Reduction In Urine Volume Research Articles

A primer on continuous renal replacement therapy for critically ill patients.

To characterize the multiple continuous renal replacement therapy (CRRT) techniques available for the management of critically ill adults, and to review the indications for and complications of use, principles of drug removal during CRRT, drug dosage individualization guidelines, and the influence of CRRT on patient outcomes. MEDLINE (January 1981-December 1996) was searched for appropriate publications by using terms such as hemofiltration, ultrafiltration, hemodialysis, hemodiafiltration, medications, and pharmacokinetics; selected articles were cross-referenced. References selected were those considered to enhance the reader's knowledge of the principles of CRRT, and to provide adequate therapies on drug disposition. CRRTs use filtration/convection and in some cases diffusion to treat hemodynamically unstable patients with fluid overload and/or acute renal failure. Recent data suggest that positive outcomes may also be attained in patients with other medical conditions such as septic shock, multiple organ dysfunction syndrome, and hepatic failure. Age, ventilator support, inotropic support, reduced urine volume, and elevated serum bilirubin concentrations have been associated with poor outcomes. Complications associated with CRRT include bleeding due to excessive anticoagulation and line disconnections, fluid and electrolyte imbalance, and filter and venous clotting. CRRT can complicate the medication regimens of patients for whom it is important to maintain drug plasma concentrations within a narrow therapeutic range. Since the physicochemical characteristics of a drug and procedure-specific factors can alter drug removal, a thorough assessment of all factors needs to be considered before dosage regimens are revised. In addition, an algorithm for drug dosing considerations based on drug and CRRT characteristics, as well as standard pharmacokinetic equations, is proposed. The use of CRRT has expanded to encompass the treatment of disease states other than just acute renal failure. Since there is great variability among treatment centers, it is premature to conclude that there is enhanced survival in CRRT-treated patients compared with those who received conventional hemodialysis. This primer may help clinicians understand the need to individualize these therapies and to prospectively optimize the pharmacotherapy of their patients receiving CRRT.

Nerve-mediated antidiuresis and antinatriuresis after air-jet stress is modulated by angiotensin II.

A putative interaction between angiotensin II (Ang II) and the sympathetic nervous system within the kidney has been reported. We tested the hypothesis in conscious rats that endogenous Ang II modulates the renal effects of a stress-induced increase in sympathetic nerve activity. We recorded mean arterial blood pressure, heart rate, renal sympathetic nerve activity, renal hemodynamics, urine volume, and urinary sodium content in conscious rats. We used the Ang II type 1 receptor blocker ZD 7155 to inhibit the effects of endogenous Ang II. Ten minutes of air-jet stress increased renal sympathetic nerve activity by 98 +/- 4% (n = 6) without changing systemic hemodynamics. Air-jet stress reduced urine volume (from 31 +/- 3 to 8 +/- 4 microL/min per gram kidney weight, P < .05, n = 12) and sodium excretion (from 4.3 +/- 0.9 to 1.2 +/- 0.3 mumol/min per gram kidney weight, P < .05, n = 12). After renal denervation, air-jet stress had no effect on either parameter. Six micrograms of the Ang II type 1 receptor inhibitor ZD 7155 blunted the decrease in urine volume and sodium excretion in response to air-jet stress, although the increase in renal sympathetic nerve activity during air-jet stress and the pressor response to exogenous Ang II were not affected. Glomerular filtration rate and renal plasma flow were also not affected. Higher doses of 30 and 60 micrograms ZD 7155 inhibited the pressor response to exogenous Ang II and abolished the changes in urine volume and sodium excretion in response to air-jet stress. None of the ZD 7155 doses affected urinary sodium excretion permanently. Hence, the Ang II type 1 receptor antagonist ZD 7155 impaired or abolished the renal nerve-mediated antinatriuresis and anitidiuresis in response to air-jet stress. We conclude that endogenous Ang II modulates the renal effects of centrally mediated changes of sympathetic nerve activity in conscious rats.

Restoration of plasma volume after 16 days of head-down tilt induced by a single bout of maximal exercise.

