Failure of changes in intracapillary pressures to alter proximal fluid reabsorption

To determine the role that peritubular capillary oncotic and hydraulic pressures play in regulating urinary sodium excretion in the euvolemic state, experiments were carried out in rats under conditions which altered these pressures without volume expanding the animal. In cross-circulation experiments, the donor rat was expanded with plasma or Ringer's solution while the recipient rat remained euvolemic. Micropuncture measurements in the euvolemic recipients demonstrated significant increases in efferent plasma flow rate (QEA), capillary hydraulic pressure (Pc), and decreases in mean capillary oncotic pressure (pi c). There were no changes in nephron GFR (SNGFR), absolute proximal reabsorption (APR), or UNaV. In additional studies, peritubular oncotic pressure was lowered markedly by plasmapheresis of the experimental animal. Large decreases in pi c were produced without any change occurring in SNGFR, APR, or UNaV. Measurements of interstitial hydraulic pressure (Pi) with a subcapsular pressure pipet revealed that Pi was unaltered under all of these conditions but rose markedly in rats undergoing a saline-expansion diuresis. Our findings indicate that APR and UNaV can remain constant despite large changes in pi c, Pc, and QEA in nonexpanded animals. Furthermore, the changes in pi c, Pc, and QEA induced in the euvolemic non-diuretic rats were the same as those in the saline-expanded diuretic rats. We conclude that under euvolemic experimental conditions, urinary sodium excretion and APR do not correlate with intracapillary pressures or flow rates in the renal cortex. The only difference found between the nondiuretic and diuretic rats was a rise in Pi in the latter group.     

RENAL ACTIONS OF ENDOTHELIN-1 UNDER ENDOTHELIN RECEPTOR BLOCKADE BY BE-18257B

Purpose

Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors. The present study examined the renal actions of ET-1 after ET-A receptors were blocked by BE-18257B to unmask the functions of ET-B receptors.

Materials and Methods

Renal hemodynamics and clearance measurements were obtained in anesthetized dogs after intrarenal infusion of BE-18257B at 100 ng./kg./min. (Group 1), after intrarenal infusion of ET-1 at 2 ng./kg./min. (Group 2), or after intrarenal infusion of ET-1 superimposed on BE-18257B (Group 3).

Results

In Group 1, BE-18257B infusion did not alter arterial pressure, renal blood flow (RBF), GFR or tubular function. In Group 2, ET-1 infusion led to a significant decrease in RBF and GFR (37 and 40%, respectively) without altering arterial pressure. Urinary volume and sodium excretion were not changed but osmolality decreased significantly. In Group 3, BE-18257B infusion significantly attenuated the decrease in RBF caused by ET-1 and increased GFR by 40% without altering arterial pressure, associated with significant diuresis and natriuresis.

Conclusion

Renal vasoconstriction caused by ET-1 is attenuated by ET-A receptor blockade with BE-18257B, which unmasks the hemodynamic and tubular actions of ET-B receptors. As a result, it limits the ET-1 induced decrease in RBF and raises GFR, and leads to a diuresis and natriuresis.     

The medullary microcirculation

Like other regional circulations, the medullary circulation supplies oxygen and other primary substrates to the medulla and removes carbon dioxide and other waste metabolites. It also acts as a countercurrent exchanger and simultaneously removes water reabsorbed from the renal tubule to preserve mass balance. Our present understanding of how the medulla serves both these functions at the same time is illustrated in Figure 3. Blood leaves the efferent arteriole with an elevated plasma protein concentration as a consequence of glomerular filtration, and flows down descending vasa recta within a vascular bundle. The increased interstitial osmotic-concentration coupled with a finite capillary reflection coefficient for small solutes causes additional water to be extracted so that at the termination of descending vasa recta, the plasma protein concentration exceeds that in the systemic circulation by approximately twofold. Solute, urea more than sodium chloride, also enters descending vasa recta. As blood flows through the interconnecting capillary plexus and up ascending vasa recta, transcapillary oncotic and osmotic pressure differences combine to cause capillary uptake of fluid. There is also simultaneous loss of urea such that the medullary trapping of urea is very effective. Countercurrent exchange of sodium chloride, however, appears to be less efficient and as a consequence, not only water but sodium chloride is removed from the medulla. Antidiuretic hormone reduces medullary blood flow, both directly by its vasoconstrictor (V1-receptor mediated) effect and indirectly by its antidiuretic (V2-receptor mediated) effects. Prostaglandins are able to enhance medullary blood flow by counteracting vasoconstrictive influences.(ABSTRACT TRUNCATED AT 250 WORDS)     

