Angiotensin: physiological role in water-deprivation-induced thirst of rats.

Cerebroventricular infusion of P-113, the blocking agent of angiotensin II, into rats for 75 minutes prior to their being allowed to drink, significantly attenuated their water intake when they had been deprived of water for 30 hours. However, a similar infusion had no effect on the food intake in rats fasted for 30 hours. The results indicate a physiological role for angiotensin II in the drinking response of rats deprived of water.

The origins of U.S. safety standards for microwave radiation.

An analysis is made of the scientific research and values influencing the policy decisions that led to the adoption of the 1966 U.S. standard for exposure to microwave radiation. This analysis is used as a tool for understanding the problems faced by those who set standards. An effort is made to unravel the complex motivations that lay behind the adoption of the microwave standard. Based on the past record, it is suggested that standard setting remain distinct from basic scientific research and that adversary procedures be used only as a last resort in seeking consensus over a proposed standard.

Effects of chronic potassium deficiency on plasma renin activity.

Serial determinations of plasma renin activity, sodium balance, urinary potassium excretion rate, and plasma sodium and potassium concentration were done in five dogs during dietary-induced potassium depletion and repletion. Duration of depletion for the different animals ranged from 5 to 7 wk. Plasma renin activity increased in all animals during depletion, with rises being demonstrated as early as the 1st depletion day in two of the dogs. Maximum values in the five dogs were recorded from the 2nd to the 28th day of depletion. Early in depletion, changes in renin activity did not correlate with changes in sodium balance. Late in the course of depletion, plasma renin activity decreased concurrently with a progressive retention of sodium. However, in every case increased renin activity persisted throughout depletion despite development of sodium retention sufficient to inhibit renin release in normal dogs. Potassium repletion resulted in a prompt decrease in renin activity to predepletion values. This study indicates that potassium deficiency has a stimulatory effect on renin release that is independent of any effect on sodium balance.

Increased vasodilator responses to acetylcholine in psychosocial hypertensive mice.

Responsiveness to endothelium-dependent (acetylcholine and A23187) and endothelium-independent (nitroprusside and 8-bromo cyclic guanosine 3',5'-monophosphate [cGMP]) vasodilators was examined in two vascular preparations from hypertensive and normotensive mice. CBA Agouti mice were made hypertensive by exposure to social stress in a complex population cage. After 2 months, the hindquarter vascular bed was pump-perfused at a constant flow with plasma substitute to evaluate changes in perfusion pressure, and helical strips of aorta were suspended in muscle baths for measurement of isometric force generation. Tissues were treated with methoxamine to induce contractile tone. Threshold dilator responses to acetylcholine were elicited at a significantly lower dose in the hindquarters of hypertensive mice than in those from normotensive mice, indicating increased vasodilator sensitivity. In contrast, vasodilator responsiveness to nitroprusside in hindquarters of hypertensive mice did not differ from that in hindquarters of normotensive mice. Aortas from hypertensive mice were more sensitive (lower ED50) to the relaxant effects of acetylcholine and A23187 than those from normotensive mice. The relaxant effects of nitroprusside and 8-bromo cGMP on aortas from hypertensive mice were not significantly different from those in normotensive aortas. Aortic strips that had been rubbed on the lumen surface with a wooden stick did not relax to acetylcholine or A23187. In aortas that were not initially contracted with methoxamine, acetylcholine and A23187 caused small contractions from baseline. The magnitude of these contractile responses were potentiated after removal of the endothelium, and the potentiation was greater in aortas from hypertensive mice. These results demonstrate an increased responsiveness to endothelium-dependent vasodilators in this psychosocial model of hypertension.

Increased vascular sensitivity to angiotensin ii in psychosocial hypertensive mice.