Seven healthy men performed maximal exercise 24 h before the end of 16 days exposure to 6 degrees head-down tilt (HDT) to test the hypothesis that such an exercise technique could restore plasma volume (PV) at the end of a simulated space mission. Exercise consisted of supine cycling with graded work rates increasing by 16 W/min to volitional fatigue and required an average of 16 min. The experimental protocol was a standard cross-over design in which the order of treatment (exercise or control) was counterbalanced across all seven subjects. PV, fluid intake (ad libitum), urine output, renal function, and hormones associated with fluid homeostasis were measured before HDT, 24 h before the end of HDT just prior to exercise, and at the end of HDT 24 h after exercise. HDT reduced PV by 16% in both control and exercise conditions. Maximal exercise completely restored plasma volume within 24 h to 3.9 +/- 3.2% of pre-HDT levels despite continued HDT. Compared with control, exercise induced a 660-ml larger positive fluid balance because of greater fluid intake and reduced urine volume during the 24 h after exercise. These results suggest that one bout of maximal leg exercise before return from 16 days of spaceflight may be completely effective in stimulating thirst and restoring plasma volume to preflight levels.

A Case of Familial Central Diabetes Insipidus: The Response of Urinary Prostaglandins to 1-Deamino-8-D-Arginine Vasopressin

A case of familial central diabetes insipidus and dilatation of the urinary tract is reported. Administration of desmopressin for 1 year improved urinary tract dilatation with a concomitant reduction in urine volume. Urinary cyclic adenosine monophosphate and prostaglandin E2 excretion increased after treatment.

Kidney concentrating ability of a subterranean xeric rodent, the naked mole-rat (Heterocephalus glaber).

The naked mole-rat (Heterocephalus glaber) is a strictly subterranean mammal inhabiting the arid zones of north-east Africa. These animals have no access to free water and water balance thus might be facilitated by regulating renal water loss. The urinary concentrating ability of the naked mole-rat was determined using five dietary manipulations in which both water and salt content were altered. "Control" animals (n = 7) received a high quality protein cereal mixed to a thin paste with water (1 g cereal: 8.5 g water). Water stress was induced by reducing the water content of the diet by either 50% (n = 7) or 65% (n = 7). Salt loading was facilitated by replacing the water with the same volume of either 0.9% salt (n = 7) or 3.0% salt (n = 4) solutions. Changes in body mass, food consumption and urine volume were measured daily. The effect of diet on osmolality and electrolyte concentrations of urine and plasma were determined on termination of the diet trials. Although energy intake was not reduced, naked mole-rats lost body weight with both water stress treatments. Urine volume voided per day decreased significantly with both water stress treatments (P < 0.05), such that the most extreme water stress led to an 80% reduction in urine volume. Mildly salt-loaded animals gained weight, yet underwent a sodium diuresis, as indicated by a 1.3-fold increase in the daily volume of urine voided (P < 0.05). Maximum urine concentration (1521 +/- 250 mmol.kg-1) was achieved with mild water stress and was 4.6 +/- 0.9 times that of plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats.

Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCl diets (131 +/- 4 mm Hg, n = 12) was not different from that in normal rats. Two percent NaCl diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167 +/- 4 mm Hg, n = 12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCl loading. During this period, the deficient rats secreted less urine (9 weeks old, P < .05) and less urinary sodium (11 weeks old, P < .05). Serum levels of sodium in deficient rats were higher (P < .05) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P < .05) than in normal rats throughout NaCl loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCl-loaded deficient rats induced a reduction (P < .01) in blood pressure and increases (P < .05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCl-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCl loading.

Effect of water restriction on energy and water balance and osmoregulation of the fruit bat Rousettus aegyptiacus.

The energy budget, water balance and osmoregulation of the fruit bat, Rousettus aegyptiacus, were studied during normal hydration and during water restriction (oven-dried apple diet). The water input and output were balanced during both normal hydration and water restriction. The kidney of the fruit bat is well adapted to handle the water load from its fruit diet by excreting large volumes (14% of the body mass per day) of dilute urine (113 +/- 25 mosmol.kg H2O-1) as well as reducing urine volume (-95%) and increasing urine osmotic concentration (555 +/- 280 mosmol.kg H2O-1) during water restriction. The haematocrit, plasma haemoglobin and total protein concentrations did not increase during water restriction and heat exposure, suggesting the conservation of plasma volume. Gross energy intake was not affected by water restriction. However, digested energy intake and digestibility were significantly reduced. The effective regulation of energy and water budgets during water restriction suggests that the fruit bat can cope with seasonal climatic changes and with variable fruit supply during various seasons.

