6R-L-erythro-5, 6, 7, 8-Tetrahydrobiopterin (6R-BH₄) is known as a cofactor for the hydroxylases of phenylalanine, tyrosine and tryptophan and also as a cofactor for nitric oxide synthase. Recently, a novel function of 6R-BH₄ has been found: that is, 6R-BH₄ acts on specific membrane receptors to directly stimulate the release of monoamine neurotransmitters such as dopamine and serotonin, independently of its cofactor activity. In addition, it indirectly stimulates the release of non-monoamine neurotransmitters such as acetylcholine and glutamate, through activation of monoaminergic systems. In this paper, we briefly review recent experimental data, which provide new insights into the role of 6R-BH₄ as a regulator of neuronal function. We also discuss the possibility of treatment by 6R-BH₄ of neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, depression and infantile autism.

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The effects of some analgesic-antipyretics on the spinal reflex potentials were studied in spinal cats. Aminopyrine at 25 ?? 100 mg/kg, i.v. produced a marked increase in mono and poly-synaptic reflex potentials (MSR and PSR), and a decrease in dorsal root reflex potentials (DRR) in a dose-dependent manner. The amplitude of DRR decreased by aminopyrine was reversed by diazepam at 0.2 mg/kg, i.v.; however, the increased amplitudes of MSR and PSR were not affected by diazepam. Pretreatment of semicarbazide at 200 mg/kg, i.v. did not influence the increasing effect of aminopyrine on MSR and PSR. DL-5-Hydroxytryptophan produced facilitation of the MSR and PSR. In DL-5-hydroxytryptophan-treated cats, the amplitude of MSR was further increased by aminopyrine. Methysergide at 1 mg/kg, i.v. antagonized this increasing effect of aminopyrine on MSR and PSR. These observations suggest that the excitatory action of aminopyrine may be partly related to 5-hydroxytryptamine and not connected to the GABAergic mechanism. Other pyrazolone derivatives were also studied. Isopropylantipyrine at 50 mg/kg, i.v. produced increases in MSR and PSR. Intravenous sulpyrine at 500 mg/kg, antipyrine at 50 mg/kg or 4-aminoantipyrine at 50 mg/kg did not affect the reflex potentials. The non-pyrazolones, acetaminophen and indomethacin, did not increase the MSR and PSR. These results suggest that the N-dimethyl or isopropyl residue at the 4 position of the pyrazolone structure plays an important role in the excitatory action of analgesic-antipyretics in cat spinal cord.

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The present study examined the preventive effects of green tea extract on D-galactosamine (GalN)-induced hepatic injury in rats, an animal model of viral hepatitis. A single i.p.-injection of GalN (700 mg/kg) to male Wistar rats caused fulminant hepatitis by 48 hr as assessed by marked increases in the serum aspartate aminotransferase (GOT), alanine aminotransferase (GPT) and alkaline phosphatase (ALP) activities; decreases in the serum protein and cholesterol levels and the amount of liver microsome P-450; and marked changes in organ weights. The lecithin: cholesterol acyltransferase (LCAT) activity markedly increased at 8 hr and markedly decreased at 24 hr after the GalN injection. In the experiment, animals were orally administered green tea extract at doses of 50, 100 or 200 mg/kg five times each before and after the GalN injection. Treatment with green tea extract significantly prevented the increases in the GOT, GPT and ALP activities in a dose-related manner. It also significantly prevented the decreases in serum albumin and total cholesterol, although not in a dose-related manner. A tendency to prevent the increase in LCAT activity and the decrease in liver microsome P-450 was also noted. Little effect was found on the other abnormal changes in the serum lipids and proteins and the organ weights. These results suggest that green tea may have an ameliorating effect on hepatic dysfunction.

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The insulin mimetic effects of vanadium salts on glucose metabolism have been well-documented in STZD rats. In this study, the long-term effects of vanadyl sulfate (vanadium) on osteopenia in STZD rats were examined and compared with those of insulin. From 2 days after an intravenous injection of streptozotocin (30 mg/kg), the rats with hyperglycemia (> 300 mg/dl) received either vanadium (0, 0.02, 0.1 or 0.5 mg/ml) in drinking water or daily subcutaneous injections of insulin (0, 0.4 or 4.0 U/day) for 54 days. Their tibiae and femurs were examined by chemical analyses, by contact microradiography and by the method of double tetracyclin labeling. Decreases in bone mass, bone density and in the rate of bone formation were observed in STZD rats. Development of these symptoms in the STZD rats with osteopenia was prevented by the administration of either vanadium or insulin in a dose-dependent fashion. The effects of vanadium at a dose of 0.5 mg/ml for preventing bone loss in STZD rats were similar to those of insulin at a dose of 4.0 U/day. These results indicate that vanadium has insulin mimetic effects on osteopenia in STZD rats.

