Biomedical subjects

P Lenzi

Publications and source records attributed to P Lenzi.

At least 19 recordsLinked to original sources

PubMed2005

Placental barrier breakage in preeclampsia: ultrastructural evidence.

OBJECTIVE: It is known that the placenta acts as an immunological barrier between the mother and fetal "graft" allowing two antigenically different organisms to tolerate one another. Preeclampsia may be considered as a fetal rejection consequent to severe damage at placental endothelial and syncytiotrophoblast level. In order to verify this placental barrier damage we undertook the present study by electron microscopy. STUDY DESIGN: 14 placentae from preeclaptic women, and the same number of placentae from healthy controls were examined. RESULTS: The results showed that endothelial cells from preeclamptic placentae express various and severe alterations, consisting of swollen and bulbous cytoplasm, degenerated inter-endothelial junctions with consequent crossing of fetal blood cells outside the vessels. CONCLUSIONS: These lesions could be the ultrastructural evidence of the placental barrier breakage leading to rejective reaction we presumed to be basis of preeclampsia.

Adult↗

PubMed2004

Similarities between methamphetamine toxicity and proteasome inhibition.

The monoamine neurotoxin methamphetamine (METH) is commonly used as an experimental model for Parkinson's disease (PD). In fact, METH-induced striatal dopamine (DA) loss is accompanied by damage to striatal nerve endings arising from the substantia nigra. On the other hand, PD is characterized by neuronal inclusions within nigral DA neurons. These inclusions contain alpha-synuclein, ubiquitin, and various components of a metabolic pathway named the ubiquitin-proteasome (UP) system, while mutation of genes coding for various components of the UP system is responsible for inherited forms of PD. In this presentation we demonstrate for the first time the occurrence of neuronal inclusions in vivo in the nigrostriatal system of the mouse following administration of METH. We analyzed, in vivo and in vitro, the shape and the fine structure of these neuronal bodies by using transmission electron microscopy. Immunocytochemical investigation showed that these METH-induced cytosolic inclusions stain for ubiquitin, alpha-synuclein, and UP-related molecules, thus sharing similar components with Lewy bodies occurring in PD, with an emphasis on enzymes belonging to the UP system. In line with this, blockade of this multicatalytic pathway by the selective inhibitor epoxomycin produced cell inclusions with similar features. Moreover, using a multifaceted pharmacological approach, we could demonstrate the need for endogenous DA in order to form neuronal inclusions.

Animals↗

PubMed2004

Effects of repeated low doses of MDMA on EEG activity and fluoro-jade B histochemistry.

The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine derivative that is widely abused. In previous studies, depending on the animal species, neurotoxicity has been demonstrated for either serotonin (5-HT) or/and dopamine (DA) nerve endings. These studies focused on the basal ganglia circuitry; however, in humans chronic abuse of MDMA often results in neurological symptoms that last after MDMA withdrawal and are not related to the extrapyramidal system such as electroencephalographic (EEG) abnormalities and cognitive impairment. These alterations might be due to the concomitant intake of other illicit compounds, the consequence of MDMA-induced hyperthermia, or to a primary neurotoxicity directed to extrastriatal regions. These observations call for a more in-depth analysis on the potential involvement of brain areas outside the basal ganglia in the toxic effects induced primarily by MDMA. In the present study, we treated C57Black mice chronically (25 days) with daily injections of MDMA (2.5 mg/kg). During treatments, mice were monitored in order to detect behavioral modifications, and epidural electrodes were installed to perform EEG recording. Behavioral data showed a sensitization as measured by locomotor activity, which related to progressive and long-lasting EEG changes and neuronal degeneration within the hippocampus.

Animals↗

PubMed2003

DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy).

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. Previous reports, carried out in rodents and non-human primates, demonstrated neurotoxicity to monoamine axon terminals, although no study has analyzed nigral and striatal cell bodies at the sub-cellular level. OBJECTIVE: In this study, we examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate whether, in mice, MDMA might affect nigral and striatal cell bodies. METHODS: After administering MDMA, we analyzed effects induced in vivo and in vitro using high-performance liquid chromatography (HPLC) analysis, light- and electron microscopy with immunocytochemistry, and DNA comet assay. RESULTS: We found that MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal neurons consisting of multi-layer ubiquitin-positive whorls extending to the nucleus of the cell. These fine morphological changes are associated with clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin filaments. In the same experimental conditions, we could detect oxidation of DNA bases followed by DNA damage. The nature of inclusions was further investigated using PC12 cell cultures. CONCLUSIONS: The present findings lead to re-consideration of the neurotoxic consequences of MDMA administration. In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity.

