Takeshi Niho

5-hydroxydecanoate inhibits ATP-sensitive K+ channel currents in guinea-pig single ventricular myocytes

We investigated the effect of 5-hydroxydecanoate, a novel antiarrhythmic agent, on the electrical activity of guinea-pig ventricular myocytes. The outward K+ current increased by lowering the intracellular ATP concentration (0.5 mM) was efficiently blocked by 5-hydroxydecanoate when recording in the whole cell configuration with the application of voltage ramps. The increase in the time-independent outward K+ current induced by reducing intracellular ATP to 0 mM was also blocked by 5-hydroxydecanoate (10 or 100 microM) and by tolbutamide (1 mM). Using the single channel recording technique, we found that 5-hydroxydecanoate blocked ATP-sensitive K+ channels when its channel open probability was increased by 1 mM ATP together with 1 mM ADP or by an intracellular pH of 6.6. These conditions are well documented to reflect metabolic changes in the early stages of myocardial ischemic attack. These results suggest that 5-hydroxydecanoate could inhibit ATP-sensitive K+ channels, resulting in an antiarrhythmic effect specifically on ischemic hearts.

Reduction of Myocardial Infarct Size by Trapidil in Anesthetized Dogs

Summary We studied the effect of trapidil on acute experimental myocardial infarction in anesthetized, open-chest dogs. The size of myocardial infarction 8 h after ligation of the left anterior descending coronary artery was determined by planimetry of myocardial slices stained by the nitroblue tetrazolium method. Systemic hemodynamic variables, epicardial ST-segment elevation, activity of serum creatine phosphokinase (CPK), and changes of myocardial blood flow in the ischemic area were measured. Infusion of 3 mg/kg trapidil reduced the size of infarction and ameliorated the infarction-induced deterioration of systemic hemodynamic variables, such as the decrease in left ventricular dP/dt, aortic blood flow, and regional endomyocardial blood flow in the ischemic area. This dose of trapidil also suppressed ST elevation and significantly inhibited the increase in activity of serum CPK. Hyaluronidase also reduced the size of infarction significantly. These results suggest that trapidil alters the course of acute myocardial infarction favorably, presumably by increasing regional endomyocardial blood flow.

[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．

Effects of protizinic acid on leukokinin generation and its physiological action

The effect of protizinic acid (PRT), a non-steroidal antiinflammatory drug, on thein vivo leukokinin (LK) generation system using feline acute ischemia model,in vitro LK generation system and the LK-induced contraction of the isolated smooth muscle was investigated. When 3 mg/kg PRT was injected twice intravenously to cats with acute cardiac ischemia, increased blood acid protease activity was inhibited and significant inhibitory action on the decrease of leukokininogen, the precursor of LK, was observed. Simultaneously, ST-segment elevation on the electrocardiogram tended to be suppressed and the lowered mean aortic blood pressure was significantly restored. On the LK generation induced by rabbit kininogen and acid protease derived from mouse L-1210 leukemic cells or rabbit polymorphonuclear leukocytes, PRT showed a dosedependent inhibition while indomethacin (IM) and ibuprofen (IB) at a concentration of 3×10−4M showed no effect. However, potencies of the inhibitory actions of PRT, IM and IB on the LK generation induced by bovine spleen cathepsin D were almost the same at a concentration of 3×10−4M. Furthermore, PRT as well as IM showed antagonistic action on the isolated rat uterine contraction induced by LK. These results suggest that PRT not only inhibits thein vitro andin vivo generation of LK but also antagonizes to it on the receptor site of LK.