Increase In Water Excretion Research Articles

Impaired ability to increase water excretion in mice lacking the taurine transporter gene TAUT

Cellular taurine uptake or release counteracts alterations of cell volume. Na+-coupled taurine transporter TAUT mediates concentrative cellular uptake of taurine. Inhibition of vasopressin secretion by hypotonicity may involve taurine release from glial cells of supraoptic nucleus. We compared renal function of mice lacking TAUT (taut-/-) and wild-type littermates (taut+/+). We observed renal taurine loss and subsequent hypotaurinemia in taut-/- mice. With free access to water, plasma and urine osmolality, urinary flow rate as well as urinary excretion and plasma concentrations of Na+ and K+ were similar in taut-/- and taut+/+ mice, whereas plasma concentrations of urea were enhanced in taut-/- mice. An oral water load (1 ml/16 g body weight) induced a similar diuresis in both genotypes. Repeating the oral water load immediately after normalization of urine flow rate, however, resulted in delayed diuresis and higher urinary vasopressin/creatinine ratios in taut-/- mice. In comparison, the repeated diuretic response to vasopressin V2 receptor blockade was not different between genotypes. Water deprivation for 36 h led to similar antidiuresis and increases of urinary osmolality in both genotypes. Upon free access to water after deprivation, taut-/- mice continued to concentrate urine up to 6 days, while taut+/+ mice rapidly returned to normal urinary osmolality. Urinary vasopressin/creatinine ratios and plasma aldosterone concentrations were not different under basal conditions but were significantly higher in taut-/- mice than in taut+/+ mice at 6 days after water deprivation. In conclusion, taut-/- mice suffer from renal taurine loss and impaired ability to lower urine osmolality and to increase urinary water excretion. The latter defect could reside extrarenally and result from a role of taurine in the suppression of vasopressin release which may be attenuated in taut-/- mice.

Neurohormonal antagonism in heart failure; beneficial effects of vasopressin V(1a) and V(2) receptor blockade and ACE inhibition.

To assess the long-term efficacy of vasopressin (AVP) V(1a) and V(2) receptor blockade with conivaptan, alone and in combination with angiotensin converting enzyme (ACE) inhibition on blood pressure, metabolic and neurohormonal parameters, and cardiovascular structure in a rat model of congestive heart failure (CHF). CHF was induced by left coronary artery ligation. CHF rats received conivaptan (1 mg/kg/day), ACE inhibition (captopril, 50 mg/kg/day), conivaptan and captopril (Combination) or vehicle for 4 weeks. Blood pressure was measured weekly, metabolic caging studies performed at 25 days, and rats killed and blood and tissue collected after 4 weeks treatment. Combination treatment lowered blood pressure (P<0.01), and conivaptan and Combination caused an aquaresis (P<0.01). Combination decreased plasma natriuretic peptide (P<0.05), reduced left and right ventricular mass (P<0.01) and lung mass (P<0.05). In CHF, blockade of vasopressin V(1a) and V(2) receptors was associated with increased water excretion, and the combination of conivaptan with ACE inhibition was the only treatment to reduce blood pressure, natriuretic peptide and pulmonary congestion. These results suggest conivaptan may be a useful addition to ACE inhibitors in the management of vasoconstriction and fluid retention that characterizes CHF.

Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPA-985

VPA-985 is an orally active, competitive vasopressin V2 receptor antagonist that in normal human beings increases water excretion without affecting solute excretion. Whether solute excretion is affected in patients with hyponatremia resulting from inappropriate secretion of antidiuretic hormone (SIADH) or from cirrhosis treated with VPA-985 is unknown. Six hyponatremic patients with SIADH and 5 hyponatremic patients with cirrhosis with ascitis (CWAs) were treated with 50 or 100 mg VPA-985 twice daily. Evolution of creatinine, urea, uric acid, sodium, potassium, and osmotic clearance were determined. Volume hormones (plasma renin [PR], aldosterone, antidiuretic hormone [ADH], atrial natriuretic factor [ANF]) were also determined before and after treatment. In patients with SIADH, serum sodium concentration (SNa) was generally corrected in 1 day (SNa: 126 ± 4.5 mmol/L at t = 0 hours and 133 ± 5.6 mmol/L at t = 24 hours) and associated with a decrease in sodium excretion (from 82 ± 22 mmol/24 hours to 45 ± 21 mmol/24 hours; P < 0.05) without modification in potassium excretion. Despite an increase in diuresis (from 0.84 ± 0.2 ml/min to 1.46 ± 0.4 ml/min) urea and uric acid clearances decreased. Urine osmolality decreased from 414 ± 148 mOsm/kg H2O to 209 ± 55 mOsm/kg H2O. Volume hormones did not change. In the CWAs the rise of SNa was more progressive (SNa: 126 ± 2.8 mmol/L at t = H0 to 133 ± 4.9 mmol/L at t = 48 hours) and parallel to an augmentation in sodium excretion (from 23 ± 18 mmol/24 hours to 65 6 60 mmol/24 hours the second day of VPA administration). The higher sodium excretion was also connected with a progression in potassium excretion (from 22 6 7 mmol/24 hours to 36 ± 18 mmol/24 hours). The increase in diuresis under VPA from 0.42 ± 0.2 mL/min to 1.7 ± 0.9 mL/min resulted in a higher urea clearance. Urine osmolality decreased from 509 ± 142 mOsm/kg H2O before VPA to 194 ± 106 mOsm/kg H2O after VPA. ADH increased in CWAs treated with VPA, from 1.9 ± 1.2 pg/mL to 5.3 ± 2.8 pg/mL (P < .05) while other volume hormones did not change. VPA-985 is a highly effective drug in the short-term management of hyponatremic patients with SIADH or CWAs. SNa correction is associated with urinary sodium retention in SIADH, whereas in CWAs a mild increase in sodium excretion is observed. (J Lab Clin Med 2001;138:18-21)

Water retention and aquaporins in heart failure, liver disease and pregnancy.

Water retention in excess of total body sodium frequently occurs in patients with cardiac failure or cirrhosis and in pregnancy. In fact, hyponatraemia signifies a poor prognosis in cardiac failure and cirrhosis1,2. The mechanism for this hyponatraemia, however, has not been well defined. In the era when the antidiuretic hormone (ADH) bioassay was performed in ethanol-anaesthetized rats, consistent alterations in ADH could not be demonstrated in hyponatraemic patients with cirrhosis or heart failure. Therefore it was suggested that intrarenal, non-ADH-dependent, mechanisms accounted for the water retention in these oedematous disorders. Another dilemma in understanding fluid balance in cardiac failure, cirrhosis and pregnancy relates to defining the afferent signals that could stimulate AVP release with resultant water retention. Expanded plasma volumes have been reported in all three conditions. This finding is typically associated with increased water excretion rather than water retention; thus, signals other than increased plasma volume must contribute to the water retention.

Decreased abundance of collecting duct aquaporins in post-ischemic renal failure in rats.

Increased urine flow is often a feature of mild to moderate acute renal failure. This study examines the possible role of dysregulation of collecting duct aquaporins as a factor in this increase. In rats, the left renal pedicle was clamped for 45 min followed by contralateral nephrectomy. Control rats were identical except that the renal pedicle was not clamped. Rats were sacrificed and the kidneys were homogenized at various time points after release of the clamp for semiquantitative immunoblotting of collecting duct aquaporins, as well as the thick ascending limb Na-K-2Cl cotransporter and the proximal tubule water channel, aquaporin-1. Urinary flow rate was significantly increased 18 h after the ischemic insult and remained increased through 72 h. Whole kidney aquaporin-2 protein abundance was 45% of controls at 18 h, 55% of controls at 36 h, and returned to normal 72 h after ischemia. Whole kidney aquaporin-3 protein abundance was 37% of controls at 18 h, 13% of controls at 36 h, and 45% of controls at 72 h. The decline in aquaporin-2 and -3 was confirmed by immunocytochemistry. Abundance of the thick ascending limb Na-K-2Cl cotransporter protein was not significantly decreased. Aquaporin-1 protein abundance was not significantly decreased at 18 h after the ischemic insult, but was significantly reduced after 36 h. Thus, the post-ischemic state is associated with decreased levels of the collecting duct aquaporins, coinciding with an increase in water excretion. It is concluded that decreased aquaporin protein abundance in collecting duct cells is a contributing factor in the increased urine flow seen in moderate post-ischernic acute renal failure.

