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H Valtin

Publications and source records attributed to H Valtin.

At least 19 recordsLinked to original sources
PubMed1991

Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus.

To test the hypothesis that rapid adenosine 3',5'-cyclic monophosphate (cAMP) catabolism via cyclic 3',5'-nucleotide phosphodiesterase (PDE) is a cause of the unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI), we investigated properties of PDEs and other aspects of the VP-dependent cAMP-signaling system in segments of collecting ducts [inner medullary (IMCD), cortical (CCD), and outer medullary (OMCD) ducts] microdissected from control mice and mice with NDI. The activity of cAMP-PDE, but not of cGMP-PDE, was markedly higher in IMCD (+109%), and to a lesser degree in OMCD (+41%) and CCD (+27%), of NDI mice than in normal controls. The cAMP-PDE in IMCD of NDI mice was more sensitive to inhibition by the PDE isozyme-specific inhibitors rolipram and cilostamide, but not by 3-isobutyl-1-methylxanthine, than was the cAMP-PDE in controls. Levels of cAMP in intact IMCD and CCD from NDI mice completely failed to increase in response to 10(-6) M VP. Incubation with rolipram alone, but not with cilostamide alone, restored VP-dependent cAMP accumulation in IMCD of NDI mice to the levels found in control mice; addition of cilostamide further enhanced the effect of rolipram. Analogous (but quantitatively lesser) anomalies of the VP-dependent cAMP system, including the effects of PDE inhibitors, were observed also in CCD of NDI mice. However, the activity of VP-stimulated adenylate cyclase assayed in permeabilized IMCD did not differ in NDI and control mice. These results indicate that anomalously high activities of low-Km cAMP-PDE isozymes account for the failure of collecting ducts of NDI mice to increase cAMP levels in response in VP.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus.

In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Causes of the urinary concentrating defect in mice with nephrogenic diabetes insipidus.

In a strain of mice called DI +/+ Severe, nephrogenic (or vasopressin-resistant) diabetes insipidus is caused by an inability of the antidiuretic hormone (ADH, or vasopressin) to increase the water permeability of the renal collecting system. That inability, in turn, arises from abnormally high activity of the enzyme cAMP-phosphodiesterase, specifically of the isozyme type III (PDE-III), which hydrolyzes cAMP and prevents the intracellular buildup of this second messenger. Two rather specific inhibitors of PDE-III, rolipram and cilostamide, used either in vitro or in vivo, reverse the deficiencies in DI +/+ Severe mice by increasing intracellular cAMP and water permeability toward or to their normal values. These results have implications for the treatment of nephrogenic diabetes insipidus in human patients.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Influence of oxytocin on renal hemodynamics and electrolyte and water excretion.

We examined the renal effects of synthetic oxytocin (OT) in the presence and absence of vasopressin in conscious euvolemic rats. Both sexes of the Long-Evans (LE) and Brattleboro homozygous (DI) strains were used. OT infused intravenously at 0.25 and 2.5 ng X min-1 X 100 g body wt (BW)-1 resulted, respectively, in plasma concentrations of 30 +/- 6 and 265 +/- 88 pg/ml in LE rats and 46 +/- 5 and 327 +/- 29 pg/ml in DI rats. Glomerular filtration rate (GFR) was augmented most consistently by the larger dose of hormone in LE rats (P less than 0.05), whereas the low infusion rate of OT enhanced GFR in DI rats (P less than 0.01). Effective renal plasma flow was not changed significantly. OT (both doses) increased the fractional excretion of sodium two- to threefold in each strain of animal (all at least P less than 0.05 from control), whereas the fractional excretion of potassium was largely unaffected. In LE rats, a diuresis was observed with either infusion rate of hormone, accompanied by a rise in osmolar clearance (COsm). In contrast, there was no change of urine flow with the low dose of OT in DI rats, because COsm increased and the clearance of free water (CH2O) decreased proportionately. The higher infusion rate of OT promoted antidiuresis in DI rats, with negative CH2O and little change in COsm. We conclude that oxytocin enhances GFR and is natriuretic regardless of the presence or absence of endogenous vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Renal response to pentobarbital anesthesia in rats: effect of interrupting the renin-angiotensin system.

