Arthur J. Vander

The Effects of Psychological Stress on Plasma Interleukin-6 Activity in Rats

The purpose of this study was to determine the effects of a particular psychological stress, exposure to an open-field, on plasma IL-6 activity in rats. Plasma IL-6 activity was 40.6 +/- 7.2 units/ml in control rats, 105 +/- 6.8 units/ml after 30 minutes exposure to an open-field, and 221 +/- 17 units/ml after 60 minutes of exposure (p = 0.0003). There was a positive correlation (r = .71, p = 0.043) between the change in plasma IL-6 activity and body temperature. However, we conclude, based on earlier data relating plasma IL-6 activity to body temperature changes following injection of lipopolysaccharide, that the plasma levels of IL-6 following exposure to an open-field are not high enough to account for the rise in body temperature observed in rats during this stress. In conclusion, these experiments indicate that exposure to psychological stress can elevate the plasma concentration of IL-6, a known mediator of the acute phase response.

Effects of Adenosine Compounds on Renal Function and Renin Secretion in Dogs

In anesthetized salt-depleted dogs, infusion of adenosine (20 to 500 μg/min) directly into a renal artery induced an initial decrease of renal blood flow for 1 to 2 minutes but did not change or slightly increased this flow during the steady state. Statistically significant decreases occurred in glomerular filtration rate, filtration fraction, sodium excretion, and renal venous renin activity. Calculated afferent arteriolar resistance increased and efferent resistance decreased. 5′-AMP (50 to 200 μg/min) induced changes which were smaller but qualitatively similar to those of adenosine. ATP (50 to 500 μg/min) induced no initial reduction in blood flow, and, during the steady state, caused a significant increase in blood flow and decreases in glomerular filtration rate, filtration fraction, sodium excretion, and renal venous renin. Efferent resistance decreased but afferent resistance did not change. Cyclic AMP (1 to 5 mg/min) caused a very small initial transient reduction in blood flow but induced changes similar to those of ATP during the steady state. Inosine (200 μg/min) and inosine-5′-monophosphate (50 to 200 μg/min) produced no detectable effects. It is suggested that adenosine or 5′-AMP may be normal mediators of both autoregulation and renin secretion.

Inhibition of Renin Secretion by Angiotensin .II.

Summary Intravenous infusion of angiotensin II (6.3-200 ng/kg min) inhibited renin secretion in dogs under conditions of basal or elevated renin secretion. This inhibition was independent of changes in mean renal arterial blood pressure. We propose a negative feedback effect of circulating angiotensin on renin secretion.

Further evidence that stress hyperthermia is a fever

Exposure of rats to an open-field results in a rapid rise in body temperature. Fifty-four percent of this rise in body temperature was blocked by intracerebroventricular administration of the antipyretic drug sodium salicylate. Intraperitoneal administration of indomethacin, a potent blocker of prostaglandin production, also attenuated the stress-induced hyperthermia to the same degree. Based on the data presented in this and an earlier study, we conclude that a major component of the rise in body temperature induced by psychological stress in rats is mediated by prostaglandins released by the central nervous system, and may therefore be a fever.

Hyperthermia Induced by Open-Field Stress is Blocked by Salicylate,

Psychological stress results in a rise in body temperature. Here we report that in rats, hyperthermia induced by open-field stress can be blocked by administration of the antipyretic drug sodium salicylate. These data suggest that this rise in body temperature is a true fever, perhaps mediated by prostaglandins.

Mechanism of the Effects of Furosemide on Renin Secretion in Anesthetized Dogs

Furosemide was administered to anesthetized dogs in priming doses of 0.1, 0.5, or 2.5 mg/kg followed by the same amounts per hour as infusion. When sodium and water balances were maintained constant by the continuous replacement of urinary losses with isotonic saline, the renal venous renin activity (and renin release) was not altered by the 0.1 mg/kg dose but was significantly increased by the two larger doses. This increase was manifest within 5 to 10 minutes. The larger doses also increased mean arterial pressure but did not change plasma sodium or glomerular filtration rate. Renal plasma flow was increased by the 2.5 mg/kg dose but not by the 0.5 mg/kg. In another group of dogs in which salt depletion was allowed to occur, 0.1 mg/kg produced an increased renin release within 30 minutes; this increase was completely reversed by the replacement of sodium and water losses. In this group of dogs, the glomerular filtration rate decreased and then returned to control values after restoration of fluid balance. It is hypothesized that the two higher doses of furosemide stimulated renin release by directly inhibiting macula densa sodium transport, and that the reported effects of all natriuretics can be explained in terms of a single macula densa theory.