Effects of receptor blockade on metabolism and renal actions of vasopressin in conscious dogs.

Vasopressin--but not the V2 receptor agonist [deamino-cis1,D-Arg8]-vasopressin (dDAVP)--may mediate natriuresis in dogs. The present study investigated this phenomenon by use of nonpeptide antagonists to V1a and V2 receptors 1-¿1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl¿-3,4-dihydro-2 (1H)-quinolinone (OPC-21268) and 5-dimethylamino-1-¿4-(2-methylbenzoylamino)-benzoyl¿-2,3,4,5-tetra hydro-1 H-benzazepine (OPC-31260), respectively) hypothesising that only V1a inhibition would reduce the natriuresis. In conscious dogs vasopressin secretion was suppressed by water loading (2% body weight) and replaced by infusion of vasopressin (50 pg min-1 kg-1) resulting in physiological plasma concentrations (plasma levels of AVP (pAVP) = 2.0 +/- 0.1 pg mL-1). In this setting, OPC-21268 did not change the rate of sodium excretion. OPC-31260 increased water excretion 12-fold without significant changes in sodium excretion. Heart rate, mean arterial blood pressure, glomerular filtration rate, and clearance of endogenous Li+ were unchanged. During vasopressin infusion, both antagonists increased pAVP, OPC-21268 by 20% and OPC-31260 by 100% (2.0 +/- 0.2-4.0 +/- 0.3 pg mL-1). In the absence of vasopressin infusion, OPC-31260 did not increase pAVP. Thus, the increase in pAVP appeared to be due to a decrease in metabolic clearance rate. The results indicate that the present dose of V1a receptor inhibitor OPC-21268 does not reduce sodium excretion and that both vasopressin antagonists inhibit vasopressin metabolism.

Renal and vascular consequences of the chronic nitric oxide synthase inhibition. Effects of antihypertensive drugs.

The effects of the administration of either the angiotensin converting enzyme (ACE) inhibitor, quinapril (10 mg/kg/day, orally), or the calcium antagonist, diltiazem (100 mg/kg/day, orally), on blood pressure (BP), renal function, and vascular reactivity in isolated perfused mesenteric beds were studied in rats treated for 8 weeks with the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester (LNAME, 40 mg/kg/day). The oral administration of LNAME significantly increased systolic BP values, which reached the levels of 186 +/- 7 mm Hg at week 8. Both quinapril and diltiazem reduced this, although the ACE inhibitor was more effective than the calcium antagonist. The chronic inhibition of NO resulted in an increase in water excretion whether or not the increase in systolic BP was prevented by the coadministration of either quinapril or diltiazem. At the end of the experiment, LNAME-treated rats presented higher proteinuria than control rats (140 +/- 4 mg/24 hours v 21 +/- 1 mg/24 hours, P < .05). This elevated protein excretion was normalized by both antihypertensive drugs. None of the treatments was able to modify either natriuresis or plasma creatinine levels. Endothelium-dependent relaxations to acetylcholine (10(-12) to 10(-8) mol/L) were comparable in all groups. However, the vasoconstriction induced by either the continuous infusion of phenylephrine (10(-5) mol/L) or by a bolus of angiotensin II (1 nmol) was higher in the animals that received LNAME than in control ones. The antihypertensive therapy normalized the response to phenylephrine but not to angiotensin II. These data suggest that both quinapril and diltiazem are not only able to reduce BP elevation induced by the chronic administration of LNAME in rats, but also to prevent the renal damage and the hyperresponsiveness to phenylephrine induced by this NO synthesis inhibitor.