ANP inhibits Na(+)-H+ antiport in proximal tubular brush border membrane: role of dopamine

Infusion of ANP to rats results in an inhibition of Na(+)-H+ antiport and Na(+)-Pi symport in brush border membrane vesicles (BBMV) prepared from kidneys of these animals (J Clin Invest 75:1983). iIn the present study we investigated the intrarenal mechanism by which infused ANP elicits these changes in proximal tubular transport systems. As in rats, infusion of ANP to rabbits resulted in a diuresis, natriuresis, and increase in GFR; however, unlike in rats, the fractional excretion of phosphate (Pi) was not changed. In BBMV prepared from cortices of ANP-infused rabbits, the rate of Na(+)-H+ antiport was decreased (delta -27%), but Na+ gradient-dependent uptakes of Pi and L-proline were not different from controls. Incubation of rabbit cortical tubule suspension in vitro with ANP 10(-7) M alone had no inhibitory effect on Na(+)-H+ antiport in BBMV prepared from these tubules, whereas incubation with other hormonal agents, 1 U/ml PTH (delta 61%) or with dopamine (DA) 10(-4) M (delta -34%), did inhibit the rate of Na(+)-H+ antiport in BBMV from the same pool of tubules. However, when tubules were incubated in the presence of (10(-5) M) DA, the addition of 10(-7) M ANP did cause a significant (delta -21%) decrease in Na(+)-H+ antiport activity in BBMV. In contrast, ANP did not show similar inhibitory effect in the presence of submaximal inhibitory doses of PTH. To explore whether ANP may act on proximal tubules in vivo indirectly, via mediation of DA, we evaluated the effect of ANP on some parameters of catecholamine system in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal responses to atrial natriuretic peptide are preserved in bilateral ureteral obstruction and augmented by neutral endopeptidase inhibition

PURPOSE: Atrial natriuretic peptide (ANP) contributes to post-obstructive diuresis in bilateral ureteral obstruction (BUO). In this study we examined the activity of neutral endopeptidase (NEP), an enzyme responsible for degradation of ANP, in the kidney in rats subjected to BUO for 24 hours. MATERIALS AND METHODS: Renal function was examined by the clearance method in sham operated rats and BUO rats after obstruction release. Renal responses to an intravenous bolus injection of ANP (5 microg/kg) were studied in sham operated and BUO rats with or without pretreatment with intravenous phosphoramidon (100 microg/kg per minute), a NEP inhibitor. RESULTS: In BUO rats natriuresis and diuresis occurred despite a marked decrease in the glomerular filtration rate (GFR). ANP administration increased GFR and induced marked natriuresis and diuresis in sham operated and BUO rats. Inhibition of ANP degradation by phosphoramidon induced natriuresis and diuresis, and accentuated these renal responses to ANP. CONCLUSIONS: Renal responses to ANP and renal NEP activity were preserved in 24-hour BUO. NEP inhibition to attenuate ANP degradation augmented responses to ANP in increasing GFR, natriuresis and diuresis. These findings provide the theoretical potential for facilitating the recovery of GFR after BUO release by inhibiting ANP degradation by pharmacological means.     

A role for atrial natriuretic peptide in endothelin-induced natriuresis.

