Effect of CV-2619 (idebenone) on the half-life and hemolysis of red blood cells in stroke-prone spontaneously hypertensive rats (SHRSP)

The effects of CV-2619 on the half-life and hemolysis of red blood cells (RBC) in stroke-prone spontaneously hypertensive rats (SHRSP) were examined. The half-life of RBC in SHRSP was shorter than that in control Wistar Kyoto rats (WKY) and was significantly prolonged in SHRSP kept on a diet containing 0.1% (w/w) of CV-2619 (calculated at 71.0 mg/kg/day): 11.7 +/- 0.4 days in untreated SHRSP (n = 11); 13.8 +/- 0.1 days in treated SHRSP (n = 5, P less than 0.01); and 14.8 +/- 0.5 days in WKY (n = 6). The hemolysis of RBC in salt-loaded SHRSP was accelerated compared with that in WKY. In SHRSP given CV-2619 (20 or 70 mg/kg/day, p.o.) for 2 weeks, the hemolysis was significantly inhibited; the percent hemolysis was 43.9 +/- 0.9% (n = 10) in the control, 39.5 +/- 0.9% (n = 9, P less than 0.01) in the group given 20 mg/kg CV-2619, and 37.1 +/- 0.8% (n = 9, P less than 0.001) in the group given 70 mg/kg CV-2619. These results suggest that the stabilizing effect of CV-2619 on the membrane of RBC is involved in its therapeutic effects in cerebral vascular disorders.     

Inhibitory effect of idebenone (CV-2619), a novel compound, on vascular lesions in hypertensive rats

The effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), on cerebral and renal vascular changes were examined in stroke-prone spontaneously hypertensive rats (SHRSP) and in rats with experimentally induced hypertension. CV-2619 (35 mg/kg/day, p.o.) significantly inhibited the onset of cerebrovascular lesions (stroke) and the elevation of blood pressure in SHRSP with mild hypertension. A higher dose (2 X 50 mg/kg/day, p.o.) clearly delayed the onset of both stroke and proteinuria without any effect on the blood pressure in SHRSP with severe hypertension. In DOCA-salt hypertensive rats, CV-2619 (2 X 5 or 2 X 25 mg/kg/day, p.o.) dose-dependently inhibited decreases in body weight and water balance and the development of cerebral and renal vascular changes. These results suggest that CV-2619 inhibits the development of stroke and renal vascular lesions in hypertensive rats.     

Effects of 6-hydroxydopamine on spontaneously hypertensive rats

Summary In order to evaluate the role of the sympathetic nervous system in the development and maintenance of spontaneous hypertension, spontaneously hypertensive and normotensive rats were give 6-hydroxydopamine (6-OH-dopamine).A single i.v. dose of 6-OH-dopamine (100 mg/kg) caused a biphasic rise in blood pressure in both hypertensive and normotensive rats.During long-term treatment the first dose of 6-OH-dopamine (25 or 50 mg/kg i.v.) lowered the blood pressure, measured 24 h after injection, two or three times more in hypertensive than in normotensive rats. As a result, the blood pressure reached the same level in both groups, i.e. 90–100 mm Hg. Within three days this hypotension subsided. After repeated weekly administration of 6-OH-dopamine the depressor effect declined gradually and after 4 weeks it was no longer significant. When this stage was reached, adrenal demedullation as such neither lowered the basal blood pressure, nor prevented the development of tolerance to 6-OH-dopamine. Accordingly, the adrenal medulla is not decisive in maintaining the blood pressure and in the development of tolerance to the depressor effect of 6-OH-dopamine in spontaneously hypertensive and normotensive animals.After treatment with 8 weekly doses of 6-OH-dopamine, the pressor response to noradrenaline increased in both hypertensive and normotensive rats, while the response to tyramine decreased.When, on the second day after birth, new-born rats of the hypertensive strain were given a single dose of 6-OH-dopamine (50 mg/kg i.p.) the development of hypertension was inhibited to some degree. This inhibition was more marked when the animals were given weekly doses of 6-OH-dopamine (50 mg/kg i.p.) during 5 weeks. On the other hand, when pregnant rats of the same strain received 6-OH-dopamine (50 mg/kg i.v.) twice during the last week before delivery, the offsprings did develop hypertension.It is evident that the adrenergic nervous system plays an important part in the development of hypertension in rats of a spontaneously hypertensive strain, but it is no longer of essential importance once the hypertension is established.Partly presented at the Fifth International Congress on Pharmacology, San Francisco, July 23–28, 1972 (Neuvonen et al., 1972).     