Animals↗

PubMed2003

Presence of beta-arrestin in cellular inclusions in metamphetamine-treated PC12 cells.

Cellular inclusions containing ubiquitin and alpha-synuclein were observed in PC12 cells treated with metamphetamine (MA). To study the possible involvement of beta-arrestin in inclusion formation, we treated PC12 cells with MA for different times and analyzed the ubiquitin proteosome pathway (UPP). We found that beta-arrestin is ubiquitinated in the MA-treated PC12 cell line. The involvement of beta-arrestin in UPP was further supported by electron microscopy and by confocal microscopy, which documented the presence of beta-arrestin in these Lewy body-like inclusions. Our experiments reveal an interesting and previously unappreciated connection between beta-arrestin and ubiquitination and suggest that beta-arrestin could be involved in the development of the inclusion bodies.

Animals↗

PubMed2003

Amphetamines induce ubiquitin-positive inclusions within striatal cells.

The present study explores whether effects induced by amphetamine derivatives on striatal GABA cells might be connected with effects on dopamine (DA) metabolism. Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were administered to C57Black mice following a dosage regimen in which various doses of both drugs were injected i.p. at 2-h intervals. Neuronal inclusions produced under these experimental conditions were examined under electron microscopy. Drugs reducing DA availability prevented inclusion formation; conversely we observed that increasing DA synthesis or impairing physiological DA degradation enhanced the number of inclusions. The present study indicates that the presence of extracellular striatal DA is essential for the production of subcellular alterations induced by amphetamine derivatives. This is in line with a recent hypothesis connecting striatal DA release with degeneration of striatal GABA neurons.

Adrenergic Uptake Inhibitors↗

PubMed2003

Clinical improvement in systemic sclerosis resulting from urokinase therapy explained by light and electron microscopy skin examination.

OBJECTIVE: In our previous work, patients affected by SSc were treated with intravenous urokinase and showed clinical improvement. In this study we used microscopy to document ultrastructural alterations occurring in sclerodermic skin from SSc patients treated with urokinase. METHODS: Ten patients with SSc were selected for this study. Skin biopsies were taken from the medial side of the right forearm on the third proximal on the volar surface. The patients were then treated with urokinase for 7 consecutive days. At the end of the treatment, the patients were examined and a new skin biopsy was taken close to the above-mentioned zone of the forearm for optic and electron microscopy examination. RESULTS: The patients showed a gradual improvement of the skin after urokinase treatment. Raynaud's appeared to be less intense, and they had an increased articular range, with the restoration of movements that had previously been limited. Histological findings showed that, after treatment, skin alterations appeared attenuated, in particular the connective tissue showed a decreased density and inflammatory infiltrate was slight. Electron microscopy findings showed that collagen fibres appeared to have a more regular diameter, and the capillary vessels' lining was thicker, with fewer pinocytotic vesicles. CONCLUSION: These observations show that urokinase treatment seems to be an interesting therapeutic strategy to consider for the treatment of SSc.

Adult↗

PubMed2003

Recent knowledge on molecular components of Lewy bodies discloses future therapeutic strategies in Parkinson's disease.

Lewy bodies (LB) were first described by Lewy in 1912 [1] as neuronal pale eosinophilic inclusions which became a pathological hallmark of Parkinson s disease (PD). In his original study, Lewy defined these inclusions as pale eosinophilic cytoplasmic structures, and studies since then have revealed LB to be ubiquitin-, alpha-synuclein-, and parkin-containing inclusions. This suggests that knowledge of the biochemical steps involved in the genesis of LB might disclose a final common pathway which might be responsible for different types of inherited and sporadic parkinsonism. This would lead to the identification of new therapeutic targets for interfering with disease progression. Although LB were originally described solely in PD, in the last decade these inclusions were described in a spectrum of degenerative disorders ranging from pure movement disorders to dementia. This suggests that common biochemical alterations leading to the formation of intracellular inclusions might underlie various pathological conditions. Consequently, the knowledge of the biochemical steps involved in the formation of neuronal inclusions could represent a key to develop new therapeutic strategies. In recent years it has been possible to develop both in vitro and in vivo neuronal inclusions resembling Lewy bodies. These experimental approaches have ranged from the use of alpha-synuclein transgenic mice to the continuous exposure to a mitochondrial complex I inhibitor. The aim of the present paper is to review briefly, recent advances on Lewy body research to achieve new insight into the etiology of PD and the molecular events leading to neurodegeneration.