Systemic administration of low-dose endothelin increases urinary sodium excretion rate despite mild to moderate reductions in renal plasma flow and glomerular filtration rates. The role of atrial natriuretic peptide in endothelin-induced natriuresis was investigated. Administration of 2.50 pmol/min of endothelin to euvolemic rats resulted in increases in plasma atrial natriuretic peptide levels from 127 +/- 18 to 169 +/- 23 pg/mL. However, a lower dose of endothelin (0.63 pmol/min) or saline did not increase plasma levels of atrial natriuretic peptide. Mean arterial pressure was unchanged at the lower dose of endothelin and increased only slightly in rats receiving 2.5 pmol/min. To assess functional significance, renal responses to endothelin (2.5 pmol/min) in the absence and presence of a specific anti-rat atrial natriuretic peptide antibody were compared. Equivalent reductions in renal blood flow were observed. Urinary sodium excretion rates increased significantly in non-ANP-antibody-treated rats by 33 +/- 7 and 82 +/- 20% at 10 and 30 min, respectively. Atrial natriuretic peptide antibody blunted markedly endothelin-induced natriuresis: urinary sodium excretion rates changed insignificantly by 18 +/- 10 and 30 +/- 14%, respectively. Thus, endothelin infusion results in increases in plasma atrial natriuretic peptide levels, which may contribute to endothelin-induced natriuresis, providing evidence for potentially significant interactions between these peptide hormones in the regulation of sodium balance and renal vascular tone.     

Volume Expansion Enhances the Recovery of Renal Function and Prolongs the Diuresis and Natriuresis After Release of Bilateral Ureteral Obstruction: A Possible Role for Atrial Natriuretic Peptide

Plasma atrial natriuretic peptide (ANP) levels are elevated in patients with bilateral ureteral obstruction (BUO). To further evaluate the role of ANP in postobstructive diuresis, natriuresis and recovery of renal function, 3 groups of dogs were studied: Group 1, 6 dogs that underwent 48 hours of unilateral ureteral obstruction (UUO); Group 2, 6 dogs that underwent 48 hours of BUO; and Group 3, 6 dogs volume replete with normal saline during 48 hours of BUO. All 3 groups underwent hourly hemodynamic and clearance studies for 15 hours after the release of obstruction. Group 1 experienced no increase in either urine output or sodium excretion from the ipsilateral or contralateral kidney after release of obstruction. Groups 2 and 3 both experienced an initial diuresis and natriuresis after BUO (p less than 0.01). However, in Group 2 diuresis and natriuresis after BUO ceased at 5 and 2 hours, respectively, while in Group 3 both persisted for 10 and 9 hours, respectively. Before obstruction the GFR was similar in all three groups. In Group 1 the GFR decreased significantly in the ipsilateral kidney (34.5 plus/minus 1.4 to 14.48 plus/minus 1.5 ml. per minute, (p less than 0.01)) and increased significantly in the contralateral kidney (32.4 plus/minus 2.8 to 44.4 plus/minus 2.0 ml. per minute, (p less than 0.05)) and remained so throughout the postobstruction period. The GFR in Groups 2 and 3 decreased to a similar level 1 hour after release (13.3 plus/minus 1.7 and 17.5 plus/minus 3.4 ml. per minute, respectively); however, Group 2 remained decreased during the period after release while group 3 increased to 23.4 plus/minus 3.4 ml. per minute (p less than 0.01) at 11 hours after release of obstruction. In Group 2 the control plasma ANP level was 17.9 plus/minus 3.7 pg./ml. and was not altered by BUO, whereas ANP increased significantly after 48 hour BUO in Group 3, from 30.6 plus/minus 6.7 to 63.7 plus/minus 11.7 pg./ml. (p less than 0.01). Before and after 48 hours of BUO, the pulmonary capillary wedge pressure was 5.0 plus/minus 2.0 mm. Hg and 7.0 plus/minus 1.0 mm. Hg (NS) in Group 2, while it increased from 7.18 plus/minus 1.5 mm. Hg to 11.6 plus/minus 1.9 mm. Hg (p less than 0.01) in Group 3. We conclude that volume expansion during BUO enhances postobstructive diuresis and natriuresis and allows a greater recovery of GFR after release of the obstruction. This effect may be mediated through elevated plasma levels of ANP as measured in this study.     

