The effect of more than 60 amino, oxy, aminoxy xanthine derivatives on coronary blood flow were tested by the left coronary cannulation method in dogs. The coronary dilating effect of these derivatives are shown by potency indices with theophylline ethylenediamine (TE) as 1. An interesting relation was revealed between chemical structure and coronary dilating action : comparison between theophylline derivatives and theobromine derivatives shows that the former are more potent than the latter, and comparison between 7 (γ-alkylaminopropyl)-, 7 (β-alkylaminoethyl)- and 7 (γ-alkylamino-β-oxypropyl) theophyllines shows that the last is most potent, followed by the first and the second in that order. Comparison between the number of carbon atoms substituted in the amino group at γ-position in 7 (γ-alkylamino-β-oxypropyl) theophylline shows that as the number of carbon atoms increase, there is a corresponding rise in potency but that after 4 carbons potency begins to decrease, while esterification by benzoic acid or acetic acid enhances coronary dilating activity. From these relations, several new active xanthine derivatives were found to be 3 to 4 times more active than TE. Their chemical structures are 7 (γ-dipropyl (or dibutyl)-amino-β-hydroxy (or benzoyloxy, acetoxy) propyl) theophylline. The antagonistic effect of Vasopressin and TH-24 (1), a typical potent compound, on the coronary blood flow and electrocardiographic pattern were tested. Coronary contraction and elevation of ST segment and T wave of Vasopressin 0.1 u/10sec was almost completely suppressed by simultaneous injection of TH 24 (1) 10mg-3mins.

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The effect of 47 aminoxy and amino-xanthine derivatives on blood flow of the femoral artery (f. a.) and toxicity in mice and rats of some of these compounds were tested. Comparing the effects of the compounds on f. a. and on coronary artery (c. a.), the former are more effective than the latter. The minimum effective dose of theophylline ethylenediamine (TE) and these compounds on f. a. is about 0.2mg, and that on c. a. about 1.0mg. But the potency indices of these compounds on f. a. are inclined to be smaller than on c. a. With regard to relationship between effect and chemical structure, although the effect on c. a. differs from that on f. a. in the little details, the correlation coefficient is 0.752, which seemed to indicate that both blood vessels react in a similar manner to the compounds. The relationship between toxicity and chemical structure were studied with these interesting revelations : (1) In the monoalkylaminoxypropyl xanthine derivatives, theobromine derivatives are more toxic than theophylline derivatives. (2) When C-atoms of the alkyl radicals replaced at amino radical increased, toxicity increased in direct proportion. (3) In the β-alkylaminoethyl theophylline derivatives, toxicity was strongest when the alkyl at terminal N was methyl, becoming less toxic in the case of ethyl and n-propyl in that order. And the ratio of toxicity in intraperitoneal and intravenous injection were distributed from near 1.1 to near 6.8, indicating that the compounds are well absorbed.

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The enzymatic activation of amino acid was recognized and measured by the formation of hydroxamic acids in the presence of amino acids, adenosine triphosphate and hydroxylamine. Tyrosine-activating enzyme was partially purified from the cardiac muscle of dogs by the method of Schweet. The "cell-sap" fraction of the cardiac muscle of dogs formed hydroxamic acids of 18 kinds of amino acids. Tryptophan, tyrosine, cysteine, leucine, and proline were more strongly activated. In addition of the mixture of 14 kinds of amino acids, the mean μ moles of hydroxamic acids formed in/1.0g of wet weight/hour was 0.031 and 0.076 respectively for the cardiac muscle and the liver of normal rabbits. Mean activities of the enzyme of hypertrophied cardiac muscle of dogs caused by aortic valvular lesions and of thyrotoxic cardiac muscle of rabbits were higher than those of the control, while those of the starved, hypoxic and norandrostenolone administered cardiac muscle of rabbits were lower. There was no difference between the mean value of the acute cardiac dilatation and that of the control. It is suggested from these results that the protein synthesis from the amino acid-level is present in the cardiac muscle and that it is likely to be disturbed at the level of amino acid-activation under some pathologic conditions.

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The clinical feature of anaphylactic shock in any species appeared to be superimposed by two types of biological responses, namely, allergic on one hand and shock reaction on the other hand. The major immediate allergic responses are consisted of contraction of smooth muscles, dilatation and increased permeadility of blood vessels. However, patterns of allergic responses are widely different in each species which may characterize the clinical feature of anaphylaxis substantially. For example, acute emphysema with asphyxia due to contraction of smooth muscle of bronchioli is the prominent picture of anaphylactic shock in guinea pigs. Torii et al emphasized that the acute phase of anaphylaxis is very similar to the primary shock in terms of the circulatory dynamics. If animals could survive at this stage through a defence mechanism mainly of sympathicoadrenal system, they may undergo eventually the secondary shock. The delayed phase of anaphylactic shock was reported to be similar to the secondary shock with respect to circulatory dynamics (Torii et al). The extravasation of plasma albumin appeared to characterize the pathophysiological feature of delayed phase of anaphylactic shock. Furthermore, sccording to the author's studies, the extravasation of plasma albumin appeared to be a crucial factor for the prognosis of the further course of the anaphylactic shock. The emergency therapy should be directed not only to overcome the primary shock but to prevent the secondary shock or delayed anaphylaxis at the same time. In this respect both antihistamin and antiinflammatory steroids are very important for the emergency therapy of anaphylaxis.

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With the use of our dermo-carotid artery bridge method, it has been made possible to measure the systolic and diastolic blood pressure indirectly by auscultation with no anesthesia, continuously, in any body position, any time and with a very simple apparatus for a long period of time. Through a marked decrease in the blood pressure was noted in the renal hypertensive dog after completion of a reno-portal venous shunt, such mechanism is assumed to be caused by the detoxifying process of the liver and by improvement of the renal blood flow.

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The electrocardiogram is very useful clinically for the diagnosis of ventricular hypertrophy in cardiovascular diseases. As left ventricular hypertrophy, in particular, has the highest incidence in various electrocardiograhic findings, so it is very important to diagnose left ventricular hypertophy with accuracy. For the diagnosis of left ventricular hypertrophy, Sokolow's criteria based on an increase in the QRS amplitude are used extensively even in Japan because of their more concreteness having positivity among many electrocardiographic criteria, but there are many critical reports on these criteria. Nevertheless, unexpectedly only few articles discuss accuarcy of these criteria for Japanese subjects. The author asserted in Report I that these original criteria were not applicable to Japanese subjects and it was neccessary to consider the differences due to age and sex in view of the presence of such differences of vector values including the QRS magnitude on spatial vector analysis of the electrocardiogram in normal Japanese by means of Simonson's analyzer. From this point of view, in this report, false positivities of Sokolow's criteria applying to healthy Japanese subjects were investigated and corrected values of these criteria were determined based on vector analysis of the normal Japanese electrocardiogram.

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