In vivo evidence that the rise in plasma IL 6 following injection of a fever-inducing dose of LPS is mediated by IL 1β

Although it has often been speculated that Interleukin (IL) 1 alpha and IL 1 beta are circulating endogenous pyrogens (EP), there are few data demonstrating an elevation of these cytokines in the plasma of febrile animals. We hypothesized that IL 1 is released locally and may act to stimulate the release of another pyrogen, IL 6, which circulates to the brain to cause fever. The major purpose of the present study was to determine whether pretreatment of rats with antiserum to IL 1 beta, which attenuates lipopolysaccharide (LPS) induced fever, also results in an attenuation of the rise in plasma and cerebrospinal fluid (CSF) concentrations of IL 6. Our results show that injection of IL 1 beta produced dose-dependent rises in temperature and increases in plasma and CSF IL 6 activity, and that pretreatment of rats i.v. with antiserum to IL 1 beta produced a 55% decrease in the fever caused by LPS injection, a 68% decrease in plasma IL 6, and a 67% decrease in CSF IL 6. These data confirm the findings of previous studies that IL 1 beta is required for a portion of LPS-induced fever and also provide the first in vivo demonstration that the rise of IL 6 in rats injected with a fever-inducing dose of LPS can be significantly blocked by antiserum to IL 1 beta. Overall, the data in our study can be interpreted as being consistent with the hypothesis that the pyrogenic effect of IL 1 beta is mediated mainly through the release of IL 6, but conclusive confirmation of this hypothesis must await studies with antibodies to IL 6.

Effect of Centrally Administered Interleukin-1 and Endotoxin on Food Intake of Fasted Rats

We have previously shown that interleukin-1 (IL-1), a polypeptide known to mediate many aspects of the acute phase response to infection, suppresses food intake when injected intraperitoneally into fasted rats. IL-1 acts at the level of the hypothalamus to induce fever. In view of the large number of peptides that have been shown to alter food intake as well as body temperature when injected intracerebroventricularly (ICV), we hypothesized that the receptor site for the anorexigenic activity of IL-1 would be located in a central nervous site bathed by the cerebrospinal fluid. In the present study, ICV injection of IL-1 or E. coli endotoxin (a stimulus for the synthesis of IL-1), significantly elevated body temperature, but did not affect food intake of fasted rats. We conclude that receptors mediating the anorexigenic actions of IL-1 or endotoxin are not located at a central nervous site bathed by the cerebrospinal fluid. Furthermore, fever per se is not responsible for the reduction in food intake seen following peripheral injection of IL-1 or endotoxin.

Effects of adrenalectomy and aldosterone on proximal and distal tubular sodium reabsorption.

Summary The technic of stop-flow analysis has been used to localize the site of renal sodium reabsorption which is affected by adrenalectomy and aldosterone. Following adrenalectomy, the distal tubule was not able to reduce sodium concentration to the low value achieved during stop-flow in normal dogs. Following aldosterone administration this distal reabsorptive capacity was restored. No conclusion could as yet be made regarding the effects of aldosterone on the proximal tubule.

Inhibition of Renin Release in the Dog by Vasopressin and Vasotocin

In anesthetized dogs the intravenous infusion of arginine vasotocin, 25 mU/min, or vasopressin, 10 mU/min, inhibited renin secretion when control secretion rates were normal or when they were elevated by complete ureteral occlusion. Vasotocin, 5 mU/min, or vasopressin, 1 mU/min, was ineffective. Direct intraarterial infusion of vasotocin, 5 mU/min, into the right kidney inhibited renin secretion by the right kidney only. Glomerular filtration rate and renal plasma flow were not changed, and mean arterial pressure was either not changed or was decreased. Vasotocin caused no change in urine flow but did produce a significant natriuresis secondary to decreased tubular reabsorption. The physiological implications of these polypeptide-renal relationships are discussed.