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IDENTIFICATION OF THE PRESSOR SUBSTANCE PRODUCED IN EXPERIMENTAL NEPHRITIS AND PREVENTION OF THE HYPERTENSION BY A SURGICAL PROCEDURE

English (英語)

The Kobe journal of the medical sciences

9(1)

11-33

1963

In order to investigate the possible role of the liver in removing the humoral pressor substance from the renal venous blood of hypertensive dogs with experimental nephrotoxic nephritis, an anastomosis was made between right renal vein to portal main trunk or to superior mesenteric vein of dogs whose left kidneys were previously removed. When adequate amounts of the nephrotoxic serum (serum of rabbit which was sensitized by dog kidney cortex) were given intravenously, elevation of the blood pressure, gross and microscopical hematuria, marked proteinuria, generalized edema and azotemia were observed. The systolic and diastolic pressure began to rise in one or two days after the injection of the serum, and remained on moderately high level until surgical operation or autopsy was performed several days later. When the reno-portal shunt was made before the injection, however, no increase in blood pressure could be seen, even though the condition of nephrotoxic nephritis had developed. The mode of activities of vasoconstrictor and vasopressor effects of the plasma obtained from renal 'vein of nephritic dogs were compared with those of synthetic angiotensin and essential nature of the pressor substance was discussed. In 1898, Tigerstedt and Bergmann demonstrated the prolonged rise in blood pressure in animals which follows the intravenous injection of a crude kidney extract. This rise in blood pressure was attributed to the substance called renin that was found only in renal tissue. The production of persistent hypertension in dog through the alteration of intra-renal hemodynamics by Goldblatt in 1934, has opened a new field in experimental studies, since the condition so 'caused in the animals' was similar to human hypertension. Clinically, the first successful removal of a kidney for treatment of hypertension in human being was reported by Butler in 1937. Since then, many accounts in the literature have been described about vascular and parenchymal lesions of the kidneys associated with hypertension. Experimental renal hypertension in early stage, as well as patients with acute severe hypertension, has been considered by many investigators to be the result of the release into the circulation of a pressor substance elaborated by the kidney. In 1940, a substance with theoretically required properties was described simultaneously by Page and Helmer and Braun-Menendez and his coworkers. In the course of experiments of former group, it was found that the potent kidney extract containing renin, which was known to cause a strong elevation in blood pressure when given intravenously, produced less constriction of the blood vessels that were isolated in saline. However, if small amount of plasma was added to t'1e extract, an intense vasoconstriction was restored immediately. This indicated that renin could formed an active substance when it acted upon a plasma substrate. The plasma substrate which reacted with renin, Kohlstaedt, Helmer and Page called renin-activator. This substance could be found in the alpha-two globulin fraction of the plasma proteins produced by the liver. An active substance formed by the interaction of renin and renin-activator was called angiotonin by Page and Helmer. Braun-Menendez also named this substance which was obtained by his experiments hypertensin. At a conference which was held in 1957 in commemoration of Goldblatt's investigation, Page and Braun -Menendez agreed on the term angiotensin for the pressor substance and angiotensinogen for the substrate upon which renin acts. Purification and analysis of angiotensin were slowly established. Skeggs, Marsh, Kahn and Shumway and Helmer showed the presence of two forms of angiotensin. One form, angiotensin I which is inactive, was identified as a direct product of the action of renal enzyme renin upon its plasma substrate. Other form, angiotensin II, which was formed by the action of a converting enzyme from angiotensin I, was found to be the renal pressor substance. Angiotensin I, however, is equally active in vivo, because it is rapidly converted to angiotensin II by a chloride- activated enzyme in plasma when given intravenously. The purification of a pressor peptide. derived from ox serum was described by Peart in 1956. In the same year Elliott and Peart determined that ox angiotensin I was the sequence of ten amino acids. A ten amino acid structure of horse angiotensin I was also proved by Skeggs and associates, who showed that angiotensin II was identical chain of the first ·eight amino acids of angiotensin I. According to Peart, however, valine is in the position of isoleucine which is fifth in order in horse or hog angiotentin by Skeggs. Synthesis of deca+ and octapeptides of the angiotensin series were accomplished almost simultaneously by Page and coworkers and by Schwyzer's group independently. The intensive pharmacological studies conducted by those groups have verified that synthetic angiotensin II is identical with the naturally occurring substance. In view of these humoral renal pressor mechanism, Kahn, Skeggs, Shumway and Wisenbaugh have reported the presence of increased amounts of angiotensin in arterial blood of patients with essential and malignant hypertension. Helmer and Judson reported the presence of vasoconstrictor and vasopressor activity in the renal venous and peripheral blood of patients with malignant and renal hypertension. Thus, the existence of humoral pressor substance in blood have been generally accepted. Levy and Blalock, Child and Glenn, Verney and Vogt and Maluf described that the complete portalization of the renal effluent blood could not prevent the renal hypertension produced by the constricting renal artery. On the other hand, the possible evidence to prevent or abolish the hypertension associated with renal ischemia by the reno-portal venous shunts on dogs was emphasized by Aoki. The primary purpose of the present paper is to investigate whether there exist any significant depressor effect of the complete reno-portal shunt on hypertensive condition with the nephrotoxic nephritis in dogs. Secondary, properties of this pressor substance in renal venous blood were assayed for vasoconstricting activity by means of spirally cut strips of rabbit aorta or for vasopressor action by intravenous injection in 24 hours postnephrectomized dogs, and also these two activities were compared with those of the synthetic angiotensin.

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