The effects of dihydroergotamine and etilefrine on experimentally-induced postural hypotension were examined. Although dihydroergotamine at 3 and 10 μg/kg (i.v.) increased blood pressure (BP), it did not affect cardiac output (CO). However, dihydroergotamine at 10μg/kg reduced the decrease in CO induced by the tilt. Therefore, it is suggested that the increase in BP is induced by the contraction of resistance vessels, and that the inhibition of the decrease in CO due to tilt is induced by the contraction of capacitance vessels. Etilefrine at 0.1 mg/kg (i.v.) increased BP and heart rate (HR), however it did not attenuate the decrease in BP induced by the tilt. Although it tended to increase CO, it did not attenuate the decrease in CO. It is suggested that the increase in BP is due to the contraction of resistance vessels, and to the increase in cardiac contractile force and HR. In this study, dihydroergotamine and etilefrine did not attenuate the decrease in BP due to tilt, though dihydroergotamine inhibited the decrease in CO due to tilt. As an explanation, it is suggested that dihydroergotamine induces contraction of resistance vessels as well as capacitance vessels, however the effects of the drug on resistance vessels is weak, and that etilefrine has little or no effect on capacitance vessels. In our previous study, midodrine, an alpha-1 agonist, attenuated the decreases in BP and CO due to tilt, and it has been suggested that the inhibition was induced by the contraction of capacitance vessels. Therefore, dihydroergotamine, etilefrine and midodrine show different pahrmacological profiles in experimentally-induced postural hypotension.

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Effects of (1→3)-β-D-glucans on clot formation of human plasma were examined. Gel forming 6 branched (1→3)-β-D-glucans, SSG, branched at every other main chain glucosyl unit, grifolan (GRN) and schizophyllan, branched at one third of main chain glucosyl unit, enhanced clot formation of human plasma. GRN derivatives also increased the contents of clot, but less effectively than GRN. This effect was dependent on dose, molecular weight (>20K), side chain (branching), and ultrastructure (single chain conformer) of the β-glucans. It may be important for the mechanism of (1→3)-β-D-glucan induced enhancement of plasma clotting to activate factor XII, to bind with fibrinogen, and to increase the local concentration of the clotting system by steric exclusion.

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The disposition of sodium valproate in pregnant rats was studied comparing with nonpregnant (control) rats. In the pregnant rats, the total plasma clearance decreased significantly (p<0.05) from 7.06 ml/min/kg of the control to 5.34 ml/min/kg, whereas the plasma elimination half-life of valproate did not change. The serum unbound fraction (f_s) of pregnant rats increased remarkably. The f_s of the fetal plasma was lower than that of the maternal serum in spite of the lower albumin (main binding protein for valproate) concentration in the fetal plasma. A non-linear serum (plasma) protein binding was observed both in the control and the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-plasma concentration ratio (K_p) of the brain was higher than that in the control rats, whereas the K_p values of the liver and lung were lower than those in the control rats. In other tissues, the K_p values did not show a significant difference. Rapid placental transfer was observed and the K_p value of the fetus was 0.43.

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The immunotoxicity of triphenyltin chloride (TPTC) in mice was investigated. 1) When TPTC was injected intraperitoneally (i.p.) into mice at doses between 1 and 10 mg/kg for 14 d, a reduction in the weights of thymus and spleen was noticed, however, the body weight was not changed significantly. 2) The production of hemolytic plaque forming cells in the spleen of mice immunized with sheep red blood cells (SRBC) was inhibited by the administration of 10 mg/kg of TPTC. 3) The i.p. injection of TPTC at a dose of 10 mg/kg for 5 d after the primary immunization of mice with dinitrophenylated ascaris antigen resulted in suppression of immunoglobulin E antibody formation in primary immune response, but did not affect the secondary immune response. 4) The production of antibody against polyvinylpyrrolidone (T cell independent antigen) was not affected by the administration of TPTC. 5) The production of effector T cells which are able to cause SRBC- or tuberculin-induced footpad reaction in mice and the induction of cytotoxic T cell in local graft versus host reaction in mice were also inhibited by TPTC. These results indicate that TPTC inhibits both the T cell dependent humoral and cellular immune responses in mice.