CBA mice develop hypertension when placed in complex population cages that facilitate social interactions and competition for territory. After 1 month, these mice have normal plasma renin levels, but blockade of converting enzyme lowers blood pressure to normal. To test the possibility that this normal-renin hypertension is caused by enhanced pressor responsiveness to angiotensin II (AII), we examined the effects of AII on hindquarter and renal vasculatures from 13 hypertensive and 13 normotensive mice. Both vascular beds were pump-perfused at a constant flow with plasma substitute. Optimal perfusion flows and basal pressures were similar in hindquarter (8 ml/100 g/min; 60 mm Hg) and renal vasculatures (130 ml/100 g/min; 50 mm Hg) from normotensive and hypertensive mice. Threshold constrictor responses to AII were elicited at a significantly lower dose in both vasculatures of hypertensive mice than in those of normotensive mice. Maximal pressor responses to AII were greater in the hindquarters of hypertensive mice than in those of normotensive mice, but were not different in the renal vasculatures of the two groups. Vasoconstrictor sensitivity to norepinephrine was also increased in the hindquarters of hypertensive mice; however, the changes in threshold and maximal pressor response were less than for AII. Responsiveness to norepinephrine in the renal vasculatures of hypertensive mice was not different from that in the kidneys of normotensive mice. We conclude that the hyperresponsiveness to AII in the resistance vessels plays an important role in maintaining elevated blood pressure in this psychosocial model of hypertension.

Suppression of food intake during infection: is interleukin-1 involved?

Loss of food appetite is a common manifestation of acute infectious illness and is believed to contribute to the negative nitrogen balance and loss of body weight that is seen during infection. The frequency with which anorexia occurs with infection suggests that it may be part of the acute phase response. In the present experiments, food intake of fasted rats was suppressed following injection of interleukin-1, a polypeptide that mediates many host responses to infection. We conclude that infection-induced anorexia is, in part, due to the release of interleukin-1.

The role of fever in appetite suppression after endotoxin administration.

In order to test the hypothesis that fever, and not some other aspect of the acute phase response, decreases food intake after administration of endotoxin, food intake of rats was studied under conditions of 1) fever, 2) antipyresis, and 3) endotoxin tolerance. Injection of endotoxin resulted in a significant elevation in rectal temperature and a significant reduction in food intake. Administration of the antipyretic drug sodium salicylate to endotoxin-injected animals lowered rectal temperatures to control levels, but food intake was still suppressed. When rats were made tolerant to endotoxin by repeated injections, an attenuated fever was observed, and food intake was not significantly different from that of control animals. We conclude that the effects of endotoxin on body temperature can be dissociated from its effects on food intake. We speculate that the failure of endotoxin to suppress food intake in endotoxin-tolerant rats may be due to a decreased production of endogenous pyrogen.

Chronic effects of lead on the renin-angiotensin system.

This paper reviews the chronic effects of lead exposure on the renin-angiotensin system in experimental animals and human beings. In rats, when lead exposure is begun several weeks after birth in doses that cause blood lead concentrations (PbB) of 30 to 40 micrograms/dL, the result is an increase in basal plasma renin activity (PRA) and renal renin concentration, with no change in the metabolic clearance of renin; this is presumptive evidence for increased renin secretion. PRA is also increased in 1-month-old animals whose exposure to lead (in doses that raise PbB to 9 micrograms/dL) was begun in utero. In contrast, older animals whose exposure was begun in utero manifest no change or a decrease in their PRA and renal renin concentration. Regardless of when the exposure is begun, lead can decrease the plasma concentration of angiotensin II at any given PRA, but the dose required for this effect is highly variable. The hypertension induced by lead exposure is associated with low PRA and a normal angiotensin II/PRA ratio. Chronic human exposure to lead also is associated with highly variable changes in PRA from study to study; it has been reported to be decreased under both basal and stimulated conditions, unchanged, or increased in a manner exponentially related to PbB. The human data are consistent with the tentative hypothesis that lead-exposed persons may have higher PRA than normal during the early periods of modest exposure but normal or depressed PRA following more chronic severe exposures. In a small preliminary study, blood lead concentration was found to be higher in high-renin hypertensive persons than in normotensive persons.

Human circadian rhythms in temperature, trace metals, and blood variables.

The literature supports the concept that circadian changes in body temperature reflect changes in the thermoregulatory set point. We were interested in studying the relationship between the circadian rhythm in body temperature and 24-h variations in plasma concentrations of iron, zinc, circulating leukocyte counts, and plasma interleukin 1 (IL-1) activity. Eight healthy men were studied for two separate 48-h sessions. Rectal temperature, plasma iron and zinc concentrations, plasma IL-1 activity, circulating leukocyte counts, and several other blood variables were monitored. Circadian rhythms in temperature, trace metals, and various leukocyte populations were demonstrated. The 24-h pattern of changes in plasma concentrations of iron and zinc approximate an inverse relationship with rectal temperature. Although we were unable to detect any IL-1 activity in human plasma collected at 4-h intervals, the daily changes in plasma trace metal concentrations and the variations in leukocyte populations may provide indirect evidence for a daily variation in local (e.g., in liver) or central nervous system release of IL-1.

