Age-associated decrease in vasopressin-induced renal water transport: a role for adenylate cyclase and G protein malfunction.

Aging is associated with a decline in renal concentrating ability in response to dehydration-induced arginine vasopressin (AVP) release. To examine target tissue sensitivity, cortical collecting tubules (CCT) were individually microdissected from young (3 months), middle-aged (2-3 years) and old (4-5.5 years) rabbits and subjected to in vitro perfusion analysis and tissue culture of defined epithelial monolayers. Osmotic fluid transport was compared with adenylate cyclase activity and an age-associated decline in both parameters detected in response to increasing doses of AVP. [3H]-AVP binding was unchanged in CCT epithelia of different ages, excluding receptor alterations as the underlying mechanism. Also, hydraulic conductivity measurements of isolated young and old CCT were not significantly different, excluding post-cAMP events as a major mechanism of reduced sensitivity. Effects of cholera toxin and forskolin on hydraulic conductivity and adenylate cyclase activity showed a dramatic decrease in the ability of these compounds to elicit a response in CCT epithelia from old rabbits. It was concluded that alterations in Gs proteins and the catalytic unit of adenylate cyclase-were responsible for the age-associated decline in CCT response to AVP.

Effects of prostacyclin on the cAMP system in cultured rat inner medullary collecting duct cells.

Rat inner medullary collecting tubule (RIMCT) cells produce arachidonate derivatives including prostacyclin (PGI2). In RIMCT cells, PGI2 causes a dose-dependent increase in adenosine 3',5'-cyclic monophosphate (cAMP; fmol/micrograms protein) from a basal level of 15.6 +/- 1.7 to 32.4 +/- 5.7 at 0.3 microM, 63.3 +/- 8.3 at 3 microM, and 103.5 +/- 9.4 at 30 microM PGI2. At concentrations of arginine vasopressin (AVP) from 10(-7) to 10(-9) M, cAMP was greater in the presence than absence of 3 microM PGI2, suggesting independent sites of action. To assess whether the PGI2 effect is mediated by the prostaglandin E2 (PGE2) receptor, desensitization studies were performed. A 6-h preincubation with 10 microM PGE2 blunted the response to 3 microM PGE2 by 90 +/- 2% but the PGI2 response was decreased by only 31 +/- 5%, P less than 0.001. Carbaprostacyclin (carba-PGI2), a stable analogue of PGI2, blunted the cAMP response to PGI2 by 94 +/- 3% but to PGE2 by only 46 +/- 7%, P less than 0.005. The postreceptor effect of PGI2 on components of the adenylate cyclase was examined. The response to forskolin was markedly potentiated by PGI2. PGI2 (3 microM) caused an increase in cAMP of 67 fmol/micrograms over basal in the absence of forskolin, of 164 fmol/micrograms at 10(-7) M forskolin, of 386 fmol/micrograms at 10(-6) M forskolin, and of 563 fmol/micrograms at 10(-5) M forskolin. The response of PGI2 was likewise potentiated by forskolin. Water permeability alone or in response to AVP in isolated perfused inner medullary collecting tubules was not affected by carba-PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Histidine regulation of cyclic AMP metabolism in cultured renal epithelial LLC-PK1 cells.

L-Histidine and imidazole (the histidine side chain) significantly increase cAMP accumulation in intact LLC-PK1 cells. This effect is completely inhibited by isobutylmethylxanthine (IBMX). Histidine and imidazole stimulate cAMP phosphodiesterase activity in soluble and membrane fractions of LLC-PK1 cells suggesting that the IBMX-sensitive effect of these agents to stimulate cAMP formation is not due to inhibition of cAMP phosphodiesterase. Histidine and imidazole but not alanine (the histidine core structure) increase basal, GTP-, forskolin-, and AVP-stimulated adenylate cyclase activity in LLC-PK1 membranes. Two other amino acids with charged side chains (aspartic and glutamic acids) increase AVP-stimulated but neither basal- nor forskolin-stimulated adenylate cyclase activity. This suggests that multiple amino acids with charged side chains can regulate selected aspects of adenylate cyclase activity. To better define the mechanism of histidine regulation of adenylate cyclase, membranes were detergent-solubilized which prevents histidine and imidazole potentiation of forskolin-stimulated adenylate cyclase activity and suggests that an intact plasma membrane environment is required for potentiation. Neither pertussis toxin nor indomethacin pretreatment alter imidazole potentiation of adenylate cyclase. IBMX pretreatment of LLC-PK1 membranes also prevents imidazole to potentiate adenylate cyclase activity. Since IBMX inhibits adenylate cyclase coupled adenosine receptors, LLC-PK1 cells were incubated in vitro with 5'-N-ethylcarboxyamideadenosine (NECA) which produced a homologous pattern of desensitization of NECA to stimulate adenylate cyclase activity. Despite homologous desensitization, histidine and imidazole potentiation of adenylate cyclase was unaltered. These data suggest that histidine, acting via an imidazole ring, potentiates adenylate cyclase activity and thereby increases cAMP formation in cultured LLC-PK1 epithelial cells. This potentiation requires an intact plasma membrane environment, occurs independent of a pertussis toxin-sensitive substrate and of products of cyclooxygenase, and is inhibited by IBMX. This IBMX-sensitive pathway does not involve either inhibition of cAMP phosphodiesterase activity or a stimulatory adenosine receptor coupled to adenylate cyclase.

