A reduction of central peptidergic responses in the spontaneously hypertensive rat.

The effect of intraventricular perfusion with hypertonic saline (HS) or angiotensin II (ANG II) on cerebrospinal fluid (CSF) vasopressin (AVP), blood pressure and heart rate was determined in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. There was a marked reduction in the central peptidergic response in the SHR. Pretreatment with the AVP (V1) antagonist abolished the pressor response to intraventricular HS in the WKY rats, but not in the SHR.

Involvement of central vasopressin receptors in the control of blood pressure.

Intraventricular perfusion with a hypertonic sodium chloride solution elicits increases in cerebrospinal fluid vasopressin and blood pressure and a decrease in heart rate. The central peptide response was greatly reduced in the hypertensive rat. Central pretreatment with the vasopressin (V1) antagonist completely abolished the pressor response to hypertonic sodium chloride in the normotensive animal. Results suggest that a central vasopressin receptor may play a role in the control of blood pressure.

Osmotic mechanisms regulating cerebrospinal fluid vasopressin and oxytocin in the conscious rat.

The effect of intraventricular and intravenous (i.v.) hypertonic saline on plasma and perfusate arginine vasopressin (AVP) and oxytocin (OT) levels was determined. A push-pull technique was used to sample third ventricular cerebrospinal fluid (CSF) in the conscious unrestrained rat. Intraventricular perfusion of hypertonic saline caused a 6.1- and 4.2-fold increase in perfusate levels of AVP and OT. Plasma levels with the same stimulus increased 3.5-fold for AVP and 3.4-fold for OT. Peak levels of the peptides occurred at 30 and 60 min in the CSF perfusate and plasma, respectively. Thus, the central peptide response occurred earlier and was of a greater magnitude than the systemic one. Intravenous hypertonic saline administration caused a rapid (15 min) increase in plasma AVP and OT, changes of 12.6- and 22.9-fold. Perfusate AVP did not change with i.v. hypertonic saline while OT was increased 10-fold. Two types of recovery experiments were performed (1) in which the rate of disappearance of 125I-labeled peptides from CSF was determined and (2) in which total body water was labeled with 3H2O and the amount of dilution determined. Both techniques showed that recovery of endogenous CSF in the push-pull perfusate was approximately 15%. Thus, the perfusate peptide levels represent an underestimation of in vivo secretion. Osmotic stimuli elicit specific changes in the third ventricular levels of AVP and OT. The differential response in the two hormones to i.v. hypertonic saline shows a uniqueness in the mechanisms controlling the central secretion of AVP and OT.

Toxicology of organic drinking water contaminants: trichloromethane, bromodichloromethane, dibromochloromethane and tribromomethane.

This study evaluated the subchronic toxicity of selected halomethanes which are drinking water contaminants. The compounds studied were trichloromethane, bromodichloromethane, dibromochloromethane and tribromomethane. Subchronic 14-day gavage studies were performed with the use of doses encompassing one-tenth the LD50 for the compounds. A 90-day gavage study of one of the compounds, trichloromethane, was also done. Parameters observed included body and organ weights, histopathology, hematology, clinical chemistries, and hepatic microsomal enzyme activities. Toxicity to the humoral immune system was assessed by measuring the number of splenic IgM antibody-forming cells and the serum antibody level to sheep erythrocytes. Cell-mediated immunity was evaluated by measuring the delayed type hypersensitivity response and popliteal lymph node proliferation response to sheep red blood cells. The functional activity of the reticuloendothelial system, as measured by the vascular clearance rate and tissue uptake of 51Cr sheep red blood cells was also determined. The major effects of the halomethanes were increased liver weights, elevations of SGPT and SGOT, decreased spleen weights and a decrease in the number of splenic IgM antibody-forming cells. The humoral immune system appeared to be an indicator of halomethane toxicity. There is evidence that subchronic 14-day exposure may be of greater value than long-term studies in determining the toxicity of these compounds.

Toxicology of chloral hydrate in the mouse.

Chloral hydrate has been found in our drinking water supplies at levels up to 5 micrograms/1. The purpose of this study was to evalute the acute and subchronic toxicology of chloral hydrate in the random-bred CD-1 mouse, to provide data for risk assessment. The acute oral LD50 of this compound was 1442 and 1265 mg/kg in male and female mice, respectively. Acute toxicity appeared to be related to depression of the central nervous system. Fourteen-day exposure by gavage in male mice at doses 1/10 and 1/100 the LD50 caused an increase in liver weight and a decrease in spleen weight at the highest dose level. Based on the data derived from 14 days of exposure, a 90-day study was performed. The compound was delivered via the drinking water; levels of the compound delivered per day were equivalent to those dosed in the 14-day study. The target organ in both sexes appeared to be the liver, with the males most affected. Male mice demonstrated a dose-related hepatomegaly accompanied by significant changes in serum chemistries and hepatic microsomal parameters. The females did not demonstrate the hepatomegaly observed in males, but did show alterations in hepatic microsomal parameters. No other significant toxicological changes were observed in either sex following 90 days of exposure.

Humoral and cell-mediated immune status in mice exposed to chloral hydrate.