Atrial natriuretic peptide in renal development

Although discovered little more than a decade ago, atrial natriuretic peptide (ANP) has been shown to play a significant role in the maintenance of sodium homeostasis. Immediately after birth, plasma ANP concentration is very high concurrent with right atrial dilatation and a high urinary excretion of cyclic GMP (cGMP), the second messenger for ANP. Following postnatal diuresis and natriuresis, atrial volume, plasma ANP concentration, and urinary cGMP excretion decrease to baseline levels. In the ensuling suckling period, the diuretic and natriuretic response to acute saline volume expansion are attenuated, an effect which is offset by the lower hematocrit at this age. Increase in hematocrit by isovolemic exchange transfusion results in a greater rise of plasma ANP concentration following volume expansion, but a reduced excretion of cGMP. Intravenous infusion of ANP results in greater plasma ANP concentration, and greater urinary excretion of cGMP and sodium, in adult than in young rats. This increased metabolic clearance of ANP during early development is due at least in part to increased activity of clearance receptors. In addition, neutral endopeptidase contributes to removal of circulating ANP in maturing as well as adult rats. Infusion of ANP in neonatal or adult rats results in accumulation of cGMP in glomerular podocytes, with a higher threshold for activation in immature animals. Despite the similar response of intracellular generation of cGMP following exposure to ANP in neonatal and adult rats, egression of ANP out of glomeruli is low in neonates, an effect that is due to immaturity of an organic acid transporter. It is possible that these maturational differences in the processing of cGMP account for the developmental changes in renal response to ANP or to acute volume expansion.     

Renal effects of human atrial natriuretic peptide in patients after major vascular surgery

The effects were studied postoperatively of an infusion of atrial natriuretic peptide (ANP) 7.5 pMol–kg^-1 –min^-1 on renal function and haemodynamics in seven patients who had been operated with insertion of an abdominal aortic graft. Urine flow, glomerular filtration rate (GFR), renal plasma flow (RPF) and excretion of electrolytes and osmoles were measured for three periods of 20 minutes during infusion of ANP, in the morning of the day after surgery. Haemodynamic studies were conducted, and serum levels of ANP, catecholamines and plasma renin activity were measured.
ANP levels increased from 52 to approximately 250 pMol–L^-1 during ANP infusion and decreased after infusion to a level equal to baseline. GFR increased from 92 mL–min"¹ by 58, 20 and 21%, respectively. RPF was unchanged. Urine flow rate increased from 1.99 mL–min"' by 81, 151 and 173%, respectively. Fractional clearances of sodium, chloride and osmoles were increased during the second and third ANP periods whereas fractional potassium clearance did not change during the study. There were no changes in catecholamine levels or plasma renin activity during the study. Heart rate, mean arterial pressure and calculated systemic and pulmonary vascular resistance did not change whereas reductions occurred in cardiac index, mean pulmonary artery pressure, pulmonary artery wedge pressure and mean right atrial pressure. We conclude that infusion of ANP also in the postoperative situation increases GFR, diuresis and sodium excretion.     

Atrial natriuretic peptide and other vasoactive hormones in nephrotic syndrome

Plasma levels of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), catecholamines and urinary prostaglandins (PG), as well as renal function were measured in children in the edematous state of the nephrotic syndrome before and after infusion of human serum albumin. Before albumin infusion, plasma levels of AVP, PRA, PA and noradrenaline (NA) and urinary excretion of PGE2, PGE-Met, PGF2 alpha were elevated. The mean value of plasma ANP was in the normal range. Albumin infusion produced a 36% increase in the calculated plasma volume. It was associated with a fivefold rise in the plasma level of ANP (31.6 +/- 22.6 vs. 151.4 +/- 52 fmol/ml mean, SD), and a significant fall in the levels of PRA, AVP, PA, and NA. Similarly, urinary concentration of PGE2, PGE-Met and PGF2 alpha fell. Urine flow, GFR, UNaV, FENa, and COsm increased significantly, while CH2O remained unchanged. The diuresis, natriuresis and GFR correlated with the level of plasma ANP, while urinary sodium excretion did not correlate with PA or NA levels. These findings suggest that ANP plays an important role in albumin induced natriuresis in children with nephrotic syndrome.     