Subacute oral toxicity study of benzyl isothiocyanate in rats.

The subacute toxicity of benzyl isothiocyanate (BITC) was investigated in male rats given oral doses of 0, 50, 100 and 200 mg/kg body weight/day for 4 weeks. Body weight gain and food consumption were decreased with increasing doses of BITC. Haematological changes of toxicological relevance were observed in the highest dose group. BITC administration resulted in increased serum cholesterol level in all treatment groups and decreased serum triglycerides level at 200 mg/kg. Renal dysfunction was indicated by reduced urine volume, proteinuria and enhanced urinary lactate dehydrogenase activity. BITC exposure also affected the weights of various organs and caused histological changes in the ductus choledochus, liver, ileum and mesenteric lymph nodes.

Antidiuretic and nephrotoxic effects of putrescine in rats

Putrescine, intraperitoneally injected either into intact or into hypophysectomized rats, caused a reduction in urine volume at doses of 200-300 mg/kg. At doses of 100 mg/kg or more, there was also a significant loss of potassium. The highest dose (300 mg/kg) caused haemoglobinuria, proteinuria, increased natriuresis, increased urinary osmolarity, reduced aldosteronaemia, ectasis of glomerular capillaries and tubular damage. The underlying mechanism(s) are probably mostly linked to the strong cationic charge of putrescine and to its binding to fixed anions of tubular-cell membrane.

The α‐adrenoceptor mediating the tubular actions of the renal nerves in spontaneously hypertensive and stroke‐prone spontaneously hypertensive rats

1. Experiments were undertaken in groups of pentobarbitone anaesthetized normotensive, spontaneously hypertensive or stroke-prone spontaneously hypertensive rats to determine the alpha-adrenoceptor subtype mediating renal nerve-stimulated tubular sodium readsorption at the level of the nephron. 2. In normotensive rats, stimulation of the renal nerves at low frequencies, which caused small changes in renal blood flow and glomerular filtration rate, caused significant reductions in urine volume, absolute sodium excretion and fractional sodium excretion of between 35 and 55% (P less than 0.01) respectively. The renal nerve-mediated antidiuresis and antinatriuresis were inhibited by the administration of doses of prazosin which selectively blocked alpha 1-adrenoceptor vascular responses. The magnitude of the renal nerve-induced excretory responses was unaffected by the presence of idazoxan at a dose which selectively blocked alpha 2-adrenoceptor blood pressure and renal vasoconstrictor responses. 3. Renal nerve stimulation in spontaneously hypertensive rats caused small falls in renal blood flow and glomerular filtration rate but larger significant reductions in urine flow, absolute and fractional sodium excretions of between 40 and 50%, which were of similar magnitude to those observed in the normotensive rats. The renal nerve-induced reductions in urine flow, absolute and fractional sodium were abolished in the presence of prazosin but were unaffected by idazoxan. 4. In the stroke-prone spontaneously hypertensive rat, low level renal nerve stimulation had small effects on renal haemodynamics but reduced urine flow, absolute and fractional sodium excretions by similar magnitudes to those in the other groups of rats, by between 45 and 55%. These renal nerve-induced reductions in water and sodium excretion were abolished by prazosin but not by idazoxan. 5. Together, these data show that in both normotensive rats and the two models of genetic hypertension, the renal nerves have important actions on the renal tubules to increase sodium and water reabsorption while having little effect on renal haemodynamics. In all these groups of rats this tubular action of the renal nerves was mediated by alpha 1- but not alpha 2-adrenoceptors.

The effects of water deprivation and salt load on water conservation efficiency in two Indian desert gerbils