Mechanism of neuropeptide Y inhibition of vasopressin action in rat cortical collecting tubule.

Neuropeptide Y (NPY) is a unique 36-amino acid peptide found in high concentrations in brain and peripheral neurons. Although NPY is present in kidney tissue, its role in regulation of renal function has not been delineated. We found that NPY significantly decreases arginine vasopressin (AVP) but not adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated hydraulic conductivity (Lp) in perfused rat cortical collecting tubules (CCT). Either alpha 2-adrenergic receptor blockade (yohimbine) or occupancy (clonidine) prevent NPY inhibition of AVP-stimulated Lp. By contrast, alpha 1-adrenergic receptor blockade with prazosin did not alter NPY inhibition of AVP action. Pretreatment of CCT with pertussis toxin also abolishes NPY inhibition of AVP-stimulated Lp. These data suggest that NPY acts via an alpha 2-adrenergic receptor coupled to a pertussis toxin-sensitive protein to inhibit AVP-stimulated cAMP formation and Lp in the rat CCT.

Cyclic guanosine monophosphate increases hydraulic conductivity in rabbit and rat CCT.

Although guanosine 3',5'-cyclic monophosphate (cGMP) is present in renal nephron segments, there is no information on the role of cGMP as a mediator of renal tubular transport events. We found that an activator of guanylate cyclase (nitroprusside) and 8-bromocGMP (8-BrcGMP) significantly increased hydraulic conductivity in rabbit and rat cortical collecting tubules (CCT) perfused in vitro. The effect of 10(-4) M 8-BrcGMP to increase CCT hydraulic conductivity was reversible and comparable in magnitude and time course to that produced by maximal concentrations of arginine vasopressin. In rabbit CCT, cGMP increased hydraulic conductivity in the presence of phosphodiesterase inhibition with methylisobutylxanthine and in the presence of supramaximal concentrations of arginine vasopressin. Neither nitroprusside nor 8-BrcGMP stimulated adenylate cyclase activity in microdissected CCT. These data demonstrate that cGMP can act independently of either stimulation of adenylate cyclase activity or inhibition of phosphodiesterase activity to increase hydraulic conductivity in the mammalian CCT.

Sodium taurocholate increases hydraulic conductivity in rabbit collecting tubule.

Abnormalities in renal tubular function occur commonly in the setting of hyperbilirubinemia. In the present studies, the possibility that the bile salt sodium taurocholate exerts a direct effect on renal epithelial transport was investigated in vitro. We found that addition of sodium taurocholate to fluid bathing perfused rabbit cortical collecting tubules increases hydraulic conductivity (Lp) in a manner similar in time course and significantly less in magnitude to that observed with maximal concentrations of arginine vasopressin. Sodium taurocholate reversibly potentiates rabbit cortical collecting tubular Lp stimulated by maximal concentrations of arginine vasopressin and a nonhydrolyzable cyclic AMP analogue. We also found that sodium taurocholate induces a dose-dependent leak from tubular lumen to bathing fluid of a small molecular weight substance (125I-iothalamate). Our studies suggest that sodium taurocholate increases rabbit cortical collecting tubular Lp by a cyclic AMP independent mechanism.

Fenofibrate affects the compositions of lipoproteins.