Chloral hydrate has been found in our drinking water supplies at levels up to 5 micrograms/1. The purpose of this study was to evaluate the functional status of the immune system in random-bred CD-1 mice exposed to chloral hydrate for 14 and 90 days. Male mice, following 14 or 90 days of exposure to 1/10 and 1/100 the actual oral LD50, exhibited no alterations in either humoral or cell-mediated immunity. However, female mice exposed for 90 days to chloral hydrate in the drinking water demonstrated a significant depression in humoral immune function. This depression was observed when spleen cells from exposed mice were evaluated for their ability to produce antibody against sheep erythrocytes. These females did not demonstrate any changes in cell-mediated immune status.

In vivo assessment of immunotoxicity.

The organs, tissues, and cells of the lymphoreticular system have received considerable attention as targets for chemicals causing adverse effects. A basic toxicological approach is described for assessing the risk of a chemical perturbing the immune system. CD-1 mice were exposed for 14 or 90 days to one of several chlorinated hydrocarbons: 1,2-dichloroethane, 1,2-dichloroethylene or 1,1,2-trichloroethylene. Other mice were exposed to dexamethasone, a known immunosuppressive agent. The immune system is evaluated against a background of the more standard toxicological parameters such as fluid consumption, body and organ weights, hematology, clinical chemistries, and blood coagulation. Reported here are the results for the male mice after 14-day exposure to three chlorinated hydrocarbons and after 90-day exposure to 1,2-dichloroethane and dexamethasone.Acute toxicity studies were performed to provide a basis for doses used in the subchronic studies. The LD(50) values are reported. The status of the humoral immune system was determined by measuring the number of IgM spleen antibody-forming cells to sRBC, the serum antibody level to sRBC, and the lymphocyte response to the B-cell mitogen, LPS. Of the three chlorinated hydrocarbons, only dichloroethane produced a significant (p < 0.05) reduction in antibody-forming cells. The other two chemicals produced trends towards suppression. Mice exposed to dichloroethane in the drinking water for 90 days showed no alteration in AFC, serum antibody titers or response to the B-lymphocyte mitogen, LPS. Subchronic 90-day exposure to dexamethasone produced a dose-dependent inhibition of AFC/spleen but not AFC/10(6) spleen cells when measured on the peak day of response. Response to LPS was not altered, and spleen weight and spleen cell number were reduced as much as 42%. These data suggest that dexamethasone administered in the drinking water is nonspecifically cytotoxic to the spleen cells.Cell-mediated immunity was assessed by measuring the DTH response to sRBC and the response to the T-lymphocyte mitogen, concanavalin A. After 14 days of exposure, trichloroethylene produced a 15 and 60% suppression at 24 and 240 mg/kg, respectively. Dichloroethylene produced a non-dose-dependent inhibition at 4.9 and 49 mg/kg, which was slight, but significant (p < 0.05). Subchronic 90-day exposure to dichloroethane did not alter the DTH response or spleen lymphocyte response to concanavalin A. In contrast, dexamethasone produced a dose-dependent inhibition of the DTH response and a hyperresponsiveness to concanavalin A.Dichloroethane did not alter the functional activity of the reticuloendothelial system, as measured by the vascular clearance rate and tissue uptake of (51)Cr sRBC. In the case of dexamethasone exposure, only the spleen and thymus showed decreased uptake of (51)Cr sRBC, which was directly related to decrease in size. The approaches and results from these types of studies provide a basis for judging a chemical's potential risk to the immune system.

Uterine and peripheral blood concentrations of human chorionic gonadotropin and human placental lactogen.

One hypothesis is that two placental protein hormones (human placental lactogen and human chorionic gonadotropin) are effective immunosuppressive agents that prevents the rejection of a fetus because of their very high concentrations. In patients undergoing elective repeat cesarean sections at term, we measured the concentrations of these hormones in blood obtained simultaneously from draining ovarian veins and peripheral veins, and found no significant differences.

Effect of direct injection of neutrophils from uterine horns of rats containing intrauterine devices into recipient pregnant uteri.

The purpose of this study was to determine whether or not neutrophils from uterine horns containing an intruterine device (IUD) inhibit implantation of rat blastocysts. On day 4 (6:00 P.M. to 8:00 P.M.) of gestation the uterine horns of the recipient rats were exposed and injected with neutrophils, supernatant luminal fluid, or Hanks' solution. The total volume injected was 30 mul. All of the rats were killed on day 12 of pregnancy, and the number of fetuses and resorption sites was determined. The data show that, in rats injected with neutrophils on day 4 of gestation, implantation was significantly increased as compared with controls injected with Hanks' (vehicle) solution. Whether the supernatant fluid had an effect in suppression of implantation could not be determined, since the effect was not statistically different from that observed in either the vehicle- or neutrophil-injected groups. However, the responses observed with the supernatant-injected groups. However, the responses observed with the supernatant-injected group were intermediate between those of the control horns and those of the neutrophil-injected horns. The finding supports the concept that in IUD-bearing animals in which there is a rapid influx of neutrophils the cells play a major role in suppressing implantation.