The effects of water deprivation and intraperitoneal salt loading on urine volume and on various urinary constituents have been examined in two gerbil species of the Rajasthan desert, the Indian desert gerbil (Meriones hurrianae Jerdon) and the Indian gerbil (Tatera indica indica Hardwicke). During summer, hydrated T. indica excreted 0.782 ml urine.100 g-1.d-1 which was about 60.5% higher than the volume of urine excreted by hydrated M. hurrianae (0.487 ml.100 g-1.d-1). During winter, both species excreted around 1.5 ml urine.100 g-1.d-1. The experimental treatments caused reductions in urine volume in M. hurrianae from 40 to 76% during summer and from 35 to 71% in winter. Similar treatments in T. indica caused reductions in urine volume of 50-82% in summer and 5-60% in winter. The mean increase in urine osmolarity following various salt loading treatments in T. indica ranged from 3800 to 5761 mosmol.l-1 and from 4034 to 6255 mosmol.l-1 during summer and winter, respectively. The mean values of urine osmolarity for hydrated T. indica were 2831 and 3189 mosmol.l-1 during summer and winter, respectively. In M. hurrianae salt loading treatments caused increases of urine osmolarity between 3381 and 5646 mosmol.l-1 and between 4032 and 5434 mosmol.l-1, during summer and winter, respectively, over the values recorded for hydrated animals (summer = 3292; winter = 3294 mosmol.l-1). A maximum urine osmolarity of around 7000 mosmol.l-1 was found in both species when subjected to 2% salt-loading treatment. The treatments used in this study increased urinary urea level in both T. indica (3039-4056 mM) and in M. hurrianae (1900-2180 mM) compared to the level in their respective hydrated controls (T. indica = 1628 mM; M. hurrianae = 1372 mM). The results indicate that T. indica may be better adapted to produce more concentrated urine than M. hurrianae.

The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system

Previous studies using human pituitary extracts have not resolved whether the sodium retaining effects of human growth hormone (hGH) are mediated in part by increased aldosterone secretion. We have studied the effects of an authentic biosynthetic GH (bio-hGH) preparation on sodium metabolism and on the activity of the renin-angiotensin system. Six young men were administered this preparation at 0.2 U/kg/d subcutaneously for five consecutive days. Twenty-four-hour urine collections were obtained for measurement of sodium excretion and osmolality and blood collected for quantitating changes in sodium, osmolality, plasma renin activity (PRA), aldosterone, and arginine vasopressin (AVP) concentrations. Bio-hGH administration resulted in a fall in 24-hour urinary sodium excretion (197 ± 38 to 42 ± 20 mmol, mean ± SD, P < .005), a reduction in urine volume (1,652 ± 182 to 848 ± 348 mL, P < .05) but not osmolality. PRA increased significantly from 1,118 ± 73 to 3,608 ± 1,841 fmol angiotensin 1 L/s ( P < .005), which was associated with a sevenfold increase in plasma aldosterone concentration (52 ± 12 to 402 ± 99 pg/mL, P < .001). Plasma osmolality and AVP concentrations did not change significantly. The results show that Bio-GH-induced retention of sodium involves the activation of the renin-angiotensin system. This mechanism may explain in part the occurrence of plasma volume expansion and hypertension in acromegaly and suggests a risk of fluid retention and possibly hypertension in subjects receiving supraphysiological doses of bio-hGH for treatment of short stature.

Physiological and Biochemical Indices of Neurohypophyseal Function in the Aging Fischer Rat

In order to resolve conflicting reports in the literature on the effect of aging on the hypothalamo neurohypophyseal system (HNS) in rats, multiple parameters associated with the HNS were evaluated in young (4 months), fully mature (14 months), and old (25 months) Fischer 344 rats under basal and stimulated conditions. The hypothalamic hormones oxytocin and vasopressin were compared in radioimmunoassay of serum, urine, brain and pituitary. Information on body weight, water intake, urine output, serum hematocrit and plasma osmolality was also obtained from the same subjects and analyzed together with these data. Finally, semi quantitative histofluorescence assessment of the noradrenergic innervation of the mediobasal hypothalamus from the same animals was performed to determine the extent of central afferent input to the HNS with advancing age. The circulating levels of vasopressin and oxytocin did not significantly differ in the three age groups under basal conditions. Serum vasopressin concentration was increased following water deprivation, and the increase was comparable in all age groups. Serum oxytocin was also increased following water deprivation in all groups, but the increase was greater in the 25-month-old rats relative to the 4-month-old rats. Urinary excretion of vasopressin was used as an index of daily vasopressin secretion. The urinary concentration of vasopressin was less in aged rats relative to young controls, though an increased urine volume in the mature and old animals meant that total vasopressin excretion in the urine was comparable at all ages studied. The increased urine volume in the mature and aged rats does not appear to reflect a decrease in renal sensitivity to vasopressin, since all age groups demonstrated a comparable reduction in urine volume during water deprivation, at comparable concentrations of circulating vasopressin. These data suggest that the increase in urine volume observed in the 14- and 25-month-old rats may be a function of increased fluid intake rather than hyperactivity in the HNS. The concentrations of both peptides were reduced in the posterior pituitary of aged rats, though again, the total amount of peptide in the gland did not change. Only oxytocin showed an age-related change in the hypothalamus, decreasing in the oldest subjects. These data indicate that the ability to secrete adequate quantities of vasopressin in response to dehydration is not compromised in Fisher 344 rats up to 25 months of age.