Beneficial effect of idebenone (CV-2619) on cerebral ischemia-induced amnesia in rats

An experimental model of amnesia induced by cerebral ischemia after one-trial passive avoidance learning was established to test the effects of a novel compound, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619), and some commonly used drugs in rats. One day after the vertebral artery was electrocauterized bilaterally, the common carotid artery was transiently occluded bilaterally to produce cerebral ischemia. The amnesia was estimated by the response latency for a rat to step from a light safety compartment to a dark compartment in which a foot-shock was given. The results of the retention test given 24 hr after the ischemia indicated that amnesia was successfully produced when the 200-600 sec ischemia was provided within 20 min after the avoidance learning. The effects of drugs on the amnesia induced by a 200-sec ischemia immediately after the avoidance learning were as follows: CV-2619 (10, 30 mg/kg, i.p. or p.o.) given before the retention test significantly increased the response latency, indicating a reversal effect on the amnesia. Physostigmine (0.1, 0.2 mg/kg, i.p.) and arginine-vasopressin (10 micrograms/kg, s.c.) were also effective, and calcium hopantenate (500 mg/kg, p.o.) showed a slight reversal action. Furthermore, CV-2619 (10 mg/kg, i.p.), given before or after the ischemia, significantly inhibited the appearance of amnesia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of idebenone (CV-2619) on metabolism of monoamines, especially serotonin, in the brain of normal rats and rats with cerebral ischemia

The effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619) on the contents, turnover, release and uptake of monoamines, especially serotonin (5-HT), in various brain regions of Wistar rats were studied in vivo and in vitro. In normal rats, an intraperitoneal (i.p.) dose of 100 mg/kg of CV-2619 had no significant effect on the levels of norepinephrine (NE), dopamine (DA) and their metabolites, and 5-HT in the brain regions examined, but it increased the levels of 5-hydroxyindole-3-acetic acid (5-HIAA), the main metabolite of 5-HT, in many brain regions. In rats with cerebral ischemia, a low dose (10 mg/kg, i.p.) of CV-2619 normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-HT biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.), decreased the levels of 5-HT in all brain regions to one-third of the control levels 24 hr after administration in normal rats. CV-2619 (10, 30 or 100 mg/kg, i.p.), administered 24 hr after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreases in the hippocampus, diencephalon and brain stem in a dose-dependent manner. In vitro CV-2619, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of the hippocampus and diencephalon. CV-2619 slightly inhibited and PCA markedly inhibited 5-HT uptake into hippocampal slices. The mechanism of the 5-HT releasing action of CV-2619 in hippocampal slices seems to be mediated through endogenous calcium. These results suggest that CV-2619 has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon and brain stem of rats.     

粉防己碱抑制自发性高血压大鼠心肌纤维化

目的：观察粉防己碱对自发性高血压大鼠心肌胶原和心肌僵硬度的作用。方法：测定羟脯氨酸表示胶原的量，胃酶抽提法和ＳＤＳ－ＰＡＧＥ方法测定胶原Ⅰ／Ⅲ型比例，离体灌注大鼠心脏测定左室心肌舒张僵硬度。结果：粉防己碱显著降低心肌胶原浓度和含量，降低胶原Ⅰ／Ⅲ型比例，改善心肌舒张僵硬度。结论：粉防己碱因其有效的抗纤维化作用，能逆转心肌舒张功能障碍。     

In vivo electrochemical detection of 5-hydroxyindoles in the dorsal hippocampus of anesthetized rats treated with idebenone (CV-2619)

The effect of idebenone (CV-2619), 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, on 5-hydroxyindoles in the dorsal hippocampus of rats was investigated by using in vivo differential pulse voltammetry. CV-2619 (100 mg/kg, i.p.) produced a large increase in oxidation current at 280 mV (peak 2) in the dorsal hippocampus. The increase was statistically significant at 20 and 30 min after the administration. 5-Hydroxytryptophan (150 mg/kg, i.p.) also caused a marked increase in peak 2, which was clearly inhibited by the treatment with pargyline (50 mg/kg, i.p.). Thus, the increase in peak 2 induced by CV-2619 seems to be associated with an increase in the 5-HT metabolite 5-hydroxyindoleacetic acid and also partly with an increase in 5-HT.     

