Tadao Ishioka

Release of a Thromboplastic Substance from Arterial Walls by Epinephrine

Aortic preparations of 70 rabbits including the vasa vasorum were perfused in vitro by oxygenated saline under a pressure of 100 mm Hg. The main branches of the aorta were ligated and the perfusate, which irrigates the aortic lumen, but not the vasa vasorum, was sampled every minute. The samples were assayed for thromboplastic activity by means of the calcium clotting time. The calcium clotting time was shortened significantly in samples taken one, two, and three minutes after injection of 0.005 μg epinephrine. The response was present in perfusing with Tyrodes solution as well as with 0.9% NaCl but was absent if oxygen was withheld from the solution. Larger dose of epinephrine (0.05 μg) caused an initial shortening of the calcium clotting time, followed by a prolongation in two out of five cases. Still larger doses (0.5 μg) or much smaller ones (0.0005 μg) were without effect. In the aortas of rabbits which were pretreated by 5 mg/kg of nialamide two hours before removing the aorta, the previously mentioned effect of epinephrine was prevented. However, direct perfusion of the aortic preparation by a nialamide mixture in vitro did not prevent the release of thromboplastic active substance by epinephrine. Norepinephrine in doses of 0.005, 0.05, and 0.5 μg was found to be ineffective. These observations may explain the effects of epinephrine on the clotting time of blood originally described by Cannon and Gray.5

Clinical pharmacologic evaluation of the antiatherosclerotic agent, pyridinolcarbamate. A double-blind crossover trial in the treatment of atherosclerosis obliterans

The antiatherosclerotic effect of pyridinolcarbamate in man has been subjected to the present controlled clinical trial in 43 patients suffering from atherosclerosis obliterans with relatively stable signs and short claudication times (101 ± 8 sec.). To isolate individual factors such as age, sex, constitution, social condition, and spontaneous fluctuations of symptoms from the drug effect, a double-blind crossover technique (within-subject comparison) has been applied. After the initial 3 weeks of placebo wash out, a 10 week regimen of placebo or pyridinolcarbamate (1.5 Gm. daily) and another 10 weeks of alternative regimens were given successively. After drug regimen the prolonged crest time in plethysmography was shortened (p < 0.01) and claudication time prolonged with a statistically significant correlation (p < 0.05). The statistically significant preference for pyridinolcarbamate over placebo has been established by the effect on crest time alone, claudication time alone, and also major symptoms including ischemic ulcer, cyanosis, pain, and paresthesia of affected legs (p < 0.001). The relatively slow-acting and persistent effect of pyridinolcarbamate on the clinical signs observed in these patients encourages further histologic analysis of its effect on atheromatous lesions in man.

Antithrombotic Effect of Monamine Oxidase Inhibitor (Nialamide)

A new type of antithrombotic substance, nialamide, was compared with phenindione and warfarin in its preventive effect against experimental thrombosis produced in rabbits. One hundred fifty-seven rabbits were subjected to quantitative traumatization of the endothelial surface of the retroauricular artery and marginal vein of the ear. Pretreatment of animals with 3 to 5 mg./Kg. of nialamide, which did not prolong the one-stage prothrombin time, was much more effective in preventing thrombosis than either phenindione or warfarin, both of which prolonged the prothrombin time markedly. Even in the animals pretreated by 600 to 900 mg. of phenindione, which reduced the prothrombin activity to less than 6 per cent, the preventive effect of phenindione is significantly less than the antithrombotic effect of 3 to 5 mg./Kg. of nialamide. Pretreatment of animals with 1.5 mg./Kg. of nialamide was found to be ineffective. However, the concomitant application of subeffective doses of both phenindione, 150 mg., and nialamide, 1.5 mg., was found to be effective. On the other hand, the addition of phenindione, even in doses as large as 300 to 900 mg., to an effective dose of nialamide, 3 to 5 mg./Kg., did not further enhance the antithrombotic effect of nialamide. The antithrombotic effect of nialamide was not shown to be significantly modified by sympathectomy or by denervation of the blood vessels tested. Nialamide was found to prevent the aggregation of platelets on the injured endothelial surface.

Effects of Adrenaline and Noradrenaline on Euglobulin Lysis Time and Effects of Adrenergic Receptor Blocking Agents on Shortening of Lysis Time by Adrenaline

Adrenaline in an intravenous dose of 0.1 µg per kg induced a significant shortening of the euglobulinlysis time in 8 healthy subjects. On the other hand, the euglobulin lysis time was not hastened by intravenous injections of the same dose of 1-noradrenaline in 8 healthy subjects. The shortening of the euglobulin lysis time induced by 0.1 µg per kg of adrenaline was blocked by the pretreatment with 300 mg of nethalide in 8 healthy subjects but not blocked by the pretreatment with 30 mg of phenoxybenzamine in 5 healthy subjects.

Preventive effectiveness of MAO inhibitor and ineffectiveness of prothrombinopenic anticoagulant against increase in plasma thrombin activity by adrenaline, cholesterol, and traumatization☆

T he authors found that monoamine oxidase (MAO) inhibitors prevent powerfully the appearance of thrombosis induced experimentally by traumatization of the internal surface of blood vessels in rabbits without inhibiting extravascular clotting, and that they are much stronger than anticoagulants tested in such an experimental condition.rJ The authors3 also found that MAO inhibitors prevent the acute vascular reaction which is specifically induced by adrenaline in a dose of physiologic significance, but not in a large dose, or by cholesterol. The reaction consists of an acute edematous abnormality of the blood vessel wall, involving fractionation of elastic fibers and adherence of platelets and leukocytes to the endothelial surface, accompanied by a decrease in Moolten and Vromen’s adhesive platelet count as well as a shortening of the coagulation time of whole blood. In this experiment on rabbits the shortening of the one-stage prothrombin time induced by adrenaline5 or cholesterol6 or traumatization of the internal surface of blood vessels was subjected to testing of the preventive effect of phenindione, an anticoagulant, and of nialamide, a MAO inhibitor. It was found that nialamide prevents the shortening and that phenindione does not prevent it.

Treatment of Experimental and Human Atherosclerosis with Bradykinin-Antagonist, Pyridinolcarbamate: A Preliminary Report

At the beginning of this century there were three incurable lesions having dead spaces with an accumulation of dead subtances: gummatous in syphilis, caseous in tuberculosis, and atheromatous in atherosclerosis. The discovery of modern chemotherapeutic agents has enabled cures for the first two, but the problem of atherosclerosis remains to be solved.