Ruffed Grouse Tolerance and Biotransformation of the Plant Secondary Metabolite Coniferyl Benzoate

Ruffed Grouse (Bonasa umbellus) consumption of quaking aspen (Populus tremuloides) flower buds is determined, in part, by the concentration of coniferyl benzoate (CB) in the bud. Understanding the physiological effects of this compound may clarify whether the association between annual fluctuations in CB and Ruffed Grouse population levels has a cause/effect relationship. We determined the maximum level of dietary CB that Ruffed Grouse can tolerate by feeding captive grouse a formulated diet treated with eight concentrations of CB. Loss of body mass was used to indicate toxicity. Biotransformation products from CB were identified in order to determine the detoxication mechanisms em- ployed and the presence of potentially toxic CB metabolites. Ruffed Grouse will consume up to 2 g kgg' day-' of CB before rapid mass loss ensues. High dietary levels of CB were associated with decreased food intake and increased water excretion. Serum uric acid, as- partate aminotransferase, and alanine aminotransferase levels did not change significantly with increased levels of dietary CB. Mass loss that was associated with a CB intake of 2.3 g kg-' day-' could be explained by decreased food intake but could not be attributed to any specific toxic effect. It is uncertain whether the decreased food consumption that occurred at high CB intake levels was prompted by toxicity avoidance or decreased food palatability. Ruffed Grouse appear to use glucuronic acid, sulfate, and omithine conjugation, along with hydrolysis, reduction, and oxygenation reactions, when detoxifying CB. Nine biotransfor- mation products were identified, including ferulic acid and 4-vinylguaiacol. The latter com- pounds are known to interfere with reproduction in other animals.

Broiler Water Balance and Thermobalance During Thermoneutral and High Ambient Temperature Exposure

Three experiments were conducted to evaluate the influence of heat distress (HD) on broiler water balance and thermobalance criteria including heat production, nonevaporative heat loss, evaporative heat loss (EHL), respiration rate, and apparent respiration efficiency (ARE). In the first experiment, 24 Cobb × Cobb chicks were precision fed feed and water at 3.5 and 8.5% of body weight, respectively, to determine HD effects on combined fecal and urinary water excretion. Exposing chicks to 35 C for 4 h increased water loss by 64% compared with birds housed at 24 C. In the second experiment, 10 precision-fed, colostomized birds were placed in individual respiratory chambers at 49 days of age and sequentially exposed to 24 and 35 C environments; water was consumed ad libitum. Water consumption and excretion increased (P < .05) by 78 and 133%, respectively, during HD. The increased water excretion was largely accounted for via hypo-osmotic urine with increased (P < .05) osmolar and free water clearance. Evaporative cooling (r = .73), ARE (r = .73), urine production (r = .72), and free water clearance (r = .74) were all correlated (P < .05) with water consumption. Plasma Na+ and K+ decreased (P < .05), whereas Cl− increased (P < .05) during HD. In the third experiment, supplementing the drinking water of chicks with .75% KCl increased (P < .05) water consumption by 91%, EHL by 20%, and ARE by 26.7%. The current studies suggest that broiler chicks adjust water consumption and renal handling of water during acute HD and that such handling impacts EHL.

Effect of colostomy on the utilisation of dietary nitrogen in the fowl fed on a low protein diet.

1. The effect of the inhibition of urine back-flow into the colon and caeca by colostomy on the utilisation of dietary nitrogen by fowls fed on a low protein diet and receiving free or restricted water supply was investigated. 2. Colostomy caused an increase in water excretion and a resultant increase in water intake to maintain water balance. 3. Colostomy tended to decrease nitrogen balance and nitrogen utilisation (N balance/N intake) to negative values, and these decreases became significant when water was restricted (P less than 0.05). 4. Excretory uric acid, ammonia, urea and total nitrogen were significantly increased after colostomy in water-restricted fowls (P less than 0.05), but such significant effects were not observed, except for ammonia, in fowls given water ad libitum. 5. It is concluded that the back-flow of urine into the caeca plays a significantly useful role in the utilisation of nitrogen in the fowl fed on a low protein diet especially when water intake is restricted.

