The endothelial surface of blood vessels possesses a special characteristic like silicone.'' It prevents the adherence of blood platelets and leucocytes and preserves the fluidity of the blood.Recently the authors'-5' found that several amines, polypeptides and high molecular weight substances, capable of eliciting the host response of Landy and Shear,6' induce swelling of endothelial cells resulting in the damaging of their " silicone-like property ". Namely, the swollen endothelial cells exhibit stickiness to blood platelets and leucocytes and form white thrombi. At the same time the circulating platelets decrease in number and the blood clotting time shortens. It was also found that repetitious administration of these substances to various species of animals induces intimal arteriosclerosis.In regard to the problem of atherogenesis, the significance of adrenaline and noradrenaline has been already repeatedly discussed by many investigators.7'The authors found that a small amount of adrenaline causes a transient damage to the "silicone-like property" of vascular endothelial cells, . abrupt decrease in the number of circulating platelets and shortening of the blood coagulation time in rabbits and in men, while noradrenaline was found to be far weaker as compared to adrenaline.Material and method. 63 male rabbits weighing 1.8 -2.7 kg were used. In order to see the effect of adrenaline and noradrenaline on the "silicone -like property" of blood vessels , the mesenterial arteries and veins were observed under the microscope after surgical preparation under light anaesthesia in 12 male rabbits.Both surfaces of the mesenterial membrane were attached carefully on to the object glass. Using the oil immersion the blood vessel was magnified 1,200 times and using 16 mm super anscochrome color film PN1 the morphological changes were cinematographed.Adrenaline or noradrenaline, in the dose of 0.1, 1.0, 10.0, or 50 pg per kg dissolved in 1 cc of saline, was administered intravenously into the vein of the ear. The blood specimens were also taken from the vein of the ear.In the other experiment in animals without the above-mentioned operation, several different amounts of adrenaline were injected intravenously into the vein of ear after 12 hours of fasting, and before injection and 5 and 30 min, 1, 2, and 3 hours after injection blood specimens were taken from the vein of ear for blood counting and measurement of the whole blood coagulation time. The sampling of blood specimens was carefully performed from the vein of the ear utilizing the siliconized
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 Tyrode's 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
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.
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