Effects of idebenone (CV-2619) on endogenous monoamine release and cyclic AMP formation in diencephalon slices from rats

The addition of CV-2619 (10(-4) M) stimulated the release of endogenous 5-hydroxytryptamine (5-HT) markedly and that of norepinephrine (NE) slightly from slices of rat diencephalon, but it did not affect dopamine (DA) release. The addition of CV-2619 (10(-5)-10(-4) M) or 5-HT (10(-6)-10(-4) M) stimulated cyclic AMP formation in a concentration-dependent manner. Methysergide (10(-4) M), a 5-HT receptor blocker, almost completely blocked CV-2619 (10(-4) M)- and 5-HT (10(-4) M)-induced cyclic AMP formation. These results suggest that CV-2619 stimulates cyclic AMP formation via endogenous monoamine, particularly, 5-HT release.     

Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice

RH1 (2,5-diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone) has shown preferential activity against human tumour cell lines which express high levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diaphorase) and is a candidate for clinical trials. EO9 (3-hydroxy-5-aziridinyl-1-methyl-2-[1H indole-4,7-dione]prop-beta-en-alpha-ol) is a known substrate for DTD but clinical trials were disappointing, as a result of rapid plasma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore describe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour activity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-expressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mice showed a t1/2 of 23 min with an area under the curve of 43.0 ng hr mL(-1) resulting in a calculated clearance of 5.1 mL min(-1), 10-fold slower than EO9. RH1 was also more stable than EO9 in murine blood, where the breakdown was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in both liver and kidney was slow (<100 pmol/min/g tissue), reflecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), although DTD levels were low (21.4+/-0.6 nmol/mg/min). DTD activity in the kidney cytosol was high (125+/-8.2 nmol/mg/min) and EO9 was rapidly metabolised (4396+/-1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slower (608+/-86 pmol/min/g), even though RH1 was shown to be an excellent substrate for DTD (Vmax = 800 micromol/min/mg and a Km of 11.8 microM). The two DTD substrates RH1 and EO9 are clearly metabolised differently, suggesting that RH1 may have different pharmacological properties to those of EO9 in the clinic.     

Effects of a new dihydropyridine derivative, CV-4093.2HCl, on renal hemodynamics in spontaneously hypertensive rats

The effects of a new calcium antagonist, CV-4093.2HCl, on renal hemodynamics were examined in anesthetized and conscious spontaneously hypertensive rats (SHR). In the anesthetized rats, CV-4093.2HCl (5 and 10 micrograms/ kg, i.v.) showed a long-lasting hypotensive action, dilated renal vasculature, and increased renal blood flow. These renal hemodynamic actions of CV-4093.2HCl were more prominent than those of nicardipine (5 and 10 micrograms/kg). Moreover, CV-4093.2HCl (10 micrograms/kg, i.v.) inhibited renal vascular contractions induced by intravenous norepinephrine and angiotensin II. The inhibitory effect of CV-4093.2HCl was much more marked than that of nicardipine, although the inhibitory effects of both calcium antagonists on systemic pressor responses induced by the vasoactive substances were almost the same. In addition, CV-4093.2HCl (1 and 3 mg/kg, p.o.) increased blood flow in the kidneys but not in the other organs except for the small intestine in conscious SHR. These results suggest that CV-4093.2HCl has a relatively higher affinity for the renal vascular bed (renal resistance vessels), and its effect on renal hemodynamics seems to be beneficial for treating hypertension.     