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.

Stress-induced rise of body temperature in rats is the same in warm and cool environments.

Several forms of psychological stress result in a rise in body temperature in rats. In this study, we report that rats housed at a low ambient temperature (11.1 degrees C) develop stress-induced rises in body temperature that do not differ from the responses seen when the animals are kept at a temperature within their thermoneutral zone (24.7 degrees C). These data support the hypothesis that stress-induced "hyperthermia" is a regulated rise in temperature (i.e., a rise in thermoregulatory "set-point," or fever), and is not simply the result of metabolic changes associated with the stress response itself.

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 chronic infusion of lipopolysaccharide on food intake and body temperature of the rat.

Unrestrained male Sprague-Dawley rats were infused for seven days with a low (2.45 micrograms/hr) or high (9.81 micrograms/hr) concentration of E. coli lipopolysaccharide (LPS). Compared to control (saline-infused) rats, food intake in the LPS-infused rats remained depressed for the entire infusion period. Despite this long-term suppression of food intake, fever was observed only during the daytime hours for the first two days of infusion. No significant increase in nighttime body temperature was observed. These data indicate that although tolerance to LPS occurred in rats with regard to its fever-inducing effect, tolerance with respect to its anorexigenic action did not occur.

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.

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.

Lead increases urinary zinc excretion in rats.

The major purpose of this study was to determine whether acute or chronic Pb exposure would increase urinary excretion of zinc in the rat. Four groups of unanesthetized rats were given 0, 0.03, 0.3, or 3 mg Pb (as acetate) kg intravenously, and urinary excretion of zinc, sodium, and potassium was monitored for 6 h. Only at the highest dose was urinary Zn excretion significantly elevated; there were no significant changes in sodium and potassium excretion at any dose. Two other groups of rats were studied for 9 weeks in metabolism cages before and during administration of either 500 ppm Pb (as acetate) or equimolar Na acetate in the drinking water. Two days after Pb treatment and continuing through day 35, Zn excretion was elevated in the Pb-exposed animals; beyond this day, zinc excretion became similar in the two groups. The difference in Zn excretion was not the result of lower water intake by the Pb-treated animals. At sacrifice (70 days after starting Pb exposure), Pb-exposed animals had lower Zn content of the plasma and testis, but there was no difference in kidney Zn. Plasma renin activity was significantly higher in Pb-exposed animals. We conclude that chronic Pb exposure in rats can result in some degree of decreased tissue zinc, which is, at least in part, secondary to increased urinary losses of zinc.

Effects of high altitude on plasma concentrations of testosterone and pituitary gonadotropins in man.

Ten healthy male volunteers were rapidly taken to the top of Pike's Peak, altitude 14,100 ft (4,300 m) where they remained at the research station for 6 d. There were no significant changes, compared to their values at sea-level, in the plasma concentrations of testosterone, FSH, and LH during this period. There was a highly significant direct correlation between individual changes in testosterone and the gonadotropins on Day 1. Our data provide no evidence for an acute effect of high-altitude per se on the secretion of testosterone and the pituitary gonadotropins.

The effects of pentoxifylline on lipopolysaccharide (LPS) fever, plasma interleukin 6 (IL 6), and tumor necrosis factor (TNF) in the rat.

The purpose of these studies was to test whether pentoxifylline, a drug that can inhibit the production and action of cytokines hypothesized to be endogenous pyrogens (for example, interleukin 1 and tumor necrosis factor [TNF]), is antipyretic. We also tested the effects of pentoxifylline on plasma activities of interleukin 6 (IL 6) and TNF in response to an injection of a fever-inducing dose of lipopolysaccharide (LPS). Our results showed that a high dose of pentoxifylline (200 mg/kg) caused hypothermia in control rats and blocked LPS fever, while a low dose (50 mg/kg) did not have these effects. Injection of the high dose of pentoxifylline in control rats caused a rise in plasma IL 6 but not in plasma TNF. However, the peak levels of plasma IL 6 and TNF activities following an injection of LPS were significantly reduced by pretreatment with pentoxifylline. Overall, the data are consistent with the hypothesis that pentoxifylline is an antipyretic drug, which may act at least in part by inhibiting the secretion of pyrogenic cytokines.