Hemodynamic and humoral effects of atrial natriuretic peptide on pulmonary circulation after cardiac surgery

Purpose Human atrial natriuretic peptide (h-ANP) elicits biological effects such as natriuresis, diuresis, and vasodilation, and plays a role in regulating pulmonary circulation. We conducted this clinical study to define its role and elucidate its mechanisms. Methods Twelve consecutive adult patients scheduled to undergo cardiac surgery with cardiopulmonary bypass (CPB) were prospectively selected for this study. After the completion of surgery, h-ANP was infused from the right atrium through a Swan-Ganz (S-G) catheter. Blood samples for measurement of ANP and cyclic guanosine monophosphate (cGMP), the second messenger of ANP, were drawn from the pulmonary artery (PA) through the S-G catheter and from the left atrium (LA) through the left atrial pressure line, before and after the infusion of h-ANP. Hemodynamic values were measured at the same time. Results After the h-ANP infusion, the plasma levels of ANP were significantly lower in the LA than in the PA, whereas the plasma levels of cGMP were significantly higher in the LA than in the PA. The infusion of h-ANP decreased the mean PA pressure significantly, and the systolic PA pressure remarkably. Conclusion The infusion of h-ANP after cardiac surgery stimulates the secretion of cGMP from the pulmonary vascular bed and dilates the PA, thereby decreasing the PA pressure. This work was presented at the 2nd Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences in 2005, Keystone, CO, USA.     

EDRF modulates renal hemodynamics during unilateral ureteral obstruction in the rat.

Unilateral ureteral obstruction (UUO) results in vasoconstriction of the ipsilateral kidney, and vasodilatation of the intact opposite kidney. To investigate the role of endogenous nitric oxide, an endothelial-derived relaxing factor (EDRF), in the regulation of renal hemodynamics during UUO, Sprague-Dawley rats were anesthetized for study 24 hours after left UUO or sham-operation. Total vascular resistance (TVR) and renal vascular resistance (RVR) were measured using radioactive microspheres during control periods and following infusion of the nitric oxide synthase inhibitor, L-NAME (2.5 mg/kg). Blood pressure and RVR were increased by L-NAME, with a greater increment in the RVR/TVR ratio of the kidney with ipsilateral UUO than in the intact opposite kidney or sham-operated kidneys. Infusion of L-arginine (L-Arg), a substrate for nitric oxide synthase, did not alter the RVR/TVR ratio of either kidney of rats with UUO, but reduced the ratio in sham-operated animals. L-NAME tended to reduce urine flow and urinary sodium and cyclic GMP excretion, whereas L-Arg resulted in a marked diuresis, natriuresis, and increased excretion of cyclic GMP in both operative groups. We conclude that EDRF activity is increased in the kidney with ipsilateral UUO, which serves to counteract renal vasoconstriction. This response is not limited by availability of substrate (L-Arg). Vasodilatation of the intact opposite kidney appears to be mediated by factors other than EDRF.     

Intestinal Intramural Vascular Anastomoses

Introduction: Present surgical techniques are rarely relying on intestinal intramural vascular anastomoses; however, this could open new limits in reconstructive surgery. Our aim was to study the efficacy of the antimesenteric and the longitudinal intramural vascular anastomoses in a porcine model. Material and Methods: Five minipigs were used. Antimesenteric anastomoses: jejunal loops were detubularized by cutting along the antimesenteric line (Control), in the middle between the mesenteric and antimesenteric border (Group 1) and close to the mesenteric line (Group 2). Mucosal microcirculation (red blood cell velocity, perfusion rate) was recorded with orthogonal polarization spectral imaging (Cytoscan A/R) at the long edge of the detubularized bowel. Longitudinal anastomoses: records were made on a continuous jejunal loop following antimesenteric incision, detubularization, and subsequent ligation of 2, 4, and 6 neighboring vasa recta in the middle of the loop. The same study was repeated on the free end of completely divided jejunal segments with ligation of 2, 4, or 6 vasa recta. Results: Antimesenteric anastomoses: There was no statistically significant difference in red blood cell velocity and perfusion rate between Control and Groups 1 and 2. Longitudinal anastomoses: The red blood cell velocity dropped significantly, while the perfusion rate did not change significantly after ligation of 4 vasa recta in the continuous loop. In the loop with a free end, however, both parameters decreased significantly after ligation of four vessels. Conclusion: It is safe to rely on antimesenteric intramural anastomoses but strong limitation of longitudinal intramural vascular anastomoses should be considered in intestinal reconstructions.     