Brain distribution of idebenone (CV-2619) and its effect on local cerebral glucose utilization in rats

To investigate the possible action-sites of a cerebral metabolism activator, idebenone (CV-2619), its distribution in the brain and effect on local cerebral glucose utilization (LCGU) were studied both in normal rats (WKY) and in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions. At 5 min after intravenous administration of [14C] CV-2619 (10 mg/kg), the distribution ratio in the brain was 0.45-0.56% of the dosage. Autoradiographic study showed that 14C levels were higher in the white matter than in the grey matter. When [14C] CV-2619 was administered orally (100 mg/kg) and intraperitoneally (30 mg/kg), 14C levels in eleven brain regions (15 min after administration) were 0.22-0.39 microgram/g (CV-2619 equivalent) and 1.11-1.30 micrograms/g, respectively, in WKY and 0.17-0.28 microgram/g and 1.66-1.87 microgram/g, respectively, in SHRSP. Total 14C levels were not markedly different among the brain regions of the rats. The analysis of unchanged CV-2619 and its metabolites revealed that unchanged CV-2619 in the cerebral cortex, thalamus and cerebellum was relatively higher than that in the other brain regions. Studies on LCGU demonstrated that CV-2619 (30 mg/kg/day, i.p., for 3 days) improved the decrement of LCGU in the temporal cortex, thalamus dorsomedial nucleus, subthalamic nucleus, mamillary body, hippocampus dentate gyrus, caudate-putamen, inferior colliculus and cerebellar nucleus of SHRSP with stroke. Based on these results, the possible action-sites of CV-2619 for its main pharmacological effects were discussed.     

Dissecting the role of multiple reductases in bioactivation and cytotoxicity of the antitumor agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1)

2,5-Diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is a novel antitumor diaziridinyl benzoquinone derivative designed to be bioactivated by the two-electron reductase NAD(P)H:quinone oxidoreductase (NQO1) and is currently in clinical trials. NQO1 is expressed at high levels in many solid tumors. RH1 cytotoxicity has been shown previously to be NQO1-dependent. The purpose of this study was to investigate whether other reducing enzymes such as cytochrome b(5) reductase (b5R), cytochrome P450 reductase (P450R), dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2), and xanthine oxidase/xanthine dehydrogenase (XO/XDH) also contribute to the bioactivation and cytotoxicity of RH1 in human tumor cells. For these studies, we established a series of stable MDA468 breast cancer cell lines overexpressing various levels of NQO1, b5R, P450R, and NQO2 and compared RH1-induced growth inhibition [3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium and sulforhodamine B analysis] and interstrand DNA cross-linking (comet analysis) in both parental MDA468 cells and transfected clones. RH1 toxicity correlated with NQO1 and NQO2 but not with either b5R or P450R activity levels in the respective series of transfected MDA468 cell clones. Enzymatic assays showed that RH1 was an in vitro substrate for xanthine oxidase. However, XO/XDH protein and activity could not be detected in a variety of human tumor cell lines. These studies suggest that NQO1 and NQO2 are the principal enzymatic determinants of RH1 bioactivation in MDA468 tumor cells and that b5R, P450R, and XDH/XO are unlikely to play major roles. Our studies also suggest that NQO2 may be particularly relevant as a bioactivation system for RH1 in NQO1-deficient tumors such as leukemias and lymphomas.     

Long-acting dihydropyridine calcium antagonists. 6. Structure-activity relationships around 4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-[(2-hydroxyethoxy)methyl]-5 -(methoxycarbonyl)-6-methyl-1,4-dihydropyridine

The preparation of 4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-[(2-hydroxyethoxy)methyl]-5- (methoxycarbonyl)-6-methyl-1,4-dihydropyridine (2) is described, and its potent calcium antagonist activity on rat aorta (IC50 = 4 x 10(-9) M) and marked tissue selectivity in vitro for vascular smooth muscle over cardiac smooth muscle are established. In order to exploit the excellent in vitro profile of compound 2, a range of analogues were prepared but none were found to have superior calcium antagonist potency and tissue selectivity. Compound 2 has excellent in vivo activity in the anesthetized dog (ED50 = 12 micrograms/kg for reduction of CVR) and a plasma half-life in the conscious dog of 7.2 h. The pharmacokinetic parameters of 2 are compared to those determined for the structurally related compounds amlodipine and felodipine. The plasma clearance for 2 (9.6 mL/min/kg) is similar to that of amlodipine and is consistent with the extended 2-substituent hindering approach to the cytochrome P-450 enzyme responsible for oxidation of the DHP ring to the corresponding pyridine.     