High-performance liquid chromatographic determination of an arginine-containing octapeptide antagonist of vasopressin in human plasma by means of a selective post-column reaction with fluorescence detection

A novel high-performance liquid chromatographic method was developded for the determination in plasma samples of the synthetic octapeptide SK&F 105494 { O-ethyl- d-tyrosyl- l-phenylalanyl- l-asparaginyl-5-[1-(carboxymethyl)cyclohexyl]- l-norvalyl- l-arginyl- d-arginamide, cyclic (5–1) peptide}, and active aquaretic agent which significantly increases water excretion in experimental animal models through competitive antagonism of renal epithelial vasopressin receptors. The method involves isolation of Sk&F 105494 from plasma samples by solid phase extraction prior to chromatogrpahic analysis. Following chromatographic separation, in-line fluorescence detection was accomplished via a selective-post-column reaction of the guanidino group of the arginine moiety of the peptide withalkaline ninhydrin to generate a highly fluorescent product. Optimization of the post-column reaction conditions and the use of high-performance liquid chromatography columns of reduced internal diameter (2.1 mm), resulted in an on-column detection limit of 50pg (45 fmol). The limit of sensitivity in plasma was 0.5 ng/ml. The assay was linear over the range 0.5–100 ng/ml. Precision and accuracy were within 11% across the calibration range. The assay was shown to be suitable to study the pharmacokinetics of SK&F 105494 in human subjects and animals. In addition, the methodology developed has general applicability in the detection of arginine-containing peptides in biololgical matrices.

Renal actions of atrial natriuretic factor: a mathematical modeling study

Atrial natriuretic factor (ANF) is a peptide hormone that increases renal NaCl and water excretion. Several renal sites of ANF action have been identified, but general agreement has not been reached concerning the quantitative contribution of each action to the natriuresis and diuresis. Using a five-nephron central core model of NaCl, urea, KCl, and water transport in the rat kidney, we have quantitatively evaluated the hypothetical effects on whole kidney function of three experimentally observed ANF actions: 1) inhibition of active NaCl absorption in the collecting duct, 2) inhibition of osmotic water permeability in the collecting duct, and 3) increased NaCl and water delivery out of the proximal convoluted tubule simulating an increase in glomerular filtration rate. The simulations show that inhibition of collecting duct active NaCl absorption by greater than or equal to 50% can increase NaCl and water excretion to levels that match experimental values. In addition, the model predicted that the urinary sodium concentration will increase to greater than plasma levels as observed experimentally. Simulated decreases in collecting duct water permeability predicted an increase in water excretion with little change in NaCl excretion. Simulated 2.5-5% increases in glomerular filtration rate also increased simulated NaCl and water excretion rates to experimentally observed levels in response to ANF. However, this action was less effective than inhibition of collecting duct active NaCl absorption in increasing the urinary NaCl concentration. We conclude that a combination of several actions are likely to account for the overall renal effect of ANF.

Enhanced natriuretic potency of intravenous clonidine: extrarenal site of action?

We have previously demonstrated that low intrarenal infusion rates of clonidine selectively increased water excretion, whereas higher infusion rates were required to increase solute excretion. This is in contrast to previous experiments where intravenous administration of clonidine resulted in a concomitant increase in water and sodium excretion. We therefore determined the dose response curve for an intravenous infusion of clonidine on water and solute excretion and compared this to the effects of an intrarenal infusion. Uninephrectomized rats were anesthetized and the remaining kidney isolated for the collection of urine. Clonidine (0.1, 0.3, 1 or 3 μg/kg per min) or vehicle (saline) was administered either intravenously or intrarenally. Both intravenous and intrarenal administration of clonidine produced a dose selective dissociation of water and solute excretion, that is, at low infusion rates only urine volume was increased. Higher infusion rates were required to increase sodium excretion. In addition, intravenous administration of clonidine was more potent in producing a natrieresis, suggesting that the renal effects may be, in part, secondary to additional peripheral and/or central effects of this agonist following this route of administration.