Animals↗

PubMed2002

Noradrenergic loss enhances MDMA toxicity and induces ubiquitin-positive striatal whorls.

Movement disorders involve a number of neurodegenerative conditions, mostly affecting basal ganglia. Parkinson's disease (PD) is classically defined by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Administration of specific neurotoxins represents a common tool to reproduce this lesion. Among these, amphetamine derivatives act as powerful monoamine neurotoxins, impairing striatal dopamine (DA) axons in mice. Despite the well-investigated effects on striatal DA terminals, only sporadic studies have focused on the potential toxicity of amphetamines towards post-synaptic neurons within the striatum. In the present work we found that 3,4-methylenedioxymethamphetamine (MDMA) produces ultrastructural alterations in striatal cells, featuring as membraneous whorls, positive for ubiquitin and heat shock protein 70. These morphological alterations were enhanced in locus coeruleus-lesioned mice.

Adrenergic Uptake Inhibitors↗

PubMed2002

Low-dose desmopressin infusion: renal action in healthy women in moderate salt retention and depletion, and interactions with prostanoids.

Studies were carried out to evaluate the influence of variations in sodium balance on the renal response to low-dose infusion of 1-desamino-8- D -arginine vasopressin (dDAVP), and the functional interaction between dDAVP and renal prostanoids. The studies were performed on healthy women in conditions of extracellular fluid volume expansion (SR group, n =9) and depletion (SD2 group, n=6), respectively. The study protocol included hypotonic polyuria (induced by oral water load) and subsequent antidiuresis (induced by low-dose infusion of dDAVP). Three 60-min clearance (cl.) periods were performed during polyuria (cl. P), early (cl. A1) and late (cl. A2) antidiuresis. The urinary concentrations of prostaglandin (PG) E(2) and the stable metabolites of PGI(2) and thromboxane (Tx) A(2), 6-keto-PGF(1alpha) (6KPGF) and TxB(2), were estimated. Paired renal functional explorations were performed in salt retention and salt depletion both in absence and presence of indomethacin (SR.I and SD2.I groups). In both paired and unpaired studies, the early and late effects of dDAVP on the functional excretory variables and the excretion of prostanoids were assessed as percentage variations, (A1-P)% P and (A2-A1)% A1. (I) dDAVP in salt retention and depletion. During early infusion dDAVP produced in both conditions a significant reduction in urinary flow rate, creatinine cl., absolute and fractional excretions of sodium, chloride and potassium; during late infusion dDAVP was effective in inducing a further significant reduction in urinary flow rate. In salt retention compared to depletion the early reductions in sodium and chloride (absolute and fractional) excretions were significantly lower. (II) Indomethacin pretreatment. During early infusion the dDAVP-induced reductions in the urinary flow rate and 6KPGF excretion were enhanced in both conditions. In salt depletion the dDAVP effects in reduction of creatinine cl. and urinary electrolyte excretions were also enhanced. During late infusion the antidiuretic effect of dDAVP was suppressed in salt retention, while in salt depletion creatinine cl., the urinary excretions of electrolytes and both 6KPGF and TxB(2) showed increases significantly different from the dDAVP effects in the absence of indomethacin. In conclusion, (a) the salt-retaining effect of dDAVP was less effective in salt retention compared to depletion. (b) Indomethacin pretreatment affected the renal action of dDAVP in a time-dependent pattern. The early effects in both conditions were consistent with an inhibited synthesis of modulator PGs. On the contrary, the late effects were consistent with the occurrence, at least in salt depletion, of an escape from dDAVP renal action. This escape phenomenon probably depended on a partial regression of the pharmacological inhibition of the modulating PGs.

Adult↗

PubMed2002

Morphological and biochemical evidence that apomorphine rescues striatal dopamine terminals and prevents methamphetamine toxicity.

