Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

An assessment of dioxin exposure across gestation and lactation using a PBPK model and new data from Seveso.

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4-39years old and in Subcohort B, the 18 women were 3-17years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations.

Meeting report: international workshop on endocrine disruptors: exposure and potential impact on consumers health.

The French Agency for Food, Environmental and Occupational Health and Safety (Anses) hosted a two-day workshop on Endocrine Disruptors: Exposure and Potential Impact on Consumers Health, bringing together participants from international organizations, academia, research institutes and from German, Swedish, Danish and French governmental agencies. The main objective of the workshop was to share knowledge and experiences on endocrine disruptors (ED) exposure and potential impact on consumers' health, to identify current risk assessment practices and knowledge gaps and issue recommendations on research needs and future collaboration. The following topics were reviewed: (1) Definition of ED, (2) endpoints to be considered for Risk assessment (RA) of ED, (3) non-monotonic dose response curves, (4) studies to be considered for RA (regulatory versus academic studies), (5) point of departure and uncertainty factors, (6) exposure assessment, (7) regulatory issues related to ED. The opinions expressed during this workshop reflect day-to-day experiences from scientists, regulators, researchers, and others from many different countries in the fields of risk assessment, and were regarded by the attendees as an important basis for further discussions. Accordingly, the participants underlined the need for more exchange in the future to share experiences and improve the methodology related to risk assessment for endocrine disrupters.

A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals.

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

Physiological modeling and derivation of the rat to human toxicokinetic uncertainty factor for the carbamate pesticide aldicarb.

Aldicarb (ALD, 2-methyl-2-(methylthio)-propionalaldehyde O-(methyl-carbamoyl) oxime, Temik) is widely used as an insecticide, nematocide and acaricide and it is oxidized to aldicarb sulfoxide (ALX) and aldicarb sulfone (ALU). Neither a toxicokinetic model nor an estimate of the target tissue dose of ALD and its metabolites in exposed organisms is available. The objective of this study was: (i) to develop a physiologically based toxicokinetic (PBTK) model for ALD in the rat and humans, and (ii) to determine the interspecies toxicokinetic uncertainty factor (UF(AH-TK)) of ALD. The model consists of a series of mass balance differential equations that describe the time course behavior of ALD in blood, liver, kidney, lungs, brain, fat, and rest of the body compartments. The physiological parameters of the model (blood flow rates, cardiac output, and tissue volumes) were obtained from the literature, while the maximum velocity (mg/kg/min) and the Michaelis constant (mg/l) for ALD oxidation in rats and humans were determined by in vitro AH-TK microsomal assays. The estimation of the tissue:blood partition coefficient was accomplished within the PBTK model by representing the tissues as a composite of neutral lipids, phospholipids and water, and providing the vegetable oil:water partition coefficient as input parameter. The validity of the rat PBTK model was assessed by comparing the model simulations of ALX time course blood concentrations and the inhibition patterns of acetylcholinesterase (AChE) in erythrocytes and plasma obtained by administering rats ALD (0.1 and 0.4 mg/kg, iv). The human PBTK model was validated by comparing the simulations of AChE inhibition patterns in blood with human experimental data obtained from oral administrations of ALD. The UF(AH-TK) for ALD was determined by dividing the areas under the blood and brain concentration vs time curve (AUCCV, AUCCBR) for ALD and ALX in the rat and in human exposed to the same dose. The results indicate that with respect to parent chemical, equivalent applied doses in rats and humans result in a 9.5-fold difference in the AUC(CV) and AUC(AH-TK) respectively, in the two species, and 17-fold difference in the AUC(CV) and AUC(CBR) with respect to the metabolite. In other words, in order to have toxicokinetic equivalence in rats and humans, the former species must be exposed to a dose that is 9.5 and 17 times higher than the human with respect to the parent chemical and the metabolite respectively. Overall, the present study demonstrates the applicability of PBTK models in the quantitative evaluation of UH(AH-TK), and shows that their current default values are inaccurate, at least with respect to ALD, which has potential negative implications in the alleged protection of risk estimates derived from them.

A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses.

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region.

Biological effects of embedded depleted uranium (DU): summary of armed forces radiobiology research institute research.