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We have examined the pharmacokinetics of glycosylated recombinant human lymphotoxin (LT) after intravenous bolus injection in rats and compared them with those of tumor necrosis factor (TNF) or LT species. The results are as follows. 1) The mean half-life of glycosylated LT in serum increases for each increase in dose, and the distribution volume (V) and total body clearance [(Cl (total)] tend to decrease for increase in dose. On the other hand, the half-life of TNF also increases for increase in dose, but the V tends to increase for increase in dose and Cl (total) does not change. 2) The glycosylated LT distributes to all organs so far tested except brain, and tends to accumulate to kidney more than other tissues at 6 h after the injection. 3) Nonglycosylated LT produced by E. coli and the glycosylated LT species carrying both N-type and mucin-type sugar moieties (25 kDa LT) have shorter half-lives and higher Cl (total) s than 23 kDa LT carrying N-type sugar moieties alone. The 21 kDa LT, the same species as 23 kDa LT except that it lacks 15 amino acid residues at the N-terminus, disappears much faster than 23 kDa LT and shows higher V and Cl (total). Thus, glycosylated LT shows nonlinear pharmacokinetics like TNF, but the deposition is quite different from that of TNF. The high serum concentration of glycosylated LT depends upon the presence of N-type sugar moieties, but not mucin-type sugar moieties. The N-terminal protein chain of LT also correlates with the serum concentration.

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The metabolic fate of a bile acid analog, 3α-hydroxy-7-hydroxyimino-5β-cholanoic acid, was studied in hamsters. This compound was absorbed rapidly from the intestine and secreted into the bile as either taurine- or glycine-conjugates, at the rate similar to that of chenodeoxycholic acid. The ratio of glycine to taurine conjugates for this bile acid analog, 0.2, was much smaller than that for chenodeoxycholic acid, 2.0. After oral administration of a single dose of the labeled analog to intact hamsters, radioactivity was recovered in faces but not in urine. A major metabolite found in the feces was lithocholic acid (60%), whereas unchanged material was present only in a trace amount (2.4%). After the hamsters were fed chow supplemented with 0.075% of this bile acid analog for 21 d, analysis of the gallbladder bile acids revealed that the administered compound accounted for only 1.6% of total bile acids. The biliary bile acid composition was similar to that of chenodeoxycholic acid fed group. In the strain of hamster studied, feeding of the bile acid analog decreased cholesterol absorption significantly (19% decrease, p<0.05), and tended to reduce serum and liver cholesterol concentrations.

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The effects of chronically administered hydralazine on adrenergic neurotransmission were evaluated in the perfused mesenteric artery of spontaneously hypertensive rats (SHR) preloaded with [³H] norepinephrine. The ³H overflow evoked by periarterial nerve stimulation (PNS, 2-32Hz) was greater in both young (5-week-old) and adult (13-week-old) ages of SHR in comparison with agematched Wistar Kyoto rats (WKY). Hydralazine treatment, which prevented the development of hypertension, attenuated the increased ³H overflow evoked by PNS in SHR. At adult age, the logarithmic value for the concentration (nM) of salbutamol to cause a 20% enhancement of the evoked ³H overflow was significantly smaller in SHR than in WKY. The increased sensitivity of presynaptic β-adrenoceptors in SHR was reduced by hydralazine treatment. The concentration-response curve of the facilitation of the evoked ³H overflow caused by salbutamol in hydralazine-treated SHR lay between the curves in SHR and WKY. No significant difference in the inhibitory effects of xylazine on the PNS-evoked ³H overflow was found among SHR, hydralazine-treated SHR and WKY. At young age, presynaptic α- and β-adrenoceptors were supersensitive in SHR. The results suggest that an altered adrenergic neurotransmission mediated by presynaptic β-adrenoceptors in adult SHR is partially improved by chronic hydralazine administration, this accounting for the attenuation of the increased norepinephrine release observed in hydralazine-treated SHR.