The influence of interrupting the renin-angiotensin system on the renal hemodynamic response to barbiturate anesthesia was assessed in conscious, trained, chronically catheterized rats. Anesthesia induced by pentobarbital caused a marked reduction in mean arterial pressure, heart rate, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Pretreatment of rats with captopril, an inhibitor of angiotensin I converting enzyme, prevented the impairment of renal hemodynamics by pentobarbital without restoring blood pressure. GFR remained at 100 to 110% of control values in captopril-pretreated rats receiving pentobarbital, but was reduced by pentobarbital (90-120 min after induction) to 75 +/- 5% in rats which did not receive captopril. ERPF showed similar changes. An antagonist of angiotensin II receptors, 1-sarcosine-8-isoleucine-angiotensin II, did not prevent the anesthesia-induced decrements in GFR and ERPF (GFR was reduced to 78 +/- 6% and ERPF to 68 +/- 4% at 90-120 min after pentobarbital). This failure of the antagonist of angiotensin II receptors to protect renal hemodynamics may have been due to its intrinsic agonist activity on the renal vasculature. This is suggested by the fact that, in captopril-pretreated rats, which maintained renal hemodynamics in response to pentobarbital, addition of 1-sarcosine-8-isoleucine-angiotensin II caused a reduction in GFR and ERPF and an elevated blood pressure. At 100 min after administration of pentobarbital, plasma renin activity was elevated compared to a conscious control group (3.57 +/- 0.42 vs. 1.94 +/- 0.34 ng angiotensin l/ml X hr, P less than .05). It is concluded that the renin-angiotensin system mediates an impairment of renal hemodynamics during pentobarbital anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1985

Lack of intramembranous particle clusters in collecting ducts of mice with nephrogenic diabetes insipidus.

We suggested previously, on the basis of indirect evidence, that in two strains of mice with nephrogenic defects of urinary concentration the deficiency arose from an inadequate rise in water permeability of the collecting duct system. In this study we tested the question further by assuming that the frequency of intramembranous particle (IMP) clusters seen by freeze-fracture can be used as a morphological marker of vasopressin-induced water permeability. Three genotypes of mice were studied: 1) DI +/+ Severe, with florid, vasopressin-resistant diabetes insipidus; 2) DI +/+ Nonsevere, with an intermediate deficiency of urinary concentration; and 3) normal, VII +/+ mice. In addition, we examined a group of DI +/+ Severe mice that had been injected with exogenous 1-desamino-8-D-arginine vasopressin (DDAVP) subcutaneously for 3 days. Since the results in this group did not differ from those in untreated DI +/+ Severe mice, all data for this genotype were combined. IMP clusters within luminal membranes of inner medullary collecting duct principal cells were quantified by freeze-fracture electron microscopy. Urinary osmolality and percentage of cells showing clusters were, respectively: 203 +/- 43 mosmol/kg H2O and 0% in DI +/+ Severe mice; 1,133 +/- 86 and 33 +/- 4 in DI +/+ Nonsevere mice; and 2,234 +/- 190 and 52 +/- 5 in VII +/+ animals. With the exception of one animal, there was no overlap of the data, which were significantly different from one another for each variable. We conclude that in DI +/+ Severe mice, both endogenous and exogenous vasopressin are unable to increase the water permeability of medullary collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Renal autoregulation in chronically catheterized conscious rats.

We examined renal hemodynamics and arterial plasma renin activity (PRA) concurrently in trained chronically catheterized conscious rats during decreased and elevated renal arterial pressure (RAP). Control RAP had an absolute value of 112 +/- 2 mmHg (mean +/- SE). During inflation of a suprarenal aortic cuff, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were autoregulated down to 82% of control RAP. Within this range GFR averaged 107 +/- 5% and ERPF 114 +/- 10% of the control value. During inflation of the infrarenal aortic cuff, RAP increased by 24 +/- 2% to an absolute level of 139 +/- 5 mmHg; this elevation was associated with autoregulation of both GFR (100 +/- 5% of control) and ERPF (94 +/- 6% of control). Arterial PRA had an absolute value during control conditions of 2.1 +/- 0.2 ng ANG I X ml-1 X h-1. It was not significantly altered within the autoregulatory range, being 104 +/- 10% of control during lowered RAP and 120 +/- 15% of control during elevated RAP. Nor, in separate experiments, was PRA changed significantly during the transient state, i.e., at 5, 10, or 30 min after RAP was lowered to an autoregulatory level. These studies demonstrate that, in the conscious rat, there is considerable autoregulatory capacity both below and above resting arterial pressure, and that GFR and ERPF are autoregulated concomitantly. Arterial PRA was not altered significantly within the autoregulatory range.

Animals↗
PubMed1980

Cellular action of vasopressin in medullary tubules of mice with hereditary nephrogenic diabetes insipidus.