Inhibition of platelet-activating factor induced renal hemodynamic and tubular dysfunctions with L-655,240, a new thromboxane-prostaglandin endoperoxide antagonist.

The continuous infusion or bolus injection of the platelet-activating factor (PAF) is associated with profound hypotension, marked reductions of renal plasma flow, glomerular filtration, and urinary sodium excretion. All these effects are inhibited by blocking PAF receptors. To examine further the potential mediators of PAF on renal function, we utilized L-655,240 (6 mg/kg, intravenously), a thromboxane-prostaglandin endoperoxide antagonist, to study the systemic and renal response to PAF (0.8 micrograms/kg, intravenously) in the anesthetized dog, using clearance methodology. PAF decreased blood pressure from 115 +/- 7 to 54 +/- 4 mmHg (1 mmHg = 133.3 Pa), renal plasma flow from 105 +/- 6 to 74 +/- 56 mL/min, and glomerular filtration from 43 +/- 3 to 32 +/- 1 mL/min. PAF also reduced urine volume from 1.1 +/- 0.2 to 0.4 +/- 0.1 mL/min, and urinary sodium from 158 +/- 7 to 86 +/- 7 mu equiv./min. L-655,240 alone had no significant effect on blood pressure, renal plasma flow, and filtration rate, at any dose. However, the 6-mg/kg dose resulted in a slight elevation of diuresis, from 1.1 +/- 0.2 to 1.9 +/- 0.1 mL/min, and urinary sodium, from 134 +/- 13 to 212 +/- 19 mu equiv./min. All doses of L-655,240 blocked the effect of PAF on blood pressure. However, the two lower doses of this antagonist (1 and 3 mg/kg) failed to prevent the PAF-induced fall of renal plasma flow and filtration rate, and attenuated the effect on urinary sodium in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

The Protective Effect of Thromboxane Synthetase Inhibition on Renal Function in Systemic Sepsis

To study the role of thromboxane in systemic sepsis and renal failure, peritonitis was induced surgically in 22 sheep, leading to local and systemic sepsis. A selective thromboxane synthetase inhibitor, U63,557A (Upjohn Co, Kalamazoo, MI) was given before surgery in five animals and 30 minutes after surgery in five animals. A typical picture of volume-loaded, normotensive, vasodilated septic shock developed in all animals. Twenty four hours after induction of sepsis, the control group showed a marked reduction in glomerular filtration rate (GFR), urine volume, and urinary sodium excretion. Pretreated animals showed no change in GFR and a smaller reduction in urine volume and sodium excretion. The posttreatment group showed no change in any parameters of renal function. Plasma renin activity, urinary TXB2 excretion, and urinary 6-keto PGF1 alpha excretion increased after 24 hours only in the control group. Urinary TXB2 excretion was reduced by 80% in animals given U63,557A before surgery. The results indicate a significant protective effect of U63,557A on renal function during septic shock, probably related to reduced thromboxane synthesis, with no apparent deleterious systemic effects. The results support a role for thromboxane in the pathogenesis of acute renal failure in systemic sepsis.

Transdermal permeation of vasopressin. II. Influence of Azone on in vitro and in vivo permeation

Different enhancers were evaluated by measuring in vitro diffusion of aqueous vasopressin solution through excised rat skin after pretreatment with enhancers. Azone was found to be the most effective enhancer studied, increasing the flux about 15 times. Concentrations of Azone higher than 3% v/v did not show any further enhancement of flux. The enhancement of flux by Azone in hairless mouse skin was more dramatic (about 70 times), suggesting that the mechanism of enhancement in hairless mouse skin might be different than in the rat. The effect of Azone was evaluated in vivo using adult vasopressin-deficient Brattleboro rats. Urine was collected at time intervals after topical administration of vasopressin, and urine volume, osmolality and radioactivity were determined. Significant reduction in urine volume and increase in osmolality over a 24 h period confirmed the enhancement of vasopressin absorption in presence of Azone found in vitro.