Apomorphine, given by a single injection, repeated injections, or by continuous infusion, was tested for neuroprotective effects in mice administered methamphetamine or N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in order to induce striatal dopamine (DA) depletion. In the first part of the study, the DA agonist (R)-apomorphine was administered at various doses (1, 5, and 10 mg/kg), 15 min before methamphetamine (5 mg/kg x 3, 2 h apart). Mice were sacrificed 5 days later. In the second part, apomorphine was administered either continuously by subcutaneous minipump (cumulative daily dose of 0.5, 1, and 3.15 mg/kg), or as single, repeated daily injections (up to 5 mg/kg) starting 40 h after an acute administration of MPTP (30 mg/kg). Mice were sacrificed at different time intervals (up to 1 month) following MPTP injection. In all the animals, the integrity of striatal DA terminals was evaluated by measuring striatal DA levels and TH immunohistochemistry. Apomorphine dose-dependently prevented methamphetamine toxicity. These effects were neither due to a decrease in the amount of striatal methamphetamine nor to the hypothermia, and they were not reversed by the DA antagonist haloperidol. Moreover, chronic, continuous (but not pulsatile) administration of apomorphine rescued damaged striatal dopaminergic terminals. These findings confirm a protective effect of apomorphine that also consists of a neurorescue of damaged striatal DA terminals. This suggests a new hypothesis about the long-term benefits observed during continuous apomorphine administration in Parkinson's disease patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2002

Striatal postsynaptic ultrastructural alterations following methylenedioxymethamphetamine administration.

Amphetamine derivatives, such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), act as monoaminergic neurotoxins in the central nervous system. Although there are slight differences in their mechanism of action, these compounds share a final common pathway, which involves dopamine release and oxidative stress. Apart from striatal toxicity involving monoamine axons, no previous report evidenced any alteration at the striatal level concerning postsynaptic sites. Given the potential toxicity for extracellular dopamine at the striatal level, and the hypothesis for neurotoxic effects of dopamine on striatal medium-sized neurons in Huntington's disease, we evaluated at an ultrastructural level the effects of MDMA on intrinsic striatal neurons of the mouse. In this study, administering MDMA, we noted ultrastructural alterations of striatal postsynaptic GABAergic cells consisting of neuronal inclusions shaped as whorls of concentric membranes. These whorls stained for ubiquitin but not for synuclein and represent the first morphologic correlate of striatal postsynaptic effects induced by MDMA.

Animals↗

PubMed2002

Comparative analysis of senescent exorbital lacrimal glands in male and female albino rats.

In our previous study we described a bilateral-macroscopic and structural dimorphism of young rat exorbital lacrimal gland (Loewenthal's gland), which was the probable cause of the bibliographic discrepancies in the entity and the onset of its sexual dimorphism. Relevant literature also reported sex-dependent alterations in gland structure during senescence. The present study aims to carry out a comparative analysis on age-dependent changes in glands of both sides from male and female rats, using histological, histochemical and transmission electron microscopy, to evaluate whether the gland bilateral-macroscopic and structural dimorphism might influence the kind of alterations which occur in senescence. Our findings indicate that the macroscopic and structural side-specific dimorphism is not so evident in comparison with young rats. The side-specific dimorphism is evident only in male rats, in which the roundish gland appears to be more Sudan-positive in comparison with the ellipsoidal gland. The gland bilateral-macroscopic and structural dimorphism, although more evident in comparison with young animals, does not seem to influence these kinds of alterations due to senescence, a time-window in which we still observed some sexual differences also in more aged rats.

Aging↗

PubMed2001

Central and baroreflex control of heart rate during the wake-sleep cycle in rat.