The Persian Gulf War resulted in injuries of US Coalition personnel by fragments of depleted uranium (DU). Fragments not immediately threatening the health of the individuals were allowed to remain in place, based on long-standing treatment protocols designed for other kinds of metal shrapnel injuries. However, questions were soon raised as to whether this approach is appropriate for a metal with the unique radiological and toxicological properties of DU. The Armed Forces Radiobiology Research Institute (AFRRI) is investigating health effects of embedded fragments of DU to determine whether current surgical fragment removal policies remain appropriate for this metal. These studies employ rodents implanted with DU pellets as well as cultured human cells exposed to DU compounds. Results indicate uranium from implanted DU fragments distributed to tissues far-removed from implantation sites, including bone, kidney, muscle, and liver. Despite levels of uranium in the kidney that were nephrotoxic after acute exposure, no histological or functional kidney toxicity was observed. However, results suggest the need for further studies of long-term health impact, since DU was found to be mutagenic, and it transformed human osteoblast cells to a tumorigenic phenotype. It also altered neurophysiological parameters in rat hippocampus, crossed the placental barrier, and entered fetal tissue. This report summarizes AFRRI's depleted uranium research to date.

Significant linkage for Tourette syndrome in a large French Canadian family.

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS.

Gender and functional outcome after coronary artery bypass.

BACKGROUND: Female gender is an established risk factor for increased mortality and morbidity after coronary artery bypass graft (CABG) surgery. However, the impact of gender on functional outcome after CABG is not well established. METHODS: Functional status was assessed at baseline and at 6 months with the Duke Activity Status Index (DASI) in 196 consecutive patients undergoing isolated primary CABG. Follow-up data were complete in 158 (81%) patients. The functional status of the 54 (34%) female and the 104 (66%) male patients was compared. RESULTS: The mean DASI score was significantly lower in women at baseline (19.3 +/- 13.8 vs 28.3 +/- 16.8, P = .001) and at 6 months (22.7 +/- 16.3 vs 32.8 +/- 18.2, P = .0007); however, the 6-month change in DASI score (3.3 +/- 16.9 vs 4.5 +/- 20.0, P = .7) was comparable. A similar proportion of women and men (54% vs 53%) had improved above their baseline functional level at 6 months. CONCLUSIONS: These data demonstrate that women undergo CABG at a significantly lower functional level than men; however, the functional improvement after CABG is similar across genders.

Distribution of uranium in rats implanted with depleted uranium pellets.

During the Persian Gulf War, soldiers were injured with depleted uranium (DU) fragments. To assess the potential health risks associated with chronic exposure to DU, Sprague Dawley rats were surgically implanted with DU pellets at 3 dose levels (low, medium and high). Biologically inert tantalum (Ta) pellets were used as controls. At 1 day and 6, 12, and 18 months after implantation, the rats were euthanized and tissue samples collected. Using kinetic phosphorimetry, uranium levels were measured. As early as 1 day after pellet implantation and at all subsequent sample times, the greatest concentrations of uranium were in the kidney and tibia. At all time points, uranium concentrations in kidney and bone (tibia and skull) were significantly greater in the high-dose rats than in the Ta-control group. By 18 months post-implantation, the uranium concentration in kidney and bone of low-dose animals was significantly different from that in the Ta controls. Significant concentrations of uranium were excreted in the urine throughout the 18 months of the study (224 +/- 32 ng U/ml urine in low-dose rats and 1010 +/- 87 ng U/ml urine in high-dose rats at 12 months). Many other tissues (muscle, spleen, liver, heart, lung, brain, lymph nodes, and testicles) contained significant concentrations of uranium in the implanted animals. From these results, we conclude that kidney and bone are the primary reservoirs for uranium redistributed from intramuscularly embedded fragments. The accumulations in brain, lymph nodes, and testicles suggest the potential for unanticipated physiological consequences of exposure to uranium through this route.

Scintigraphic diagnosis of polysplenia in the adult.

PURPOSE: The authors describe an adult patient with low index of suspicion for polysplenia. The diagnostic contribution of various investigative modalities is considered, and the key role of scintigraphy is specifically highlighted. RESULTS: CT scan findings revealed multiple abdominal and retroperitoneal masses. Needle biopsy of a flank mass was nonspecific. Tc-99m sulfur colloid liver spleen scintigraphy and Tc-99m heat-denatured RBC scans showed the presence of polysplenia. CONCLUSIONS: Multiple spleens can be mistaken for abdominal neoplasms on CT. Biopsy results may not always be helpful. In patients in whom there is such a diagnostic dilemma, Tc-99m heat-denatured RBC scans can successfully establish the definitive diagnosis of polysplenia.

Urinary and serum mutagenicity studies with rats implanted with depleted uranium or tantalum pellets.