Effects of dietary Angelica keiskei on lipid metabolism in stroke-prone spontaneously hypertensive rats

1. The effect of dietary Angelica keiskei on lipid metabolism was examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Six-week-old male SHRSP were fed diets containing 0.2% A. keiskei extract (ethyl acetate extract from the yellow liquid of stems) for 6 weeks with free access to the diet and water. 3. Elevation of systolic blood pressure tended to be suppressed on and after 2 weeks; however, this effect was not statistically significant. 4. Serum levels of cholesterol and phospholipid in SHRSP were significantly elevated after treatment with A. keiskei extract and this effect was accompanied by significant increases in serum apolipoprotein (Apo) A-I and ApoE concentrations. These changes in the serum were due to increases in high-density lipoprotein (HDL) containing ApoA-I and ApoE. 5. In the liver, significant decreases in relative weight and triglyceride content were observed in SHRSP after treatment with A. keiskei extract. An investigation of mRNA expression of enzymes involved in hepatic triglyceride metabolism indicated a decreased level of hepatic Acyl-coenzyme A synthetase mRNA expression. 6. In conclusion, dietary A. keiskei produces elevation of serum HDL levels and a reduction of liver triglyceride levels in SHRSP.     

Effects of ovariectomy on naloxone-modulated hypertension in spontaneously hypertensive rats (SHR)

Ovariectomy was performed at 4 weeks of age (W), and the rats were used when they were 33 and 75 W old. Systolic blood pressure (BP) was measured by the tail-cuff method. Naloxone (10 mg/kg) was given i.p. Catecholamines (CA) were determined with HPLC. Norepinephrine (NE) was not significantly altered in intact rats by naloxone; however, a significant increase in NE appeared in the plasma, hippocampus, thalamus plus mid-brain and hypothalamus in castrated rats following naloxone. With naloxone treatment, dopamine (DA) was significantly increased in the plasma and hypothalamus, but decreased in the cerebral cortex in intact rats; and with castrated rats, there was a tendency to see an increase in plasma DA and significantly increased levels of DA in the thalamus plus mid-brain and hypothalamus. This suggests that in female brain, lack of estrogen in the castrated rats leads to an increase in intrinsic opiate, and this in turn inhibits CA release. On the other hand, when naloxone was administered to castrated rats, intrinsic opiate was blocked, and, consequently, inhibition of CA release was lost and induction of CA release was enhanced.     

The in vivo metabolism of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine in rats.

The purpose of the study was to investigate the in vivo metabolic pathway of 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine (substrate) in rats. Firstly its potential metabolites, i.e. N-dealkylation, ring scission of pyridazine and aromatic hydroxylation products, were synthesized and then the substrate was given orally (100 mg/kg) to male or female Wistar rats at a dose of 100 mg/kg to body weight. Blood samples were collected at 0, 1, 2, 4, 6 and 8 hours after administration of substrate and blood was centrifuged to obtain serum. The substrate and its potential metabolites were separated using a gradient HPLC method on a reverse phase system. This study revealed that 3-oxo-5-benzylidene-6-methyl-(4H)-2-(benzoylmethyl)pyridazine was not metabolized to the proposed metabolites and was present unchanged in the serum.     

Effects of CV-4093, a new dihydropyridine calcium channel blocker, on renal hemodynamics and function in stroke-prone spontaneously hypertensive rats (SHRSP)

Renal effects of CV-4093, a newly developed dihydropyridine calcium channel blocker, were examined using anesthetized stroke-prone spontaneously hypertensive rats, and the findings were compared with those of nicardipine. An intravenous injection of CV-4093 (2 micrograms/kg) produced long-lasting hypotension with a slow-onset accompanied by moderate renal vasodilation. There were no appreciable alterations in glomerular filtration rate (GFR) and urine formation, except that urine flow (UF) increased significantly during the first 10 min after injection. When CV-4093 was administered at 10 micrograms/kg, the hypotensive action was markedly augmented. Eighty minutes after the injection, a decrease in mean arterial pressure of about 45 mmHg was observed. Simultaneously, renal blood flow increased significantly from the control value of 5.76 +/- 0.46 ml/g.min to 6.94 +/- 0.28 ml/g.min. Renal vascular resistance decreased immediately after the injection, and the response lasted for over 3 hr, thereby indicating the marked and sustained renal vasodilating effect of CV-4093. GFR was constant throughout the experiment, but UF and urinary excretion of sodium were increased significantly. Fractional excretion of sodium was also elevated, thereby suggesting an inhibitory action of CV-4093 on renal tubular reabsorption of sodium. Nicardipine at a dose of 10 micrograms/kg, a dose producing an effective hypotensive action, caused no significant increases in RBF and urine formation. The renal vasodilating and diuretic actions of CV-4093 may provide a beneficial effect in the treatment of hypertension.     

