Douglas R. Drury

Production of Hypertension in the Rat by Substituting Hypertonic Sodium Chloride Solutions for Drinking Water.

Summary and Conclusions (1) In 3 experiments, systolic blood pressure measurements were made on 27 control rats and on 31 animals watered with hypertonic sodium chloride solutions for a period of 6 weeks. (2)The animals watered with hypertonic saline solutions developed an arterial hypertension after a latent period of one to 4 weeks. At autopsy this was found! to be associated with an hypertrophy of the heart and kidneys relative to body weight. (3)Some possible mechanisms for the development of this hypertension are discussed. (4)The substitution of hypertonic sodium chloride solutions for the drinking water affords a simple, inexpensive, and dependable method for the production of arterial hypertension in the rat.

Effect of Feeding and Fasting on Sugar Utilization of Eviscerated Rabbits

In an earlier paper by one of us 1 it was shown that the eviscerated rabbit utilizes glucose at a rate that is quite definite and fairly constant for a given animal. The rate varies, however, between different rabbits. The suggestion was made in that paper that this variation was due to the differences in the degree of fasting to which the different animals had been subjected prior to operation and that the effect of fasting is to reduce the utilization rate of the eviscerated animal. The work here reported was planned to investigate this relationship. The same technique was used as in the previous work. Essentially this consisted of measuring the rate at which glucose had to be administered to the eviscerated rabbit to maintain the blood sugar at a constant normal level. Frequent blood sugar determinations served as a guide to the injection rate; if the blood sugar level rose the rate would be diminished, and vice versa. The determination was started 3 hours after completion of the operation and continued for 4 hours thereafter. Only those animals that sat up in normal posture and had normal righting reflexes after operation were used. The animals were also tested for kidney function by injecting phenol red after the operation. Any animals not secreting this dye were eliminated from the series. Ten rabbits were used in each of the two groups—one group fed to the time of operation, and the other fasted 4 to 6 days prior to operation. The glucose utilization rates are given in Table I. The rates are given for the period between the 3rd and the 7th hours after operation, In this way we could be sure that we were not getting any anesthetic effect.

2-Deoxyglucose; a metabolic block for glucose.

Summary 2-deoxyglucose rapidly enters the cells of the extrahepatic tissues in the absence of insulin. Insulin appears to accelerate the intracellular transfer. The intracellular transfer of 2-deoxyglucose inhibits the transfer and oxidation rates of glucose, thus acting as a metabolic block for glucose. It is suggested that the blocking of glucose may take place at the 6-phosphate stage.

The effect of transplanted ischemic kidneys and of temporary, complete, renal ischemia upon the blood pressure of rabbits

H OUSSAY, Taquini, and their co-workers1 have made certain observations which are of fundamental importance in the study of experimental hypertension. They were able to demonstrate that transplantation of the ischemic kidneys of dogs with Goldblatt hypertension’ caused an almost immediate rise in the blood pressure of the recipient animal after anastomosis of the renal and carotid-jugular vessels. A msore pronounced rise took place if the animals into which the transplantation was made had been previously nephrectomized. An attempt to confirm these results on another animal appeared to be of sufficient importance to justify the experiments reported in this paper. The rabbit was chosen because, like the dog, it lends itself to the production of hypertension by means of artificial renal ischemia.3 The hypertension in this animal appears to be identical with that in the dog; furthermore, it can be extremely severe, to the extent of attaining the so-called malignant phase, with widespread, neerotizing arteriolitis.4

Cardiac Performance of Hypertensive Aorta-Constricted Rabbits

A heart-lung preparation with flow limited to the coronary vessels was used to study cardiac performance 4 to 120 days after severe constriction of the abdominal aorta in rabbits. Cardiac performance was evaluated by finding the maximum mean arterial pressure against which the heart could pump. Cardiac performance began to exceed the normal, range by the second or third post operative week and was well above normal after the first month. A high cardiac performance was not necessarily associated with marked ventricular hypertrophy. Animals died of heart failure within the first month, and all had developed a much more rapid rate of blood pressure increase than those that survived without signs of decompensation. We conclude that the basic cause of heart failure after severe aorta constriction is a rapid rise in arterial pressure which exceeds the rate at which the heart develops an improved performance.

Further Observations on Development of a Colony of Spontaneously Hypertensive Rabbits.

Summary (1) Two new generations of spontaneously hypertensive rabbits showed about the same incidence of elevated systolic pressures as their progenitors at 6 and 8 months of age, 58 and 71% respectively. At 4 months, mean systolic pressure in the 2 new generations was significantly higher than in their progenitors at same age. (2) Male rabbits of the new generations in all 3 age groups had higher mean systolic values than females and than their male or female progenitors. (3) Direct arterial pressure measurements in a group of spontaneously hypertensive rabbits showed average diastolic pressure to be 10 mm Hg higher and systolic pressure 30 mm Hg higher than in normo tensive stock rabbits. (4) Direct arterial recordings from unanesthetized animals demonstrated spontaneously hypertensive rabbits to have larger Traube-Hering waves than normotensives. (5) The presence of interstitial nephritis in normotensive as well as spontaneously hypertensive animals precludes it as an etiological factor in the development of spontaneous hypertension.