This study assessed the effects of fenofibrate on lipoprotein levels and lipoprotein compositions in a subgroup of patients who participated in a multicenter fenofibrate study. Eleven men and 10 women aged 29 to 63 were studied, 12 with type II A and nine with type II B hyperlipoproteinemia. Fasting blood samples were obtained every four to six weeks. Lipoprotein lipids were quantified by procedures of the Lipid Research Clinics, and apolipoproteins by radioimmunoassay. Fenofibrate decreased mean triglyceride and cholesterol levels of the type II A patients from 130 to 99 and from 286 to 237 mg/dl, respectively. Levels of very low-density lipoprotein triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol decreased and high-density lipoprotein cholesterol levels rose. Apolipoprotein B and apolipoprotein E levels decreased, whereas apolipoprotein AI and apolipoprotein AII levels rose. The mean very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratio and low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratio decreased. The low-density lipoprotein cholesterol:apolipoprotein B ratio and high-density lipoprotein cholesterol: apolipoprotein AII ratio decreased as did the apolipoprotein AI:apolipoprotein AII ratio. In patients with type II B hyperlipoproteinemia, triglyceride and cholesterol levels decreased with fenofibrate therapy with most of the decrease in triglyceride levels due to very low-density lipoprotein triglycerides, whereas the decrease in total cholesterol levels was due to decreases in very low-density lipoprotein and low-density lipoprotein cholesterol. High-density lipoprotein cholesterol levels rose. The decrease in low-density lipoprotein cholesterol levels was not significant in this group. Apolipoprotein E levels decreased and apoliprotein AI and apolipoprotein AII levels rose. Indices of composition in type II B patients were similar to those in type II A patients but the changes were less dramatic. Very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratios decreased significantly, but low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratios did not change significantly with treatment. The mean low-density lipoprotein cholesterol:apolipoprotein B ratio, high-density lipoprotein cholesterol:apolipoprotein AII ratio, and apolipoprotein AI:apolipoprotein AII ratio all were lowered by therapy. Thus, very low-density lipoprotein and low-density lipoprotein lost cholesterol in response to fenofibrate therapy and high-density lipoprotein particles became enriched in cholesterol.

Flow dependence of vasopressin-stimulated hydraulic conductivity in rabbit collecting tubule.

Flow rate dependence of both electrolyte and nonelectrolyte transport in various nephron segments has been described. Prior studies have used relatively leaky epithelia in which the flow rate-dependent transport phenomena can be explained in terms of alterations in axial and radial concentration profiles. In this study, the flow rate dependence of either vasopressin or cyclic adenosine monophosphate-stimulated water flux (Jv), hydraulic conductivity (Lp), and osmotic permeability (Pf) were measured in isolated perfused rabbit cortical collecting tubules. Increasing perfusion rate from 6.0 +/- 0.4 to 20.7 +/- 1.2 nl/min results in highly significant increases in Jv (131%) and in Lp and Pf (120%). In this relatively tight epithelium, osmotic equilibrium did not occur. Although the mechanism of this effect remains to be elucidated, the present results mandate maintenance of constant flow rates when examining the perfused cortical collecting tubular response to vasopressin.

Calcium modulates vasopressin effect in rabbit cortical collecting tubule.

The calcium ion has been proposed to be an important mediator of the hydroosmotic response to arginine vasopressin (AVP). We examined the effect of reducing basolateral calcium activity on hydraulic conductivity (Lp) in response to AVP in rabbit cortical collecting tubules (CCT) perfused in vitro. Each tubule served as its own control. Reducing bathing fluid calcium from 0.94 mM to 4.6 microM reduced Lp in each tubule (mean decrease from 146 +/- 13 to 106 +/- 7 cm X s-1 X atm X 10(-7), n = 11, P less than 0.025). To determine whether this inhibitory effect was due to a decrease in cellular calcium uptake, we measured the effect of adding 10(-4) M lanthanum to bathing fluid on AVP-stimulated Lp. Lanthanum decreased Lp (from 109 +/- 13 to 80 +/- 10 cm X s-1 X atm X 10(-7), P less than 0.05) in each tubule. To examine the site at which low peritubular calcium activity regulates AVP action, we measured the effect of decreasing bathing fluid calcium on 8-[p-chlorophenylthio]-adenosine 3',5'-cyclic monophosphate (ClPheS-cAMP)-stimulated Lp (n = 5). Decreasing bathing fluid calcium significantly decreases (P less than 0.025) Lp response to ClPheS-cAMP. Since these results suggest that cellular calcium uptake can exert a post-cAMP effect to modulate AVP action, we examined the effect of the calcium ionophore A23187 (10(-7) M) on AVP- and ClPheS-cAMP-stimulated Lp A23187 reversibly potentiates (25-30%, P less than 0.025) the Lp response to both AVP and ClPheS-cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of intensive dialysis in acute renal failure.