Biphasic effect of a κ-opioid receptor agonist on plasma oxytocin levels in rats

The effect of the κ-opioid receptor agonist, bremazocine, on plasma oxytocin leves in rats was measured by a sensitive radioimmunoassay. Initially, a decrease in plasma oxytocin levels was seen 30 min after injection. This was in accordance with the bremazocine inhibition of oxytocin release after submaximal electrical stimulation seen in isolated neurointermediate lobes. The initial decrease in plasma oxytocin reverse, and 4 h after injection of bremazocine a 20-fold increase in the oxytocin level was seen. The rise in plasma oxytocin was paralleled by a rise in plasma sodium. The biphasic time course of the plasma oxytocin response can be explained by a combination of an inhibition of oxytocin release from the neurohypophysis and an increased water excretion leading to an elevation in plasma sodium, which may be responsible for the late rise in plasma oxytocin. Down-regulation of the opioid receptors may also contribute to the delayed rise in plasma oxytocin.

Pharmacologic probing of amphotericin B-induced renal dysfunction in the neonatal rat

Acetazolamide, furosemide, chlorothiazide, and amiloride are pharmacologic agents that act primarily in the proximal tubule, loop of Henle, early distal tubule and late distal tubule and collecting duct, respectively. In order to investigate the renal pathophysiology induced by amphotericin B, these diuretic agents were used as probes of discrete segments of the nephron in the neonatal rat. Six-day-old rats were treated with amphotericin B (20 mg/kg, sc) or the vehicle. Twenty-four hours later, when evidence of amphotericin B-induced renal pathophysiology is detectable, the responses to the diuretic agents were assessed in a 2-hr clearance test, during which creatinine clearance (CCr) and the fractional excretion (FE) of water and various components of the filtrate were determined. Amphotericin B induced alterations in basal function including azotemia, hypostenuria, increases FE water and electrolytes, and a decreased FE urea (although CCr was normal). The diuretic responses to furosemide, chlorothiazide, and amiloride were not altered, indicating that the functional viability of the respective tubular segments was not affected by amphotericin B treatment. Although the maximal response to acetazolamide also remained unchanged in amphotericin B-treated pups, there was an attenuation in the half-maximal response, reflecting an apparent shift in the sensitivity to acetazolamide. All of the diuretic agents elicited an increase in urea excretion in amphotericin B-treated pups such that FE urea approached control values. Additionally, the magnitude of this increase was proportional to the magnitude of the increase in water excretion induced by each diuretic agent. These results indicate a disruption of urea recycling in the nephron and support the hypothesis that amphotericin B acts to increase the permeability of the distal tubule to urea. Thus, results from this study demonstrate the usefulness of pharmacologic agents as functional probes in the characterization of specific components of renal pathophysiology.

Frusemide pretreatment blunts the inhibition of renal tubular sodium reabsorption by ANF in man.

The effects of atrial natriuretic factor (ANF) 15 pmol/kg/min on renal function were studied in 7 normal male volunteers during maximal water diuresis. Subjects were studied in neutral salt balance either before, or after, seven days treatment with 40 mg oral frusemide. The post-frusemide state was associated with activation of the renin-angiotensin system (RAAS) and generally higher noradrenaline levels; this state was also associated with sodium retention, mainly due to enhanced distal nephron reabsorption. Without diuretic pretreatment ANF produced a natriuresis and diuresis associated with inhibition of both proximal and distal nephron sodium reabsorption. In contrast, after frusemide pretreatment, ANF caused an increase in water excretion (urinary flow rate) but no change in sodium excretion. In the post-diuretic condition ANF did not affect renal tubular handling of sodium. The enhanced tubular reabsorption of sodium post-frusemide, and the failure of ANF to suppress this, could be due to activation of the RAAS and SNS.