THE DISPOSITION OF GLUCOSE BY THE EXTRAHEPATIC TISSUES

The use of radioactive carbon as a tracer incorporated in glucose offered a device whereby the usual uncertainties accompanying studies of the disposition of glucose in the eviscerated organism could be reduced or eliminated. Uniformly labeled C14 glucose was prepared in a good yield and with a high activity by biosynthesis using a procedure described elsewhere.’ Rabbits were used and eviscerated as previously described? With the aid of frequent blood sugar determinations, the blood sugar was maintained at a normal level for 8 or more hours by the constant injection of C1P labeled glucose. The glucose solution used for the constant injection was calculated and prepared to have the same specific activity as that of the circulating plasma glucose resulting from the injection of a priming dose of ClPlabeled glucose. The purpose of the priming dose at the start of the experiment was to produce a rapid equilibrium between the specific activity of the body glucose and the glucose to be used for the constant injection. For this calculation, the space of the body glucose is required, and we found it to be equivalent to 25 per cent of the body weight? The technical and analytical methods used have been detailed Glucose Utilization by the Extrahepatic Tissues. In the past, the preferred method for measuring the amount of glucose utilized by the extrahepatic tissues has been that of determining the rate a t which glucose must be injected in order to keep the blood sugar a t a normal constant level. The evisceration eliminates the actions of the liver, pancreas, and gastrointestinal tract-all variables which would be difficult to control. This method assumes that the liver is the sole source for the new formation of glucose, a fact which, we now know, is not true. The kidney may form glucose6 in the absence of the liver, but, since it does so only if there is a hypoglycemia, this source may be ignored in these experiments. It should be stressed that the old “utilization” rate was really the disappearance rate of glucose, and it did not tell us anything about the relative magnitude of the different routes of disposal of this glucose by the body, viz., oxidation to COa and HZO, partial oxidation and conversion to intermediate compounds, and conversion to storage substances like glycogen, protein, and fat. Under partial oxidation substances, we must distinguish between those substances that are on the way to complete oxidation, and those that might be called “dead-end” glucose derivatives, which, in the normal animal, are reconverted to glucose by the liver. Using C14 glucose enables one to distinguish between glucose which disappears and that which is oxidized. Typical results comprise TABLE 1. Not more than a fifth of the glucose which disappears in the eviscerated organism is actually

Experimental Arterial Stenosis: Post Stenotic Dilatation and Collateral Blood Flow

formation. On the other hand, Holman (2) and Greene (9) claim that the change in pressure gradients produced by the constriction of the artery is responsible for at least the dilatation and/or hypertrophy of the collateral vessels. They explain that the intra-arterial pressure just above the site of constriction rises slightly and the pressure below that site drops more markedly, thus increasing the pressure gradient in existing anastomotic channels connecting the preand post stenotic areas of the constricted artery. This results in an increased blood flow through these anastamotic (collateral) channels, and this increase in blood flow is the stimulus for the dilatation and/or hypertrophy of the latter channels. Both Lewis (8) and Holman (2) use evidence from observations on the arterial changes in arteriovenous fistulae to support their favorite theories concerning these changes in the case of arterial stenosis or occlusion. We are primarily interested in investigating the degree and extent of the post stenotic dilatation, and the role of tissue ischemia in producing it. We used the renal artery in our studies, since one of us (D. R. D.) observed that post stenotic dilatation does occur in this artery and since the degree of renal ischemia produced by constricting that artery apparently can be gauged by the degree of the ensuing systemic hypertension (10). Although renal hypertension may spontaneously disappear in the dog (10)-apparently through adequate collateral circulation formation, this has not been reported in the rabbit. Presumably any ischemia

The Effect of Potassium on the Occurrence of Petechial Hemorrhages in Renal Hypertensive Rabbits

Administration of extra potassium to rabbits with renal hypertension reduces the incidence and severity of petechial hemorrhages. It also enables the animals to sustain higher blood pressure levels. Potassium apparently protects the vascular system to some extent against the damage caused by hypertension.

Mechanism of Insulin Action

The primary action of insulin is familiar to everyone. It causes glucose to disappear from the blood. The blood sugar is in equilibrium with that in the interstitial fluid, so that when glucose is injected intravenously, it quickly distributes itself evenly in the extracellular compartment. Its passage from here into the cells is limited to a comparatively low rate. The glucose that insulin causes to leave the blood has but one place to go—into the cells. Investigators in the past have proposed the theory that insulin primarily increases the oxidation of glucose, and that the insulin-induced disappearance of glucose from the blood was the result of increased oxidation of the glucose in the cells. Experimental work does not support this view. We can follow the behavior of the glucose molecule in the body by labeling it with radioactive carbon atoms (C). In order to carry out an accurate quantitative study of glucose metabolism, it is usually best to eliminate certain variable factors that are difficult to control, by removing the liver, pancreas, intestines, and kidney. Thus we have usually worked on the eviscerated rabbit. When an eviscerated rabbit is given enough insulin to produce a maximal effect, the disappearance rate of glucose immediately reaches a high level, with little or no further rise if administration of insulin is continued. The rate of oxidation of the glucose, as determined from the amount of tagged carbon in the expired carbon dioxide—increases slowly, and even