The efficacy of vigorous dialysis in the management of acute renal failure remains controversial. In order to examine the beneficial role of vigorous dialysis, a prospective study was carried out in 34 patients paired by acute renal failure etiology and treated with sufficient dialysis to maintain predialysis blood urea nitrogen and serum creatinine below either 60 and 5 mg/dl (intensive) or 100 and 9 mg/dl, respectively (non-intensive). Serum creatinine was at least 8 mg/dl in all patients prior to random assignment to intensive or non-intensive dialysis. Mean predialysis blood urea nitrogen and serum creatinine, respectively, were 60 +/- 23 and 5.3 +/- 1.5 mg/dl in the intensively dialyzed group and 101 +/- 18 and 9.1 +/- 1.4 mg/dl in the non-intensively dialyzed group (both p less than .001). Predialysis serum bicarbonate and blood pH were lower and serum phosphate higher in the non-intensively dialyzed patients. Daily weight changes, increases in blood urea nitrogen, protein and calorie intakes were similar. While hemorrhagic episodes tended to be more frequent in non-intensively dialyzed patients, overall complication rates were not different between the two groups. Mortality rates, which were 58.8% in the intensive and 47.1% in the non-intensive groups, also were not different. On the other hand, urine output prior to dialysis did influence survival. It is concluded that, within the limits of the study, there is no advantage to intensive dialysis in the management of acute renal failure.

Inhibition of vasopressin action by atrial natriuretic factor.

Atrial natriuretic factor results in diuresis in animals and humans, perhaps because atrial natriuretic factor increases renal blood flow. The possibility that this diuresis is due to direct inhibition of renal tubular epithelial water transport was examined in rabbit collecting tubules perfused in vitro. Atriopeptin III inhibition of the hydraulic conductivity response to the hormone arginine vasopressin but not to either 3'5'-cyclic adenosine monophosphate or forskolin was found. These results suggest that atriopeptin III acts proximal to cyclic adenosine monophosphate formation to directly affect vasopressin-stimulated water transport in the mammalian nephron. They also suggest a potential role for inhibition by atrial natriuretic factor of the renal response to arginine vasopressin as a contributor to a diuretic state.

Effect of trifluoperazine on rabbit cortical collecting tubular response to vasopressin.

Anuran membrane studies suggest that the calcium-binding protein calmodulin is necessary for arginine vasopressin (AVP) to exert a hydro-osmotic effect. We therefore examined the effect of trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphtholene sulphonamide (W-7), chemically dissimilar calmodulin inhibitors, on hydraulic conductivity (Lp) response to AVP in rabbit cortical collecting tubules perfused in vitro. Trifluoperazine but not W-7 increased basal Lp in rabbit cortical collecting tubules. When cortical collecting tubules were pre-treated with either trifluoperazine or W-7, the effect of AVP to increase Lp was significantly inhibited. To determine the site of this inhibition, Lp responses to exogenous cyclic adenosine 3',5'-phosphate (AMP) were studied. Both trifluoperazine and W-7 pretreatment significantly inhibited the effect of a cyclic AMP analogue to increase rabbit cortical collecting tubule Lp. These results suggest that calmodulin may be an important mediator of the hydro-osmotic response to AVP in the mammalian cortical collecting tube by acting at a site or sites distal to cyclic AMP formation.

Pertussis toxin prevents homologous desensitization of adenylate cyclase in cultured renal epithelial cells.

The biochemical mechanisms of adenylate cyclase desensitization in arginine vasopressin-responsive epithelial cells remain unclear. Preincubation of cultured rabbit renal cortical collecting tubular cells with arginine vasopressin leads to a 30-100% decline in arginine vasopressin-stimulated adenylate cyclase activity. This loss of adenylate cyclase activity is time- and arginine vasopressin concentration-dependent. Preincubation with arginine vasopressin does not result in significant changes in basal, NaF-, forskolin-, isoproterenol- or cholera toxin-stimulated adenylate cyclase activity. Preincubation of cells with chlorophenylthio-cAMP, forskolin, and cholera toxin does not result in loss of arginine vasopressin-stimulated adenylate cyclase activity. Since products of cyclo-oxygenase inhibit arginine vasopressin action, cells were preincubated with indomethacin. Arginine vasopressin-induced adenylate cyclase desensitization is not reversed by indomethacin. By contrast, incubation with pertussis toxin prevents arginine vasopressin-induced adenylate cycle desensitization. These data demonstrate that arginine vasopressin induces homologous desensitization in membranes from cultured rabbit cortical collecting tubular cells and suggest that this desensitization is mediated, at least in part, by pertussis toxin substrate. These observations provide a unifying mechanism for desensitization of adenylate cyclase-coupled hormone receptors.