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In the present study we tried to determine the relative contributions of sarcoplasmic reticulum (SR) calcium release and gated calcium entry through voltage-dependent calcium-channels (VDC) to the contractions induced by norepinephrine (NE, 10 μM) and acetylcholine (ACh, 10 μM) in the vas deferens of the guinea pig. NE and ACh at 10μM caused contractions composed of three phases : a prephasic, a phasic and a tonic component. Nifedipine strongly inhibited the contractions induced by potassium (K, 100mM) and abolished phasic components of the contractions induced by NE or ACh. However, the tonic components of NE- or ACh-induced contractions were slightly attenuated by nifedipine. Pretreatment with ryanodine in combination with caffeine attenuated prephasic and tonic components of the contractions induced by NE and ACh in a dose-dependent manner. The inhibitory effects of ryanodine and caffeine on the phasic component of NE-induced contractions were divided into two types : 1) abolishment of the phasic contractions and 2) a delayed appearance of the phasic contractions without attenuation of magnitude. However, ryanodine with caffeine minimally affected phasic component by ACh-and K-induced contractions. Ryanodine pretreatment in combination with NE, ACh or K had no effect on the contractions induced by each agonist. These results suggest that 1) SR Ca release is essential for the initiation and/or the maintenance of the tonic components of NE- or ACh-induced contractions as well as for the initiation of the prephasic components, 2) the phasic components by NE depend on both the SR Ca release and gated Ca entry but those induced by ACh depend only on gated Ca entry, 3) the Ca-induced Ca-release mechanism may be scarcely involved in SR Ca release induced by NE and ACh.

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Male and female rats were fed on a diet containing 0.01% (w/w) perfluorooctanoic acid (PFOA) for 2, 22, or 26 weeks and effect of PFOA on activities of microsomal 1-acylglycerophosphocholine acyltransferase, microsomal stearoyl-coenzyme A (CoA) desaturase, peroxisomal β-oxidation and on acyl composition of microsomal phosphatidylcholine in liver were studied. The treatment of male rats with PFOA for 2 weeks caused increases in the activities of stearoyl-CoA desaturase, 1-acylglycerophosphocholine acyltransferase, and peroxisomal β-oxidation. The elevated activities of microsomal 1-acylglycerophosphocholine acyltransferase and peroxisomal β-oxidation were unchanging throughout the long-term treatment. The induced activity of microsomal 1-acylglycerophosphocholine acyltransferase was found to be highly correlated with the induced activity of peroxisomal β-oxidation. In contrast to these two enzymes, the increased activity of stearoyl-CoA desaturase by the short-term treatment of rats with PFOA did not last for 26 weeks, although the activity in rats treated for the long-term was higher than that of age-matched controls. The treatment of male rats with PFOA caused great alterations in the acyl composition of microsomal phosphatidylcholine. The high correlation seen between proportion of 18 : 1 in the C-2 position of phosphatidylcholine and activities of both stearoyl-CoA desaturase and 1-acylglycerophosphocholine acyltransferase suggest that these two enzymes participate actively in the regulation of acyl composition of phosphatidylcholine in rat liver. The present results show that hepatic responses to PFOA remain consistent throughout the period of the administration, but the elevated activities of the hepatic enzymes and the altered acyl composition of microsomal phosphatidylcholine returned to control levels within 4 weeks after PFOA was withdrawn from the diet. Even after the chronic administration of PFOA, these parameters of female rats responded only slightly to the challenges by the chemical, which indicates a marked sex-related difference being still apparent in the response of rat liver to PFOA.

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