左旋氨氯地平对自发性高血压大鼠胸主动脉重构及内皮功能的影响

目的 观察左旋氨氯地平(降压药)对自发性高血压大鼠胸主动脉结构及内皮依赖性舒张功能的影响.方法 20只自发性高血压大鼠,分为左旋氨氯地平治疗组和高血压对照组;同周龄WKY大鼠作为正常对照.治疗组,给予左旋氨氯地平(2 mg·kg-1·d-1),12周后,观察胸主动脉对乙酰胆碱和硝普钠的舒张反应,比较各组主动脉中膜厚度及中膜截面积,检测血清一氧化氮、内皮素的水平.结果 同高血压对照组相比,治疗组的胸主动脉对乙酰胆碱的最大舒张反应明显增强,(48.39±14.86)%vs(34.71±9.23)%,P=0.03;胸主动脉中膜厚度及截面积明显减小(P<0.05),血清一氧化氮浓度明显增加(P<0.05).结论 左旋氨氯地平能够改善自发性高血压大鼠血管内皮依赖性舒张功能,抑制血管重构,机制可能与增加一氧化氮的合成和释放有关.     

Effects of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo [3,4-c]thieno[2,3-e][1,4]diazepine (Y-7131) on the metabolism of biogenic amines in brain.

A new derivative of thienodiazepine, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine (Y-7131) decreased the turnover of 5-hydroxytryptamine (5-HT) but not that of dopamine (DA) in the rat brain. The potency of Y-7131 in inhibiting the 5-HT turnover was stronger than that of diazepam. Imipramine decreased the turnover of 5-HT, whereas chlorpromazine increased the turnover of DA. Y-7131 decreased the turnover of norepinephrine (NE) in the mouse brain. With diazepam, such an action was not recognized. Imipramine did not affect the turnover of NE, whereas chlorpromazine increased it. Y-7131 inhibited the uptake of NE in the mouse brain, although it did not inhibit the uptake of 5-HT. Diazepam was devoid of such an action. Imipramine inhibited the uptake of both amines. The increase of the turnover of 5-HT, NE and DA due to foot-shock stress in the rat brain was suppressed by the administration of Y-7131. In this antagonistic effect, Y-7131 was more potent than diazepam. Neither imipramine nor chlorpromazine showed these antagonistic effects. The results obtained suggest that Y-7131 has biochemical profiles similar to diazepam but differs from it in exhibiting inhibitory effect on the NE turnover and its uptake.     

Effect of chronic treatment of propranolol on lipid metabolism in spontaneously hypertensive rats (SHR)

The effects of propranolol on lipid metabolism were studied in spontaneously hypertensive rats (SHR). Male SHR and corresponding Wistar Kyoto rats (WKY) were used at 5 weeks of age. The SHR were given 10 mg/kg/day of dl-propranolol . HCl by gavage for 10 weeks. Body weight gain in untreated SHR and propranolol-treated SHR (SHR-P) groups were low, as compared with those of the WKY group. Total cholesterol, phospholipid and total lipid of the serum and liver in the SHR-P group were higher than in the SHR group. In the early weeks of treatment, serum triglyceride and non-esterified fatty acid levels in the SHR-P group were slightly lower than those in the SHR group. Aortic lipid levels in the SHR-P group were lower than those in the SHR group. During the later weeks of treatment, blood glucose level in the SHR-P group was higher than in the SHR group. The serum immunoreactive insulin value in the SHR-P group was slightly lower than in the SHR group. These results may suggest that propranolol inhibits hormone-sensitive lipase activity in the early weeks of treatment and influences cholesterol biosynthesis and/or catabolism.