During the 1991 Persian Gulf War several US military personnel were wounded by shrapnel fragments consisting of depleted uranium. These fragments were treated as conventional shrapnel and were not surgically removed to spare excessive tissue damage. Uranium bioassays conducted over a year after the initial uranium injury indicated a significant increase in urine uranium levels above natural background levels. The potential mutagenic effects of depleted uranium are unknown. To assess the potential mutagenic effects of long-term exposure to internalized depleted uranium, Sprague-Dawley rats were implanted with depleted uranium and their urine and serum were evaluated for mutagenic potential at various times after pellet implantation using the Ames Salmonella reversion assay. Tantalum, an inert metal widely used in prosthetic devices was used for comparison. Enhancement of mutagenic activity in Salmonella typhimurium strain TA98 and the Ames II mixed strains (TA7001-7006) was observed in urine samples from animals implanted with depleted uranium pellets. In contrast, urine samples from animals implanted with tantalum did not show a significant enhancement of mutagenic activity in these strains. In depleted uranium-implanted animals, urine mutagenicity increased in a dose- and time-dependent manner demonstrating a strong positive correlation with urine uranium levels (r = 0.995, P < 0.001). There was no mutagenic enhancement of any bacterial strain detected in the sera of animals implanted with either depleted uranium or tantalum pellets. The results suggest that uranium content in the urine is correlated with urine mutagenicity and that urinary mutagenicity might be used as a biomarker to detect exposure to internalized uranium.

Lung cancer in women compared with men: stage, treatment, and survival.

BACKGROUND: In cardiac disease there appears to be a difference in the treatment of men and women, and thus an advantage in survival in men. This study aimed to determine whether these differences exist in lung cancer. METHODS: We undertook a retrospective cohort study in a university hospital. The study population consisted of 104 consecutive women and 104 consecutive men with newly diagnosed lung cancer between March 1988 and June 1990. The following information was collected: sex, age, presenting symptoms, investigations, histology, stage, treatment, and survival. RESULTS: The location of the tumor, presenting symptoms, investigations, and stages were similar in men and women. There was a difference in the distribution of the various histologic types of lung cancer: Small cell lung cancer was more frequent in women (25% versus 11.5% in men) and squamous cell carcinoma more frequent in men (38% in women versus 51% in men). The overall survival was similar among the two sexes, but there was a survival advantage in women when adjusted for stage. CONCLUSIONS: There was a higher incidence of small cell carcinoma in women and squamous cell carcinoma in men. There was evidence of a difference in the survival rate of lung cancer in favor of women according to stage.

The distribution of protein kinase C in human leukocytes is altered in microgravity.

Protein kinase C (PKC) is an ubiquitous enzyme that mediates intracellular signal transduction in eukaryotes. Jurkat and U937 cells were exposed to microgravity during a Space Shuttle flight and stimulated with a radiolabeled phorbol ester (3H-PDBu) that specifically activates and labels several PKC isoforms. Both the total amount of 3H-PDBu labeling per cell and the relative distribution of labeling between subcellular compartments were altered in microgravity compared to onboard and ground 1 g control samples. The amount of total phorbol ester labeling per cell was increased approximately twofold in microgravity samples when compared with onboard 1 g samples for both cell lines. The subcellular distribution of PKC in the cytosol and nuclear fractions appeared to be correlated with the applied acceleration. In both cell types the relative amount of phorbol ester labeling in the nuclear fraction decreased with applied acceleration, whereas the labeling in cytosolic fraction increased with g level. No significant differences were observed between labeling levels in the membrane fraction in both cell types. Interleukin-1beta synthesis by U937 cells was markedly decreased in microgravity when compared to the onboard 1 g control, suggesting that the observed alterations in PKC distribution may have functional consequences. The results may have important implications for the effect of gravity on cellular signal transduction.

In vivo and in vitro homologous desensitization of rat glomerular bradykinin B2 receptors.

We investigated the effects of bradykinin on glomerular bradykinin B2 receptor functions and parameters in vivo, after intrarenal infusion of bradykinin, and in vitro, after incubation of isolated rat glomeruli with bradykinin. Bradykinin transiently increased renal plasma flow whereas a second challenge was ineffective. Scatchard analysis demonstrated the presence of two populations of bradykinin binding sites whose densities were similarly decreased by about 40% after intrarenal bradykinin infusion. This decrease was not altered by an acid wash suggesting internalization of the radiolabelled ligand. The effect of bradykinin was prevented by a bradykinin B2 receptor antagonist. Pre-exposure of isolated rat glomeruli to bradykinin mimicked the in vivo results because there was a reduction in bradykinin-induced prostaglandin E2 and prostaglandin F2 alpha release. Rapid recovery was observed 15 min after washing out the bradykinin. Our results directly demonstrate a negative homologous down-regulation of B2 glomerular bradykinin receptor density under both in vivo and in vitro conditions, an effect which involves a rapid sequestration of the receptor.

[Endoscopic YAG laser and palliative therapy of cancer of the esophagus]. / Le laser YAG endoscopique et la thérapie palliative du cancer de l'oesophage.