Our previous studies (1974. J. Clin. Invest.54: 753-762.) suggested that impaired metabolism of cyclic AMP (cAMP) may be involved in the renal unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI). To localize such a defect to specific segments of the nephron, we studied the activities of VP-sensitive adenylate cyclase, cAMP phosphodiesterase (cAMP-PDIE), as well as accumulation of cAMP in medullary collecting tubules (MCT) and in medullary thick ascending limbs of Henle's loop (MAL) microdissected from control mice with normal concentrating ability and from mice with hereditary NDI. Adenylate cyclase activity stimulated by VP or by NaF was only slightly lower (-24%) in MCT from NDI mice, compared with controls. In MAL of NDI mice, basal, VP-sensitive, and NaF-sensitive adenylate cyclase was markedly (> -60%) lower compared with MAL of controls. The specific activity of cAMP-PDIE was markedly higher in MCT of NDI mice compared with controls, but was not different between MAL of control and NDI mice. Under present in vitro conditions, incubation of intact MCT from control mice with VP caused a striking increase in cAMP levels (>10), but VP failed to elicit a change in cAMP levels in MCT from NDI mice. When the cAMP-PDIE inhibitor 1-methyl-3-isobutyl xanthine (MIX) was added to the above incubation, VP caused a significant increase in cAMP levels in MCT from both NDI mice and control mice. Under all tested conditions, cAMP levels in MCT of NDI mice were lower than corresponding values in control MCT. Under the present experimental setting, VP and other stimulating factors (MIX, cholera toxin) did not change cAMP levels in MAL from either control mice or from NDI mice. The results of the present in vitro experiments suggest that the functional unresponsiveness of NDI mice to VP is perhaps mainly the result of the inability of collecting tubules to increase intracellular cAMP levels in response to VP. In turn, this inability to increase cAMP in response to VP is at least partly the result of abnormally high activity of cAMP-PDIE, a somewhat lower activity of VP-sensitive adenylate cyclase in MCT of NDI mice, and perhaps to a deficiency of some other as yet unidentified factors. The possible contribution of low VP-sensitive adenylate cyclase activity in MAL of NDI mice to the renal resistance to VP remains to be defined.

Adenylyl Cyclases↗
PubMed1980

Human neurophysins as potential tumor markers for small cell carcinoma of the lung: application of specific radioimmunoassays.

A study of 61 patients with small cell carcinoma of the lung using specific RIAs for 2 human neurophysins (HNPs) has revealed that plasma levels of 1 or both HNPs are substantially elevated (> 3 times) in 62% of the patients before the commencement of therapy. These elevated HNPs may be a consequence of production/release by tumor. Eighteen patients with elevated plasma HNPs and 14 with normal values were followed during therapy. All of the patients with normal pre-therapy levels maintained these normal levels regardless of the course of their disease. For all patients with elevated HNP levels before therapy, there was good agreement between changes in these elevated values and clinically assessed responses. Partial or complete remission (12 patients) was associated with a 2- to 30-fold reduction in HNP levels, progressive disease (6 patients) was associated with a rise in HNP levels, and relapse after a previous objective response (6 patients) was associated with an increase in plasma HNPs over values found during remission. For many of the patients in clinical remission, HNPs remained elevated above normal values, and RIA data seem to forecast recurrent disease several weeks before clinical recognition. These data provide good evidence that our RIAs for HNPs can provide a valuable guide to therapeutic management of small cell carcinoma of the lung.

Carcinoma, Small Cell↗
PubMed1979

Urinary concentrating ability during dehydration in the absence of vasopressin.

Despite the apparent absence of vasopressin (ADH), Brattleboro homozygotes [diabetes insipidus (DI) rats] can concentrate their urine when deprived of drinking water. Since other investigators have shown that reducing glomerular filtration rate (GFR) improves the concentrating ability of water-loaded dogs, the present studies were undertaken to quantify the magnitude and time course of changes in GFR during dehydration. Clearance experiments were performed in 10 conscious DI rats before and following 3, 6, 9, 12, 15, and 24 h of dehydration. Urine osmolality increased from 155.0 +/- 12.6 (SE) to 696.7 +/- 8.4 mosmol/kg H2O after 24 h. GFR averaged 984.3 +/- 79.6 microliters . min-1 . 100 g body wt-1 in the control phase, fell to about 80% of this value over the first 12 h of dehydration, and then declined to 27% at 24 h. The rats lost 20% of their body weight over the 24 h. The osmolality of the papillary tip averaged 896 +/- 44 mosmol/kg H2O at 24 h compared to a control value of 493 +/- 28. The lack of osmotic equilibration between urine and papillary interstitium suggests that dehydration did not appreciably increase the water permeability of the distal nephron. These experiments clearly show a progressive decline in GFR as urine becomes concentrated during dehydration in the absence of ADH; these events may or may not be causally related.