UNLABELLED: Spontaneous fluctuations in Heart Period (HP) and Mean Arterial Pressure (MAP) make it possible to evaluate baroreceptor-heart rate reflex sensitivity (BRS). 30-s sequences of HP and MAP beat-to-beat values were considered in the different wake-sleep states (Wake, W; Quiet Sleep, QS; Active Sleep, AS) in rats to assess whether 1) BRS changes between states and 2) the different indexes supply consistent BRS measures. BRS indexes were calculated according to validated literature procedures as regression coefficients of HP vs. MAP 1) within all ramps of increasing or decreasing MAP of four beats or more, with HP and MAP changing in the same direction (baroreflex-mediated fluctuations, BRSp), 2) within all such ramps irrespective of the relative direction of HP and MAP changes (baroreflex + non-baroreflex, i.e. non-homeostatic centrally driven, fluctuations, BRSA). HP vs. MAP regression coefficient along the entire 30-s sequence (bHPMAP) was also calculated. RESULTS: BRSp did not change among states, BRSA decreased from QS to W to AS, bHPMAP decreased from QS to W and became negative in AS. CONCLUSIONS: 1) as indicated by BRSp, baroreflex sensitivity is state independent, 2) BRSp to BRS(A) to bHPMAP are increasingly affected by non-baroreflex fluctuations, BRSp being most apt to measure BRS, 3) non-homeostatic MAP and HP fluctuations increase from QS to W and prevail in AS. These potentially harmful fluctuations are normally buffered by baroreflexes: in the case of baroreflex impairment, circulatory risk may arise in conditions like AS, when they prevail.

Animals↗

PubMed2001

Seriate histomorphometry of whole rat stomach: an accurate and reliable method for quantitative analysis of mucosal damage.

The evaluation of mucosal damage in experimental models of gastric injury is commonly based on macroscopic detection of gross lesions and/or histological examination of tissue samples and is limited by the subjectivity of the examiner and by the paucity of nonrepresentative samples. This study proposes a novel method for the histomorphometric analysis of gastric damage, based on the examination of seriate parallel strips taken from whole rat stomachs. Strips were cut perpendicular to the lesser curvature, placed on a glass slide, with the side of each strip distal to the pylorus upward, and processed for routine histology. Sections were then observed by light microscopy: the length of damaged mucosa divided by the total length of mucosa, measured on a micrometric scale and expressed in percentage values, was indicated as the lesion index. Furthermore, to evaluate the severity of the damage, three types of lesions were discriminated depending on their depth: type I, lysis of luminal cells; type II, damage involving the cells lying on both surface mucosa and gastric pits; and type III, damage involving the lower part of the lamina propria with injury of glands associated with detachment of whole mucosal layers. Three models of acute gastric damage (ethanol, hemorrhagic shock, and indomethacin) were examined and treatment was also carried out with the antiulcer drugs omeprazole, ranitidine, and misoprostol, to show the advantages of this histomorphometric approach. The results indicate that this method allows an accurate quantitative analysis of gastric damage, and the effects of different antiulcer drugs can be better discriminated.

Animals↗

PubMed2001

Subcellular localization of a glutathione-dependent dehydroascorbate reductase within specific rat brain regions.

Recently, we described the occurrence of a dehydroascorbate reductase within the rat CNS. This enzyme regenerates ascorbate after it is oxidized during normal aerobic metabolism. In this work, we describe the neuronal compartmentalization of the enzyme, using transmission electron microscopy of those brain areas in which the enzyme was most densely present when observed under light microscopy. In parallel biochemical studies, we performed immunoblotting and measured the enzyme activity of the cytoplasm and different nuclear fractions. Given the abundance of ascorbate in the caudate-putamen, we focused mostly on the occurrence of dehydroascorbate reductase at the striatal subcellular level. We also studied cerebellar Purkinje cells, hippocampal CA3 pyramidal cells and giant neurons in the magnocellular part of the red nucleus. In addition to neurons, immunolabeling was found in striatal endothelial cells, in the basal membrane of blood vessels and in perivascular astrocytes. In neuronal cytosol, the enzyme was observed in a peri-nuclear position and on the nuclear membrane. In addition, in both the striatum and the cerebellum, we found the enzyme within myelin sheets. Dehydroascorbate reductase was also present in the nucleus of neurons, as further indicated by measuring enzyme activity and by immunoblotting selected nuclear fractions. Immunocytochemical labeling confirmed that the protein was present in isolated pure nuclear fractions. Given the great amount of free radicals which are constantly generated in the CNS, the discovery of a new enzyme with antioxidant properties which translocates into neuronal nuclei appears to be a potential starting point to develop alternative strategies in neuroprotection.

Animals↗

PubMed2001

Immunohistochemical evidence and ultrastructural compartmentalization of a new antioxidant enzyme in the rat substantia nigra.