The acute and chronic effects of nicardipine on blood pressure, heart rate, neurocirculatory reflexes and renal function in hypertensive patients

Abstract 1 Two groups of untreated patients with essential hypertension were studied. 2 Eight patients (casual BP 180/110 ± 27/12 mm Hg) received a single oral dose of 30 mg nicardipine, followed by 30 mg three times daily for 2 months. 3 After 2 months, the mean intra-arterial BP had fallen from 161/102 ± 13/9 to 147/93 ± 12/7 mm Hg (P < 0.05). The heart rate remained virtually unchanged (84 ± 12 vs 80 ± 9 beats min-1). 4 There was no change in baroreflex sensitivity after either acute or chronic treatment, but the set point of the reflex was reset to a lower pressure following chronic therapy. 5 In the second set of six patients with essential hypertension, renal and metabolic balance studies were performed after nicardipine infusion (80 μg kg-1 h-1) and 6 weeks oral therapy (20 to 40 mg three times daily) were performed. 6 At a minimum of 20% fall in mean arterial pressure, there was 100% increase in water excretion, and 300% increase in sodium excretion. GFR did not change significantly but renal plasma flow increased significantly. The diuresis and natriuresis were not observed on chronic therapy, but there was a significant reduction in GFR and ERPF. 7 Nicardipine produces significant acute changes in blood pressure, heart rate, neurocirculatory reflexes and renal function, but none of these effects seem important in maintaining the long-term hypotensive action.

Increased water excretion in hyperprolactinemic rats.

The role of PRL in mammalian salt and water balance remains controversial. To avoid the methodological problems of exogenous PRL administration, endogenous hyperprolactinemia was established in normal rats by implantation of extra anterior pituitary glands under the kidney capsule. To eliminate excess glucocorticoid secretion in these rats, they were adrenalectomized, implanted with corticosterone replacement pellets, and given 0.9% saline drinking fluid. A highly significant increase in urine flow was found in pituitary-grafted male Fischer rats compared to control rats (38.9 +/- 3.8 vs. 20.7 +/- 1.6 ml/24 h X 100 g BW; P less than 0.0005). Urine osmolality was lower in pituitary-grafted rats, but sodium and potassium excretion were not abnormal. Although fluid intake was also greater in hyperprolactinemic rats, the urine flow remained elevated when adjusted for fluid intake. Renal binding sites for radioactive PRL were not decreased in pituitary-grafted rats. Thus, the hyperprolactinemic rat has increased water excretion that may be attributed to a direct renal effect rather than to glucocorticoid excess or a primary change in thirst. Since it is possible that water absorption in the gut is also increased by PRL, multiple effects of PRL may be responsible for the diuresis observed in hyperprolactinemic rats.

Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, verapamil and nitrendipine are reviewed. Although nifedipine stimulates plasma renin activity on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on any of the components of the reninangiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function; glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although diltiazem and nifedipine increase salt and water excretion on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are unchanged. Thus, calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.

Effect of somatostatin on renal water handling in the dog.

When somatostatin was infused into the left renal artery of anaesthetized, hydropenic dogs in doses ranging from 1 to 10 micrograms/min, it produced an increased flow of a more dilute urine from the ipsilateral kidney. Similar infusions in dogs undergoing a maximal water diuresis had no effect. If aqueous antidiuretic hormone (ADH) was administered intravenously into water-loaded dogs prior to the intraarterial infusion of somatostatin, this latter peptide was able to produce an augmented flow of a more dilute urine from the ipsilateral kidney. If the left kidney was made to excrete a concentrated urine in the face of maximal water loading by restricting arterial perfusion, then the infusion of somatostatin had no effect on urinary dilution, though this peptide could increase water excretion in hydropenic dogs when the left kidney was similarly restricted as to arterial inflow. In dogs undergoing a water diuresis that were given cyclic AMP (4 mg/min) into the left renal artery, a decrease in ipsilateral water excretion was observed. The subsequent infusion of somatostatin produced no urinary dilution. We conclude that somatostatin increases renal water excretion by antagonizing the ADH effect on the renal tubule, and that this event probably occurs at a pre-cAMP site within the cell.