Animals↗
PubMed1978

Renal excretion of prostaglandins E2 and F2alpha in diabetes insipidus rats.

On the assumption that the antagonism between prostaglandin E2 and vasopressin might represent a negative feedback system, we evaluated the hypothesis that vasopressin stimulates, in vivo, the renal production of prostaglandins. For these studies we used Brattleboro homozygous rats with diabetes insipidus and Long-Evans rats for controls, Brattleboro homozygotes show a substantial reduction in the renal excretion of prostaglandin E2 and prostaglandin F2alpha. Homozygotes excreted 39 +/- 5 ng/24 h prostaglandin E2 and 40 +/- 4 ng/24 h prostaglandin F2alpha, compared to 217 +/- 40 and 221 +/- 18 ng/24 h, respectively, in control rats (P less than 0.001). Therapy of homozygotes with vasopressin tannate in oil resulted in a prompt increase in the urinary excretion of prostaglandin E2 and prostaglandin F2alpha. 1-Desamino-D-arginine vasopressin, a nonpressor analogue of vasopressin, also enhanced the renal production of prostaglandin E2. We conclude that vasopressin (antidiuretic hormone) stimulates renal production and excretion of prostaglandin E2 and prostaglandin F2alpha in vivo. It is possible that this increment of prostaglandin synthesis serves a negative feedback function by modulating the action of vasopressin on the renal tubule.

Animals↗
PubMed1978

Antidiuretic hormone-induced intramembranous alterations in mammalian collecting ducts.

Freeze-fracture electron microscopy had previously revealed antidiuretic hormone-induced aggregates of intramembranous particles in amphibian urinary bladder. To investigate the effects of antidiuretic hormone (ADH) in another ADH-sensitive epithelium, namely, mammalian renal collecting ducts, freeze-fracture studies were carried out in Brattleboro homozygous rats. Collecting duct luminal membranes of ADH-treated homozygotes showed intramembranous particle clusters (117 +/- 17/100 micron2) that were loosely packed and that occurred on both exoplasmic (E) and protoplasmic (P) faces. Untreated, control homozygous rats had significantly less (3 +/- 1/100 micron2) clusters. Changes similar to those seen in ADH-treated rats were observed in water-deprived Wistar rats. The clustered particles differed from those seen in ADH-treated amphibian urinary bladder in that the latter occurred only on the P face and were more densely packed. Nevertheless, our observations suggest a common membrane effect for ADH action that may apply in mammals and amphibia alike.

Animals↗
PubMed1978

Characterization of an antiserum used in a radioimmunoassay for arginine-vasopressin: implications for reference standards.

The region of the arginine-vasopressin (AVP) molecule critical for binding to the effective antibodies in a RIA has been localized to the vicinity of the Phe3 position by using the cross-reaction in the assay between AVP and a number of its structural analogs. Binding seems to be almost independent of any direct contributions from components of the tripeptide tail of AVP. Using this RIA it was found that disequilibrium conditions of incubation produce a 5-fold increase in assay sensitivity over equilibrium conditions. Amino acid analysis revealed that three synthetic peptide preparations used as reference standards comprised only 70-80% of their weight as peptide and this finding points up the need to correct such reference standards for their peptide content. The ratio of rat vasopressor activity to RIA activity of these three preparations as well as of a natural AVP preparation, however, approximated unity. Results obtained comparing measurements of AVP in rat neural lobes by RIA and rat vasopressor assay show a correlation between RIA and bioassay of 0.9406, a slope of 1.086, and an intercept of 20 mU, suggesting good agreement for AVP determined by these two assay systems.

Animals↗
PubMed1977

Structural and functional heterogeneity of mammalian nephrons.

Since the anatomical descriptions of Bowman showing differences between nephrons originating in the superficial and deep cortex, the concept of heterogeneity has been extended from identification of dissimilarities between nephrons to recognition of inhomogeneity within major portions of individual nephrons. We are now aware of functional correlates for the anatomical differences between nephrons, between analogous parts of different nephrons, and between the three portions of the proximal tubule and the three or more parts of the distal tubule. The implications of all of these differences for major renal processes, such as isosmotic fluid transport, salt balance, hypertension, urinary acidification, and the concentration or urine are now being defined. It seems likely that new conceptual and technical approaches, especially electron probe microanalysis, will add appreciably to defining the role of heterogeneity in these and other processes. Despite the increasing complexity of nephron heterogeneity, it is recommended that our basic nomenclature be retained and that new findings be incorporated into the schema set forth by Karl Peter. It would be very helpful if reports of investigations on single nephrons or segments of nephrons were to include diagrams delineating the structures on which the work was performed.

Animals↗