Intrarenal dopamine acts at the dopamine-1 receptor to control renal function.

Exogenous dopamine increases renal blood flow and produces diuresis and natriuresis in mammalian species. Dopamine is produced intrarenally and dopamine-1 receptors have been demonstrated within the kidney. However, the role of intrarenal dopamine in the control of renal function is unknown. We studied the renal effects of a specific dopamine-1 antagonist, SCH 23390 (SCH, MW 398, Schering-Plough, Bloomfield, New Jersey, USA) infused into the renal artery of uninephrectomized conscious dogs (n = 5) in metabolic balance at a sodium intake of 40 mmol/day. The infusion of SCH at 0.01 pmol/kg per min did not change the urinary flow rate or urinary sodium excretion. Significant dose-dependent reductions in urine volume, urinary sodium excretion and fractional excretion of sodium were observed with intrarenal SCH administration at 0.1, 5.0 and 10 pmol/kg per min. Rebound diuresis and natriuresis occurred after cessation of SCH administration. There were no changes in renal haemodynamic function, systemic plasma renin activity (PRA), plasma aldosterone concentration or mean arterial pressure during intrarenal SCH administration. These results demonstrate for the first time that intrarenal dopamine controls renal function physiologically by acting at the renal dopamine-1 receptors.

Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats.

1. Flosequinan (BTS 49 465, 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg-1 and 20 mg kg-1 flosequinan causing similar falls in mean blood pressure to 1 mg kg-1 and 3 mg kg-1 hydralazine respectively. In normotensive cats, 5 mg kg-1 flosequinan caused similar falls to 0.5 and 1.0 mg kg-1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2. The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P less than 0.05). 3. In normotensive dogs, flosequinan, 10 and 20 mg kg-1 orally, caused a small but non-significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg-1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P less than 0.01). 4. Neither flosequinan, 10 mg kg-1 orally, nor hydralazine 1 mg kg-1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p-aminohippuric acid clearance in normotensive dogs. 5. The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.

Short-term toxicity study of allyl isothiocyanate in rats.

Allyl isothiocyanate (AITC) was given in doses of 0, 10, 20, or 40 mg/kg (5 days/week) by oral intubation to male rats for up to 6 weeks. The highest dosage level caused a decrease in body weight, thymus weight, blood glucose and serum globulin levels. Haematological examination revealed an increased percentage of neutrophils and a decreased percentage of lymphocytes after treatment for 2 weeks. Increased liver and adrenal weights were found in all test groups. Renal dysfunction was indicated by increased urinary aspartate amino-transferase activity, reduced urine volume and changes in the specific gravity of the urine. Histopathological changes were observed in the kidneys of animals at dosages of 20 and 40 mg/kg and in the livers of animals at the highest dosage level.

Renal sensitivity to angiotensin II in the conscious dog.

Local formation of angiotensin II (AII) within the kidney has been demonstrated. Changes in renal function induced by inhibitors of the renin-angiotensin system have been the basis for the postulate that AII may act as a paracrine substance in the kidney. We studied the renal action of chronic intrarenal infusions of AII at doses between 2 and 2000 fmol/kg X min in uninephrectomized conscious dogs monitored on 80 meq daily sodium intake. Exogenous AII was confined to the kidney, as demonstrated by the absence of systemic pressor and adrenal cortical responses during the intrarenal infusion. After 2 control days, each dose of AII was infused intrarenally for a period of 3 days. The smallest intrarenal dose of AII that caused significant antinatriuresis and antidiuresis was 20 fmol/kg X min. A significant reduction in urinary volume and sodium excretion occurred during the first 24 h of the infusion period and was proportionate to the amount of peptide infused. Renal escape from the antinatriuretic and antidiuretic effects of the peptide ensued on the second and third days of infusion. There were no significant changes in urinary potassium excretion, plasma renin activity (PRA), plasma aldosterone concentration, or blood pressure throughout the period of intrarenal AII administration. These data demonstrate dose-dependent direct antinatriuretic and antidiuretic actions of low AII concentrations. Escape from the sodium-retaining action of intrarenal AII occurred by 48 h and was independent of suppression of endogenous renin-angiotensin. These results indicate that AII alters renal function by direct intrarenal mechanisms.