We previously described in the rat the presence of dehydroascorbate reductase, an enzyme regenerating ascorbic acid, which is constantly lost during oxidative processes occurring at a fast rate within the central nervous system. In the present study, we specifically evaluate the occurrence of this enzyme in the rat substantia nigra by using immunohistochemistry, and by analyzing the neuronal compartmentalization of dehydroascorbate reductase within nigral neurons by immunoblotting and transmission electron microscopy coupled with immunocytochemistry. The enzyme occurs in various portions of the substantia nigra, but it is more abundant in the ventromedial part extending through the ventral tegmental area, and the dorsal portion, involving the pars compacta. Within nigral neurons, the cytosolic enzyme is present in a perinuclear position, close to mitochondria, and in the nuclear membrane; we also found the enzyme in nigral axons close to the myelin sheath. In addition, dehydroascorbate reductase was present in the nucleus of nigral neurons. The nuclear occurrence of the enzyme was confirmed by immunocytochemical labelling and immunoblotting of isolated nuclei. The nuclear enzyme was constantly evident as clusters of immunogold particles on chromatin. This localization suggests new roles for dehydroascorbate reductase (eg. prevention of DNA oxidative damage and regulation of gene transcription).

Animals↗

PubMed2001

Volume-induced natriuresis in healthy women: renal metabolism of prostacyclin and thromboxane, and physiological role of prostanoids.

In healthy women submitted to a short-term expansion in extracellular fluid volume we have evaluated the urinary excretory profile of the stable metabolites of prostaglandin(PG) I2 and thromboxane(TX) A2, 6-keto-PGF1 alpha(6KPGF) and TXB2 respectively, and assessed the physiological role played by the prostanoids in this experimental condition. Salt retention (SR group, n=9) was induced by repeated i.v. infusion of saline solution (0.9% NaCl). At the end of the treatment the body weight had increased by 0.7+/-0.2 kg (mean+/-SEM) (P<0.05). Renal functional exploration [clearance (cl.) method] was performed during hypotonic polyuria (induced by oral water load) and subsequent moderate antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue). Urinary 6KPGF and TXB2 concentrations were estimated by RIA method during polyuria (P cl. period), early and late antidiuresis (A1 and A2 cl. periods). Paired functional explorations were performed in absence (control study) and presence of indomethacin. Basal values of plasma sodium and potassium concentrations, plasma renin activity (PRA) and urinary aldosterone excretion were determined just before the control study. The results in salt retention were compared to those previously obtained in healthy women submitted to a moderate salt depletion (SD2 group, n=6), in absence and presence of the drug. Women in salt retention received 100 mg i.m. of the drug, whereas salt-depleted women received only a halved dose as in previous studies in salt depletion the full dose produced prolonged anuria. (I) Salt retention vs salt depletion. The basal values of PRA and urinary aldosterone excretion were significantly lower. During polyuria, urinary excretion of 6KPGF, 6KPGF/TXB2 ratio, urinary flow rate, creatinine cl. and absolute and fractional excretions of sodium and chloride were significantly higher. In salt retention during polyuria, significant positive correlations were found between 6KPGF excretion and functional excretory parameters. (II) Indomethacin in salt retention. The following effects were significant: (a) a reduction in prostanoid excretions in P and A1 cl. periods only; (b) during polyuria, an increase in arterial pressure, a reduction in urinary flow rate and creatinine cl. (saluresis showed not significant reduction). During polyuria significant positive correlations occurred between the absolute effects of indomethacin on 6KPGF excretion and those on functional excretory parameters. (III) Comparative effects of indomethacin in salt retention and salt depletion. Despite the double dosage of the drug, the significant reductions in urinary metabolite excretions were not significantly different during P cl. period and significantly lower in A1 cl. period compared to the corresponding significant reductions in salt depletion. During polyuria, the significant increase in arterial pressure was significantly different from the not significant effect in salt depletion; the not significant effect on saluresis was significantly different from the significant reduction in salt depletion. The results suggest the following conclusions: (1) The present model showed the functional pattern of the volume-natriuresis; (2) In salt retention, in contrast with salt depletion, indomethacin induced an increase in arterial pressure consistent with the inhibition of a PG-dependent vasodilator mechanism active at the systemic level; (3) In salt retention, in contrast with salt depletion, indomethacin failed to induce a significant reduction in saluresis. This failure can be attributed to the drug's blunted effectiveness in inhibiting the renal synthesis of saluretic PGs, and probably to the interference of the concurrent increase in arterial pressure in the renal treatment of sodium and chloride.

6-Ketoprostaglandin F1 alpha↗