Effects of Helichrysum ceres extracts on renal function and blood pressure in the rat

OBJECTIVE: To evaluate the effects of Helicrysum ceres root and leaf extracts on mean arterial blood pressure and renal fluid and electrolyte handling in anesthetized male Sprague-Dawley rats. DESIGN: Cross sectional study. SETTING: Departments of Physiology and Pharmacy, University of Zimbabwe. SUBJECTS: Eight separate groups comprising of control and treated Male Sprague-Dawley rats (n =6 in each group) were anesthetized and placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). The left carotid artery was cannulated with polythene tubing and then connected to a pressure transducer for blood pressure measurements. After 3 h equilibration period, consecutive 20 min urine collections and blood pressure measurements were made over the subsequent 4 h of 1 h 20 min control, 1 h treatment and I h 40 min post-equilibration periods for measurements of urine flow and Na+ and K+ excretion rates. Helichrysum ceres leaf extracts at 0.3, 0.6 and 1.2 microg min(-1) roots 0.3, 3 and 6 microg min(-1) were added to the infusate during the treatment period. To establish whether the extracts had activities comparable to drugs already in use, a separate group of animals was administered furosemide (0.12 microg min(-1)) during the treatment period. MAIN OUTCOME MEASURES: Hypotension, Natriuresis and Diuresis. RESULTS: Infusion of graded doses of aqueous leaf extracts of Helicrysum ceres provoked an increase in urine flow rates but did not achieve statistical significance. However, the extracts produced dose dependent decrease in potassium excretion as well as increases in urinary Na+ outputs and diuresis. Administration of the various doses of aqueous root extracts of Helicrysum ceres significantly increased urine flow rate and urinary Na+ excretion in all groups. The intravenous (i.v.) administration of the aqueous root or leaf extracts of Helichrysum ceres significantly depressed mean arterial blood pressure (MAP). The diuretic and natriuretic effects of plant extracts were not significantly different to that of furosemide. CONCLUSION: The results suggest that oral administration to rats of aqueous crude Helicrysum ceres root or leaves extracts induce hypotension and natriuresis.     

The natriuretic peptide system in obesity-related hypertension: new pathophysiological aspects

The association between obesity and hypertension is well known but the pathophysiology of weight-related changes on blood pressure is still a matter of debate. Although obesity-related hypertension is considered to be sodium-sensitive, little attention has been given to a possible pathophysiological role of Atrial Natriuretic Peptides (ANP) and their receptors (NPr) system. Since the early phase of weight loss induced by very-low-calorie diet or fasting is followed by a significant increase in diuresis and natriuresis together with an increase in circulating ANP, we focused our attention on the possible role of adipose tissue in mediating these changes. We first demonstrated that human and rat adipose tissue contain high levels of mRNA specific for both type A (NPr-A), which is biologically active, and type C (NPr-C) which is biologically inactive, receptors. We then demonstrated in the rat that fasting exerts a tissue-specific and gene-specific suppression of NPr-C gene expression in adipose tissue that appears to be accompanied by an increased biological activity of ANP. These experimental observations were confirmed in man studying gene expression of NPr-A and NPr-C in adipose tissue obtained through subcutaneous peri-umbilical needle aspiration in obese and non-obese hypertensive patients. We found that NPr-A: NPr-C mRNA ratio was significantly lower in obese hypertensive patients as compared with non-obese hypertensives. These findings suggest that overxpression of the clearance receptor in the obese may trap more molecules of circulating ANP so reducing their biological activity at renal level. More recent results were obtained in obese hypertensive patients in whom the intravenous bolus injection of ANP (0.6 mg/kg body weight) was performed before and after four days of very-low-calorie diet which induced a weight loss accompanied by a significant reduction of BP and an increase in the urinary excretion of cGMP. The infusion of ANP after low-calorie diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis and natriuresis significantly increased only after caloric restriction and the effects of ANP infusion on BP were more pronounced. Taken together our studies suggest that the abundance of NPr-C in adipose tissue may play a significant role in explaining at least part of the sodium retention characteristic of obesity associated hypertension.     

Pericyte regulation of renal medullary blood flow

Pericytes are contractile smooth muscle-like cells that surround descending vasa recta (DVR) and provide their capability for vasomotion. The importance of the medullary pericyte derives from the role of DVR to distribute most or all of the blood flow from juxtamedullary cortex to the renal inner and outer medulla. Physiological processes that are likely to be influenced by pericyte constriction of DVR include the urinary concentrating mechanism and pressure natriuresis. Oxygen tensions in the medulla are low, so that subtle variation of pericyte vasomotion might play a role to abrogate hypoxia and prevent insult to the medullary thick ascending limb of Henle. Known vasoconstrictors of DVR include angiotensin II, endothelins, norepinephrine, acetylcholine, and adenosine. Vasodilators include prostaglandin E2, adenosine, acetylcholine, bradykinin, and nitric oxide.     