In our institution, the YAG laser has been used to treat 110 patients with inoperable esophageal carcinoma. Therapy was palliative as patients presented metastases (41.8%), advanced systemic disease (22.7%), extensive local disease (18.2%) or recurrent carcinoma (10%). The study group included 92 men (mean age 68.4 years) and 18 women (mean age 67.0 years); 47.3% of the patients had received no previous treatment while 52.7% had been treated previously with either radiotherapy, chemotherapy, surgery, stents or dilatation. The majority of lesions were adenocarcinomas (57.3%) with squamous cell carcinomas in 37.3%; 66.3% of cancers were located in the distal third of the esophagus. The patients received a mean of 2.4 laser treatments with 4883 joules per treatment on average. The rate of major complications was 2.7% and the rate of mortality 1.8%. The median survival for the group was 4.5 months. No significant difference was found in the length of survival according to the histology of the tumour (p = 0.35), the presence of metastases (p = 0.24) and the association of other treatment modalities with the laser (p = 0.06). Functional results were considered good to excellent in 82.1% of cases. In conclusion, the YAG laser does not influence overall survival of inoperable patients, but this therapy is effective and safe and is presently the treatment of choice for these patients.

Spontaneous primary and secondary pneumothorax: a 10-year study of management alternatives.

OBJECTIVE: To study the outcome of conservative and surgical management of spontaneous pneumothorax. DESIGN: Retrospective study between January 1980 and December 1990, with a mean follow-up of 6.5 years. SETTING: A tertiary-care university hospital with a referral thoracic surgical unit. PATIENTS: All patients seen in the study period with spontaneous pneumothorax. Those with traumatic, iatrogenic or ventilator-associated pneumothoraces were excluded. There were 366 consecutive patients who had 508 episodes of spontaneous pneumothorax. Two hundred and thirty-nine patients had primary spontaneous pneumothorax (group 1); 127 had secondary spontaneous pneumothorax (group 2). INTERVENTIONS: Tube thoracostomy, apical resection with either pleurectomy or pleural abrasion. MAIN OUTCOME MEASURES: Recurrence and outcome after surgical management relative to recurrence, complications, operative technique and mean hospital stay were evaluated by clinical review and questionnaire by an independent observer. RESULTS: No significant differences were noted between the two groups with respect to the incidence of recurrent spontaneous pneumothorax after the first or second episode, and no significant differences were noted between the two operative techniques with respect to recurrence, complications, operative technique or death rate. However the mean hospital stay was doubled for group 2 patients (9.9 versus 4.3 days). CONCLUSIONS: Conservative treatment, including tube thoracostomy, was effective for primary and secondary spontaneous pneumothorax. Open surgery was effective in preventing recurrence in 95% of cases in both groups.

Evidence for existence of two distinct bradykinin receptors on rat mesangial cells.

We investigated the possible presence of bradykinin (BK) B1 receptor on rat mesangial cells (MC) by binding studies and by the effect of the B1 agonist des-Arg9-BK on intracellular calcium concentration ([Ca2+]i) and DNA synthesis in comparison with the effects of BK. Binding studies demonstrated specific, saturable binding for des-Arg9-[3H]BK inhibited by B1 but not by B2 antagonists. Scatchard analysis revealed a single class of B1 binding site with a maximum density of 15 fmol/mg protein and an affinity of 8.7 +/- 2.4 nM. Saturation and competition studies of 125I-[Tyr0]BK demonstrated the presence of two classes of B2 binding sites [dissociation constant (Kd) = 0.1 and 4 nM, respectively]. On fura-2-loaded adherent MC, both des-Arg9-BK and BK induced a biphasic increase (a transient enhancement followed by a sustained phase) in [Ca2+]i, both in primary culture and in cloned MC. Both the transient and sustained phases of [Ca2+]i induced by des-Arg9-BK were dose dependent, whereas BK induced a transient dose-dependent rise in [Ca2+]i, but the sustained phase remained constant. The increases in [Ca2+]i induced by des-Arg9-BK and BK were specifically abolished by B1 and B2 receptor antagonists, respectively, and showed homologous but not heterologous desensitization. Des-Arg9-BK and BK induced a significant proliferation (tested by cell counting and [3H]thymidine incorporation) of quiescent MC. Furthermore, the effects of des-Arg9-BK and BK were additive on Ca2+ mobilization but not on mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of cicletanine on hypertension-induced decreases in the renal kallikrein-kinin and prostaglandin systems in stroke-prone spontaneously hypertensive rats.

We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGF1 alpha in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems.(ABSTRACT TRUNCATED AT 250 WORDS)