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Hypoglycemic effects of the extracts of two Siamese plants, Momordica charantia (M.c.) and Phyllanthus urinaria (P.u.), were examined in streptozotocin-induced diabetic rats. Oral administration of a 50% methanol extract (30 mg/kg) of M.c. and P.u. decreased the blood glucose levels (BGL) by 25% and 24%, respectively, at 3 hr after administration. Among other fractions such as the ethyl ether or water soluble fractions, the 10 and 30 mg/kg n-butanol soluble fraction from M.c. extract was most effective in lowering BGL by 26% and 34%, respectively. Similarly with M.c., the n-butanol fraction from P.u. extract decreased BGL by 23% and 39% at the doses of 10 and 30 mg/kg, respectively. In the oral glucose tolerance test, n-butanol fractions from M.c. and P.u. (30 mg/kg, p.o.) both inhibited the initial increase in BGL to the same degree. In the intraperitoneal glucose tolerance test the n-butanol fraction of M.c. inhibited the increase of BGL prominently, but the n-butanol fraction of P.u. did not. These plants generally contain moderately non-polar hypoglycemic compound (s) soluble in n-butanol; and specifically, with regards to the hypoglycemic mechanism, the M.c. extract seems to act like insulin or via insulin secretion from the pancreas, like the action of sulfonyl ureas, and the P.u. extract may act via facilitation of glucose metabolism and/or the inhibition of glucose absorption in the gut like the action of biguanides.

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The aim of the present study was to clarify acute anti-fatiguing effects of three crude liquid drug preparations (S1-S3), containing almost the same amounts of Ginseng Radix, Epimedii Herba and Agkistrodon Japonicae, with each differentially containing an additional 11, 13 or 15 crude drugs. After preloading forced swimming or tetrabenazine (TBZ: 50, 100 mg/kg, i.p.), each of the S1-S3 preparations applied orally (0.1 ml/ 10 g) significantly increased the duration times of swimming together with decreased total duration times of immobility during swimming. These effects peaked 60 min postinjection with the following decreasing order of effectiveness: S3>S2>S1. The same order of efficacy was also found for increased locomotor activity and decreased durations of swimming immobility after TBZ. After pretreatment with 200 mg/kg TBZ preparations S1-S3 also increased the numbers of jumping on a hot plate with greatly reduced latency. Without preloading the forced swimming, S1-S3 did not have any effect on jumping and its latency, but both S2 and S3 significantly, but more weakly, as compared to those after its preloading, decreased the immobility times. These results indicate that these crude preparations may cause tonic effects and so far tested, these effects seem to be more effective on subjects fatigued with physical and/or mental works than an normal subjects.

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We examined the effects of M6434 on mean blood pressure and heart rate in consciuos rabbits and dogs and on experimental models of postural hypotension in conscious rabbits and anesthetized dogs. M6434, given orally, elevated the mean blood pressure in conscious rabbits and dogs. The pressor effect of M6434 was more potent than that of midodrine, but the bradycardiac action of M6434 was weaker than that of midodrine. M6434 (1.0 and 3.0 mg/kg, p.o.) prevented the head-up tilt-induced reductions of mean blood pressure and cerebral tissue blood flow in conscious rabbits, and these effects of M6434 were about 3 times more potent than those of midodrine. In the postural hypotension of anesthetized dogs, M6434 at the doses more than 10 μg/kg, i.v. also produced the preventive effects on mean blood pressure and cerebral tissue blood flow. These effects of M6434 were about 10 ?? 30 times more potent than those of midodrine. These results show that M6434 possesses a potent hypertensive effect with a weaker bradycardiac action and suggest that M6434 may be a potential candidate for an anti-hypotensive agent that can prevent the deterioration of hemodynamics in postural hypotension.

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Liver injury by 30-min ischemia following reperfusion was examined biochemically and histopathologically. A greater increase in the level of LDH was observed after 1-hr reperfusion. However, the level of LDH decreased in proportion to the period of reperfusion, while the levels of GOT and GPT were also in creased rapidly and reached its peak at 12 hr following reperfusion and were almost restored to the control level by 48 hr. A similar increase was obtained in the lipid peroxides of the liver. In addition, cyt. P-450 content and NADPH cyt. c reductase activity decreased in proportion to the period of reperfusion up to 12 hr and then recovered by 96 hr. On the other hand, heme oxygenase activity was significantly increased by ischemia-reperfusion. The ischemia-reperfused liver resulted in various morphological changes with the period of reperfusion. The destruction of Disse's space, vacuolization of the cytoplasm and nonviable hepatocytes were observed after 12-hr reperfusion. These results indicate the greatest damages of the liver induced by 30-min ischemia following reperfusion is observed after 12-hr or 24-hr reperfusion. The liver injury by ischemia-reperfusion could be a useful experimental model to develop for future studies.

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The antihypertensive effect of felodipine was examined in various hypertensive animal models. In spontaneously hypertensive rats, felodipine administered singly at 0.1 ?? 1.0 mg/kg (p.o.) had a dose-dependent antihypertensive effect. Nifedipine was effective at 1 mg/kg. In the repeated oral administration experiment, both the maximum decrease in blood pressure and duration of the effect increased gradually and reached steady levels at 3 weeks of administration, which were maintained thereafter. Similar results were noted with nifedipine, but felodipine was longer-acting (4 ?? 6 hr) in the steady state than nifedipine (1 ?? 2 hr). No development of tolerance was observed during the administration period. In DOCA-salt and renal hypertensive (2K1C) rats, felodipine at 0.1 ?? 0.5 mg/kg (p.o.) was superior to nifedipine in the maximum decrease in blood pressure and duration of the effect. Felodipine up to 1 mg/kg (p.o.) caused no significant heart rate increase in any rat model. In renal hypertensive (2K2C) dogs given felodipine at 0.2 ?? 0.5 mg/kg (p.o.), the effect lasted for 2 hr after injection. This felodipine effect was stronger and longer lasting than the nifedipine one. At 0.5 mg/kg of felodipine, the heart rate was transiently increased. The present results show that felodipine has a stronger and long-lasting antihypertensive effect than nifedipine in the hypertension models.

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