Masami Sato

Effects of ethyl all-cis-5,8,11,14,17-icosapentaenoate on the physical properties of arterial walls in high cholesterol diet-fed rabbits

The effects of ethyl all-cis-5,8,11,14,17-icosapentaenoate (EPA-E) on in vivo physical properties of arteriosclerotic aorta and femoral artery in high cholesterol diet (HCD)-fed rabbits were studied. The aortic pulse wave velocity (PWV) of rabbits fed HCD for 12 weeks (control group) tended to be higher than that of rabbits fed a normal diet (normal group). Because the PWVs in HCD-fed rabbits administered orally with 30 and 300 mg/kg/day EPA-E were significantly lower than the PWV of the control group, the distensibility of arteriosclerotic aorta was improved with administration of EPA-E. The stiffness parameter (β) value as an in vivo indicator of arteriosclerosis was significantly higher in the control group than in the normal group and improved with administration of EPA-E to almost the same level as that of the normal group. The β-values were in significant negative correlation with medial elastin content and medial smooth muscle cell (SMC) density in thoracic aorta and in positive correlation with the free cholesterol content in abdominal aortic SMC. On the other hand, they were not correlated with either the cross-sectional area of intimal thickening lesions or the plasma lipid levels measured simultaneously. The femoral PWVs were, like those in the aorta, higher in the control group as compared with the normal group, and the changes were improved with administration of EPA-E. These results show that EPA-E improved the in vivo distensibility of arteriosclerotic arteries in HCD-fed rabbits. The mechanism of this improvement with EPA-E appeared to be related to histologic amelioration in the aortic medial elastic fibers and SMC and to protection from free cholesterol accumulation in SMC as one of the probable causes.

Effects of dienogest (a synthetic steroid) on coagulation, fibrinolysis, and platelet aggregation in female monkeys.

We investigated the effects of dienogest (0.1-10 mg/kg per day, p.o.) on coagulation, fibrinolysis and platelet aggregation in female rhesus monkeys. Then, we also examined those of medroxyprogesterone acetate (MPA, 10 mg/kg per day, p.o.) or danazol (10-1000 mg/kg per day, p.o.) on these parameters in the same species. In addition, we assessed the effects of dienogest (1 and 3 mg/kg per day, p.o.) or MPA (10 mg/kg per day, p.o.) on platelet aggregation and platelet lipids in female cynomolgus monkeys. At doses of 0.3 mg/kg or greater, dienogest increased the levels of several coagulation and anticoagulation factors, but had no effect on the prothrombin time, activated partial thromboplastin time, fibrinolysis, or platelet aggregation. MPA (10 mg/kg) had no effect on coagulation or fibrinolysis, but significantly potentiated platelet aggregation in response to ADP and collagen and also increased the platelet cholesterol-to-phospholipid ratio. Danazol (10 mg/kg or more) increased the activities of coagulation factors V, VII, VIII, X, XI, and XII in comparison to dienogest and MPA. Consequently, dienogest caused less potentiation of platelet aggregation than MPA and less potentiation of coagulation than danazol.

高コレステロール食飼育ウサギにおける動脈壁弾性と血管内皮依存性弛緩反応およびethyl all-cis-5，8，11，14，17-icosapentaenoate(EPA-E)の影響

We studied the elasticity and endothelium-dependent relaxation (EDR) of the aorta in 1% cholesterol diet (HCD)-fed rabbits. Furthermore, the effects of ethyl all-cis-5,8,11,14, 17-icosapentaenoate (EPA-E) were examined in this model of atherosclerosis. After 12 weeks of feeding with HCD, the animals showed increase in plasma total cholesterol level, formation of atherosclerotic plaque, decrease in aortic elasticity and impairment of EDR to acetylcholine (ACh). The levels of aortic elasticity in HCD-fed rabbits administered orally with EPA-E (300 mg/kg for 12 weeks) were almost the same as those of rabbits fed a normal diet, although EPA-E showed no effects on the plasma total cholesterol level and formation of atherosclerotic plaque in HCD-fed rabbits. On EDR in response to ACh and cyclic GMP formation in the HCD-fed rabbit aorta, EPA-E improved the impairment of these parameters, but not significantly. Therefore, EPA-E had little effect on the endothelium in this model of atherosclerosis, although EPA-E improved the decrease in the aortic elasticity. Because the levels of aortic elasticity showed no significant correlation with the magnitude of EDR to ACh or the size of atherosclerotic plaque, the decrease of aortic elasticity in this model of atherosclerosis was thought to have little relation to the dysfunction of the endothelium.

Pharmacological studies of intracoronary administered urokinase

The pharmacokinetics of intracoronary administered urokinase was investigated in anesthetized open-chest dogs, together with its effect on the cardiovascular system, and the influence of urokinase in isolated guinea-pig heart was also examined. After intracoronary administration of 20,000 IU/kg of 125I-urokinase, radioactivity in plasma was eliminated biexpomentially with half-lives of 6.8 min and 4.4 hr. At 4 hr after the administration of 125I-urokinase, 32% of the total radioactivity remained in the TCA-insoluble fraction of plasma, and only 0.13% of the administered radioactivity was excreted as a TCA-insoluble fraction in the urine, suggesting that the administered urokinase may be metabolized for the most part into low molecular weight compounds. In hemodynamic measurements, we observed some decrease in cardiac function which was thought to be attributable to bleeding from the incision of open-chest surgery, probably caused by the fibrinolytic activity of urokinase, and urokinase, up to the dose of 2,000,000 IU/kg (approximately 100 times of therapeutic dose), did not appear to show any direct action on the cardiovascular system. This result was supported by the fact that urokinase (10,000-1,000,000 IU/heart) did not have any effects on contractile force, heart rate and coronary flow in isolated guinea-pig heart. From these results, we confirmed that the pharmacokinetics of intracoronary administered urokinase was essentially the same as that of intravenously administered urokinase and that intracoronary administered urokinase showed virtually no direct effect on the cardiovascular system.

[Pharmacological studies of MO-8282, a new antidepressant].

MO-8282の抗うつ薬としての薬理学的特性を検討した．MO-8282はラット大脳皮質膜分画の3H-clonidine特異結合を阻害し，その作用はmianserinより約5倍強力であった．また，モルモット摘出回腸標本のfield stimulationにより生ずる攣縮反応においてもclonidine拮抗作用を示したことから，α2-アドレナリン受容体遮断作用を有することが示唆された．MO-8282はin vivoの実験において，30 mg/kg, i.P.投与においても脳内noradrenaline(NA)，dopamine(DA)およびserotonin(5-HT)の取込みを阻害しなかったが，mianserinは脳内5-HTの取込みのみを阻害した．MO-8282は，ラット大脳皮質シナプトゾームからの3H-NAの自然遊離には影響をおよぼさなかったが，線条体シナプトゾームからの3H-DAおよび3H-5-HTの自然遊離を軽度に促進し，これらの作用はmianserinに類似していた．MO-8282 30 mg/kg, i.p./day 15日間投与により，脳内NAの代謝回転の亢進がみられたが，脳内DAおよび5-HTの代謝回転は不変であった．以上の成績は，MO-8282の薬理学的特性が，これまでの三環系抗うつ薬と異なり，mianserinと同様主としてα2-アドレナリン受容体遮断作用を介する中枢NA系への作用を有することを示唆するものと思われた．