Effects of vasopressin antagonist on vasopressin binding, adenylate cyclase activation, and water flux.

We studied the effect of an arginine vasopressin (AVP) analogue, (1-[beta-mercapto-beta, beta-cyclopentamethylenepropionic acid],2-O-ethyltyrosine, 4-valine)AVP(d[CH2]5Tyr[Et]VAVP), on the stimulation of adenylate cyclase by various hormones in the isolated nephron segments and 3H-AVP binding to renal papillary membranes from the rat. The net water flux across the renal cortical collecting tubules of the rabbit was also examined. We found that d(CH2)5Tyr(Et)VAVP significantly inhibited adenylate cyclase activation by AVP in cortical, medullary, and papillary collecting tubules and in the medullary thick ascending limb. In contrast, the AVP analogue did not alter the stimulation of adenylate cyclase by parathyroid hormone in the cortical thick ascending limb, by glucagon in the medullary thick ascending limb, and by calcitonin in cortical collecting tubules. In addition, d(CH2)5Tyr(Et)VAVP blocked [3H]AVP binding to renal papillary membranes. The enhanced net water transport induced by AVP in isolated, perfused rabbit cortical collecting tubules also was completely blocked by this AVP analogue. These results indicate that d(CH2)5Tyr(Et)VAVP specifically antagonizes the cellular action of AVP on the medullary thick ascending limb and on the cortical, medullary, and papillary collecting tubules. Evidence is also presented for competitive antagonism as the cellular mechanism of action.

Selected health care maintenance policies in chronic dialysis centers.

Although a large number of patients are maintained on chronic dialysis, there is little information regarding the medical care rendered to these patients. We therefore obtained information on health care maintenance policies from 90 dialysis centers (8,104 patients) selected from each End-Stage Renal Disease (ESRD) Network. All centers except one obtained BUN, creatinine, electrolytes, calcium, and phosphorus at intervals of 1 month or less; 85% of centers obtained a multiple-test laboratory panel at monthly intervals. Annual physical examination, ECG, and chest x-ray were performed in 80% or more of the centers. Immunization policies varied with 88%, 64%, and 17% of centers offering influenza, pneumococcal, and hepatitis B vaccine, respectively. Patterns of surveillance for anemia, osteodystrophy, and hepatitis were variable. In view of the high frequency and cost of testing, prospective studies to determine optimal methods of health care maintenance in the chronic dialysis center are indicated.

Defined human renal tubular epithelia in culture: growth, characterization, and hormonal response.

Individually microdissected nephron segments of defined epithelial origin from human kidneys were cultured in vitro in the present studies. Nephron segments of proximal convoluted tubule, proximal straight tubule, cortical thick ascending limb of Henle, and cortical collecting tubule were grown in defined media. Each cell type retained differentiated characteristics as assessed by ultrastructural morphology, marker enzyme profiles, and adenylate cyclase response to selected hormones. These studies demonstrate the feasibility of using primary cultures of well-defined segments of the human nephron to study human renal tubular epithelia in vitro.

Purinergic regulation of basal and arginine vasopressin-stimulated hydraulic conductivity in rabbit cortical collecting tubule.

An extracellular adenosine responsive site that stimulates adenylate cyclase activity has been identified in several tissues. There is limited information on the presence and physiologic significance of adenosine receptors in well-defined segments of the mammalian nephron. We therefore examined the effect of adenosine and selected analogues on basal hydraulic conductivity in rabbit cortical collecting tubules (CCT) perfused in vitro. Adenosine and analogues with an intact ribose moiety produced a significant, sustained increase in hydraulic conductivity. No increase in hydraulic conductivity was seen in either time control CCT's or CCT's exposed to an adenosine analogue with an altered ribose moiety. These experiments are compatible with the presence of a functional adenosine receptor which requires an intact ribose moiety and acts to increase hydraulic conductivity in the mammalian CCT. An intracellular adenosine responsive site, termed the "P site," which inhibits adenylate cyclase activity, has also been described in several tissues. We therefore examined the effect of a P site agonist on hydraulic conductivity responses to arginine vasopressin, forskolin and cAMP. P site stimulation with 2'5' dideoxyadenosine inhibited the effect of AVP and of forskolin but not of cAMP to increase hydraulic conductivity. These results are compatible with a functional P site in the rabbit CCT which acts at the catalytic subunit of adenylate cyclase to inhibit hydraulic conductivity. Together, these results demonstrate purinergic modulation of basal and arginine vasopressin-stimulated water flux in the mammalian collecting tubule.