Selective endothelin B receptor blockade does not influence BNP-induced natriuresis in man

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54+/-6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3',5' guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.     

Atrial natriuretic peptide as a preload depressor in acute renal failure secondary to congestive heart failure

The present study was undertaken to verdy the hypothesis that infusion of atrial natriuretic peptide (ANP) might lower preload and be beneficial in the treatment of pulmonary congestion even without a diuresis in patients with acute renal failure (ARF) secondary to severe congestive heart failure (CHF). We studied 22 patients with ARF secondary to CHF. The mean age of the patients (14 men and 8 women) was 72 years (range 36 to 85 years). Seven of the patients had dilated cardiomyopathy, ten had ischemic heart disease, and five had valvular heart disease. ANP was infused intravenously and the following data before and 1 hour after the start of ANP infusion were recorded; urinary output, systemic blood pressure (SBP), pulmonary blood pressure (PBP), right atrial pressure (RAP), cardiac index (CI), heart rate (HR), and arterial blood oxygen pressure. Diastolic PBP were employed as plumonary capillary wedge pressure. Urinary output did not change. Mean SBP decreased from 92 to 85 mmHg (p < 0.05), and mean PBP decreased from 34 to 28 mmHg (p < 0.01). Mean RAP decreased from 11 to 9 mmHg (p < 0.01) and diastolic PBP decreased from 25 to 19 mmHg (p < 0.01). HR did not change significantly and CI increased 2.4 to 2.5 mi/min/m² (p < 0.05). Arterial blood oxygen partial pressure increased significantly from 71 to 82 mmHg (p < 0.05). In conclusion, ANP decreased and improved arterial blood oxygen partial prissure, though diuretic response to ANP is attenuated in ARF secondary to CHE. Infusion of ANP will be very beneficial in cases in which dyspnea and pulmonary edema due to elevation of preload are the principal clinical problems.     

Factors inducing post-obstructive diuresis in rats

1 day after bilateral ureteral occlusion (BUO), the extracellular fluid (ECF) volume of rats was increased by 2.8 ml/100 g body weight above those values observed after either a sham operation or after 1 day of unilateral ureteral occlusion (UUO). The plasma urea concentration of BUO rats averaged about five times the values of either sham or UUO groups. The release of BUO of 1-day duration resulted in post-obstructive diuresis and natriuresis, whereas oliguria was observed after the release of UUO of 1-day duration. Contralateral nephrectomy of the normal kidney after the release of UUO 1-day duration (UUO-RN) resulted in an improvement of the damaged kidney functions, possibly due to an elevation of renal blood flow. Polyfructosan clearance of the UUO kidney was increased to a level significantly above the corresponding BUO value, 147 +/- 34 as compared to 101 +/- 8 microliters/min/100 g body weight. However, post-obstructive diuresis was not observed. When the ECF volume of UUO-RN rats was elevated, towards those values observed in BUO rats by saline infusion, the rate of urine formation was insignificantly elevated above the nontreatment group, even though the sodium excretion rate was increased about three times the values of both the UUO-RN and BUO groups. When the plasma urea concentration of the UUO-RN group was elevated towards the BUO value, moderate diuresis was observed. But when both the ECF volume and plasma urea concentration of UUO-RN rats were increased towards the level of the BUO rats, post-obstructive natriuresis and diuresis were evident.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products.

Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 +/- 5.9; post, 47.9 +/- 6.1 microEq/min/100 g) and fractional (pre, 85.7 +/- 3.0; post, 64.7 +/- 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 +/- 8.4 versus 46.3 +/- 5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 +/- 0.2; post, 7.3 +/- 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 +/- 0.1; post, 6.6 +/- 0.8 microL/min), and in absolute (pre, 0.33 +/- 0.04; post, 0.37 +/- 0.05 microEq/min) and fractional (pre, 0.10 +/- 0.02; post, 0.11 +/- 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.