from anesthetized dogs on the isolated kidney functions. Both kidneys of a dog were simultaneously perfused on 2 Nizet's pump oxygenators, one kidney serving as control for the other. Renal blood flow was decreased in kidneys perfused with portal blood, as compared to the paired control kidneys perfused with sus-hepatic blood (group A experiments). Addition of polymyxin B to the portal blood restored the renal blood flow to the control level (group B experiments). No significant changes appeared between experimental and control kidneys for glomerular filtration rate, urine output, sodium and water excretion, renin activity, angiotensin II levels, plasmatic PGE₂ levels, in group A as well as in group B. We conclude that portal blood of dogs contains vasoactive substances reducing renal blood flow; their action is mediated neither by the renin-angiotensin system nor by changes in renal PGE₂ production. The complete abolition of this effect by Polymyxin suggests that these substances may be endotoxins.     

Renin stimulation by isoproterenol and theophylline in the isolated perfused kidney.

The intrarenal mechanisms of renin release were studied in the isolated perfused rabbit kidney during stimulation by isoproterenol, 0.01 mug/kg per min, and by theophylline, 0.87 mg/kg per min. In the absence of urinary flow during the early stages of perfusion, isoproterenol caused a 17% increase of renal vein serum renin concentration (RVSRC) (P less than 0.001) without changing renal blood flow, renal vascular resistance, or serum potassium. dl-Propranolol, 2.0 mg/kg per min. abolished this isoproterenol-induced renin release. A moderate reduction in perfusion pressure prior to the infusion of isoproterenol resulted in a marked additional stimulation of renin release. Studies during and following ureteral occlusion demonstrated that theophylline stimulates renin release by decreasing renal vascular resistance, whereas the concomitant increase in sodium transport to the macula densa exerted an opposite effect. dl-Propranolol did not affect theophylline-induced renin secretion. It is concluded that single exogenous stimuli may activate more than one intrarenal mechanism simultaneously. Isoproterenol has a direct renin-stimulatory effect on intrarenal beta-adrenergic receptors that may be reinforced by baroreceptor stimulation. Theophylline stimulates renin via a baroreceptor mechanism, with simultaneous renin suppression via a sodium-macula densa effect.     

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.     

Characterization of the renal phenotype in a mouse model of Marfan syndrome

The microfibrillar protein fibrillin-1 is expressed abundantly in the vasculature and the glomerulus of the kidney. Mutations in the fibrillin-1 gene lead to Marfan syndrome. The most common complication of this disease is aortic dilatation due to elastic deficiencies of the vascular wall. Several case reports describe glomerular disease in patients with Marfan syndrome, and fibrillin-1 has been implicated in nephrogenesis. To study the role of fibrillin-1 in renal development and function, we characterized the renal phenotype of fibrillin-1-underexpressing mice. Kidney histology was evaluated by means of morphometry and stereology. Relative kidney weights, daily urine excretion, urinary albumin excretion, serum and urinary creatinine, as well as serum urea were not different than wild-type mice. Glomerular number and renal capillarization were normal. The size of the renal filtration surface was comparable in wild-type and fibrillin-1-underexpressing mice. There was no indication for glomerular, renal vascular, or tubulointerstitial injury. However, glomerular volume and mesangial area were reduced. No changes in glomerular cell numbers were detected, but the cellular volume of mesangial cells was significantly lower in glomeruli of fibrillin-1-underexpressing mice. Thus, despite the high abundance of fibrillin-1 in glomeruli of wild-type animals, underexpression of fibrillin-1 did not lead to functional deficiencies of the glomerulus. Alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area likely due to a reduced mesangial cell volume.     

C-type natriuretic peptide does not affect plasma and urinary adrenomedullin in man.

To investigate whether C-type natriuretic peptide (CNP) at pathophysiological plasma levels stimulates the release of adrenomedullin (ADM) in man, six healthy subjects (three men and three women, mean age 35 +/- 3 years, range 33-40 years) received an intravenous infusion of synthetic human CNP-22 (2 pmol kg-1 min for 2 h), in a single-blind, placebo-controlled, random order, cross-over study, with measurements of the plasma levels of cyclic guanosine monophosphate (cGMP), ADM, renin and atrial natriuretic peptide (ANP), arterial pressure, heart rate, renal blood flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and the urinary excretion rates of cGMP, ADM and sodium. Infusion of CNP induced increases in its own levels (from 1.17 +/- 0.11 up to 21.13 +/- 1.41 pmol l-1) without modifying the plasma levels of cGMP, ADM, renin and ANP, the urinary excretion rate of ADM and cGMP, renal haemodynamics and sodium excretion. These data indicate that circulating CNP is not involved in the regulation of ADM release, renal haemodynamics and sodium excretion in man.     

Effects of renal lymphatic occlusion and venous constriction on renal function.

The effects of renal lymphatic occlusion or increased lymph flow due to renal vein constriction on renal function were investigated in rats. In each experiment, the renal lymphatics or vein of the left kidney were occluded or constricted and the right kidney served as a control. Occlusion of renal lymphatics caused renal enlargement, no change in glomerular filtration rate, a marked increase in urine flow and solute excretion without any change in urine osmolality, and enhanced urinary loss of urea, potassium, sodium and ammonium. Urea concentrations in medullary and papillary tissues were significantly elevated. Renal vein constriction caused renal enlargement and a marked drop in glomerular filtration rate, urine volume, urine osmolality and solute excretion. tissue concentrations of urea and potassium were decreased in the medulla and papilla and total tissue solute was significantly decreased in the papilla. The data indicate that in the rat, renal lymphatic occlusion traps urea in the medulla and induces a urea diuresis resulting in a large flow of normally concentrated urine. On the other hand, increased lymph flow secondary to renal vein constriction decreases medullary urea and potassium concentrations and papillary osmolality. These changes and the reduced glomerular filtration rate result in a small flow if dilute urine. Thus both renal lymphatic occlusion and enhanced lymph flow have a significant effect on renal function.     

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     

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.     

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.