Forskolin increases osmotic water permeability of rabbit cortical collecting tubule.

Forskolin is a unique diterpene that may directly activate the catalytic subunit of adenylate cyclase. We therefore examined the effect of 50 microM forskolin on osmotic water permeability in rabbit cortical collecting tubules perfused in vitro. Forskolin increased net volume flux (Jv, from 0.30 to 1.22 nl/mm/min, P less than 0.02) in all tubules. The hydro-osmotic effect of forskolin was similar with respect to magnitude and time course to that produced by a maximal dose (250 microU/ml) of arginine vasopressin. An additive effect on Jv and Lp was not observed when maximal concentrations of forskolin and arginine vasopressin were given simultaneously. The compound d(CH2)5Tyr(Et) VAVP, which noncompetitively inhibits the vasopressin receptor, significantly reduced collecting tubular hydro-osmotic response to arginine vasopressin. In contrast, the hydro-osmotic response to forskolin was maintained in the presence of d(CH2)5 Tyr(Et)VAVP. However, the hydro-osmotic response to forskolin could be inhibited by 1.0 microM guanine 5'-(beta,gamma-imido) triphosphate (GppNHp) and by the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). These results demonstrate that forskolin exerts an hydro-osmotic effect in the mammalian nephron which occurs independent of the vasopressin receptor. Guanine nucleotide regulatory proteins may modulate the osmotic water permeability effect of forskolin. Finally, calmodulin is required for full expression of the effect of forskolin to increase osmotic water flux.

The renal concentrating defect after gentamicin administration in the rat.

The present studies were carried out to delineate the mechanism of the polyuric state and renal concentration defect seen after gentamicin. Gentamicin was given at a dosage of 100 mg/kg/day subcutaneously for either 4 or 5 days to Sprague-Dawley rats and resulted in a reversible, polyuric form of acute renal failure. This nonoliguric acute renal failure was accompanied by significant polydipsia and a renal concentrating defect 11 days after gentamicin. To assess the role of polydipsia in the polyuria and renal concentrating abnormality, water intake was restricted in gentamicin-treated animals to match intake of control animals. Elimination of the polydipsia failed to eliminate the polyuria and to improve the renal concentrating abnormality. Postdehydration plasma vasopressin levels were higher in gentamicin-treated than control animals, suggesting that the renal concentrating defect was nephrogenic in origin. Daily urinary prostaglandin E2 excretion was comparable in gentamicin-treated and control animals. However, indomethacin failed to improve urinary concentrating ability, suggesting that the renal concentrating defect was prostaglandin E2 independent. Finally, depressed postdehydration inner medullary tonicity was found in gentamicin-treated animals In summary, gentamicin administration in the rat was associated with a reversible polyuric form of acute renal failure and a renal concentrating defect. This concentration defect was nephrogenic in origin, independent of polydipsia and prostaglandin E2, and was associated with a decrease in inner medullary tonicity.

Role of renal nerves, angiotensin II, and prostaglandins in the antinatriuretic response to acute hypercapnic acidosis in the dog.

Although clinical studies suggest that chronic hypercapnic acidosis may be associated with renal sodium retention, little information is available on the effect of acute hypercapnic acidosis on renal sodium excretion. We, therefore, increased PCO2 from 23 to 74 mm Hg in anesthetized dogs and observed a marked antinatriuresis as absolute sodium excretion (235 to 60 muEq/min, P less than 0.001) and fractional excretion of sodium (4.0 to 1.2 %, P less than 0.02) decreased significantly. This decrease in sodium excretion occurred independent of consistent changes in renal perfusion pressure, PO2, glomerular filtration rate, renal blood flow, extraction of P-aminohippuric acid, and filtration fraction. The antinatriuretic response to acute hypercapnic acidosis could be attenuated significantly by surgical renal denervation, intrarenal phenoxybenzamine, and by intrarenal infusion of 1-sarcosine,8-glycine angiotensin II. Administration of 10 mg/kg indomethacin enhanced the antinatriuretic response to hypercapnic acidosis in denervated kidneys. These results suggest that renal alpha-adrenergic nerves and the renal angiotensin system result in an antinatriuretic effect during acute hypercapnic acidosis. Renal prostaglandins or related substances may serve to attenuate this antinatriuretic response.