James E. Fewell

Prenatal exposure to nicotine impairs protective responses of rat pups to hypoxia in an age-dependent manner.

Experiments were carried out on rat pups to investigate the interaction between prenatal exposure to nicotine and postnatal age on protective responses that promote survival during exposure to hypoxia. From days 6 or 7 of gestation, pregnant rats received either nicotine (approximately 6 mg of nicotine tartrate/kg of body weight per day) or vehicle continuously via a 28-day osmotic minipump. On postnatal days 1--2, 5--6 and 10--11, the pups were exposed either to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) and 3% CO(2)) and their time to last gasp determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea determined. Prenatal exposure to nicotine decreased the time to last gasp, but only in the 1--2-day-old animals. The total number of gasps was, however, increased in this age group due to the effect of nicotine on the gasping pattern. Furthermore, prenatal exposure to nicotine decreased the number of successful autoresuscitations and influenced the cardiorespiratory events preceding death in the 1--2- and 5--6-day-old pups but not in the 10--11-day-old pups. Thus, our experiments show that prenatal exposure to nicotine impairs protective responses of rat pups that may sustain life during exposure to hypoxia in an age-dependent manner.

Pregnancy influences the plasma cytokine response to intraperitoneal administration of bacterial endotoxin in rats

Rats have an attenuated febrile response to intraperitoneal (i.p.) administration of exogenous pyrogen (e.g. bacterial endotoxin) near the term of pregnancy. To investigate possible mechanisms of this unique thermoregulatory response, the present experiments were carried out on 18 non‐pregnant and 16 near‐term pregnant Sprague‐Dawley rats to test the hypothesis that pregnancy alters the balance of pyrogenic cytokines and antipyretic and/or cryogenic (antipyretic/cryogenic) cytokines in response to exogenous pyrogen. To test our hypothesis, we measured plasma levels of interleukin (IL)‐1β, IL‐6, interleukin‐1 receptor antagonist (IL‐1ra) and tumour necrosis factor α(TNFα) at 2 and 4 h following i.p. administration of 160 μg kg−1E. coli lipopolysaccharide (LPS) (i.e. EC100 dose, or the smallest dose that elicits a maximal febrile response in non‐pregnant rats) in non‐pregnant as well as pregnant rats at day 20 of gestation (term ∼21 days). In non‐pregnant rats, E. coli LPS elicited statistically significant increases in plasma concentrations of IL‐1β, IL‐6, IL‐1ra and TNFα as compared to that observed following administration of vehicle. However in pregnant rats, E. coli LPS elicited statistically significant increases in antipyretic/cryogenic cytokines (IL‐1ra and TNFα) but not in pyrogenic cytokines (IL‐1β and IL‐6). Thus, a differential pyrogenic and antipyretic/cryogenic plasma cytokine response may mediate in part the attenuated febrile response to exogenous pyrogen observed in rats near the term of pregnancy.

Influence of Pregnancy on Plasma Cytokines and the Febrile Response to Intraperitoneal Administration of Bacterial Endotoxin in Rats

Rats have an attenuated febrile response to exogenous (e.g. bacterial endotoxin) and endogenous pyrogen (e.g. interleukin‐1β) near the term of pregnancy, the mechanism of which is unknown. The present experiments were carried out on 71 non‐pregnant and 181 pregnant Sprague‐Dawley rats to determine if basal levels of the endogenous antipyretic substance, interleukin‐1 receptor antagonist (IL‐1ra), change relative to interleukin‐1β (IL‐1β) throughout gestation. Furthermore, we have constructed complete Escherichia coli lipopolysaccharide (LPS) dose‐core temperature response curves in non‐pregnant and pregnant rats on days 10, 15 and 20 of gestation (term of gestation ∼21 days) to determine if the attenuated febrile response near the term of pregnancy results from a simple shift of the dose‐response relationship or results from a dampening of the overall dose‐response relationship. Basal IL‐1β, as determined by ELISA on trunk blood from non‐pregnant and pregnant rats on days 10, 15 and 20 of gestation (d10, d15, d20), did not change significantly during pregnancy. Basal IL‐1ra, however, was increased significantly in d15 rats as compared to non‐pregnant, and d10 and d20 rats. The attenuated febrile response near the term of pregnancy, as determined by biotelemetry, did not result from a simple shift of the E. coli LPS dose‐core temperature response curve but rather a dampening of the overall dose‐response relationship. The febrile responses to EC50 and EC100 doses of E. coli LPS were preceded by a period of hypothermia, and were delayed and attenuated near the term of pregnancy as compared to that observed early in pregnancy and in non‐pregnant rats. Our data provide evidence that pregnant rats are more sensitive to the hypothermia‐producing effects of E. coli LPS than are non‐pregnant rats and allow us to speculate that elevated basal IL‐1ra may play a role in mediating the attenuated febrile response to pyrogen on day 15 but not on day 20 of gestation in rats.

Coordination of autonomic and behavioral thermoregulatory responses during exposure to a novel stimulus in rats

The induction of psychological stress in rats is accompanied by an elevation of core temperature. Our experiments were carried out to determine whether the latency, duration, magnitude, or effector mechanisms of the core temperature response to psychological stress would be altered when rats were allowed to use behavioral as well as autonomic thermoregulation. Core temperature, oxygen consumption, and ambient temperature were measured in adult rats before and after handling and a sham intraperitoneal injection. Seven rats were studied in a thermocline (gradient of 7 to 42 degrees C) and eight rats were studied in a metabolic chamber (25 degrees C). The rats studied in the thermocline selected a warm ambient temperature following the sham intraperitoneal injection and exhibited an increase in core temperature of shorter latency, greater magnitude, and greater duration than those studied in the metabolic chamber. The rats studied in the metabolic chamber exhibited an oxygen consumption response of greater magnitude and duration than the animals studied in the thermocline. Thus the characteristics in addition to the effector mechanisms of the core temperature response to psychological stress are altered when rats are allowed to use behavioral as well as autonomic thermoregulatory effectors.The induction of psychological stress in rats is accompanied by an elevation of core temperature. Our experiments were carried out to determine whether the latency, duration, magnitude, or effector mechanisms of the core temperature response to psychological stress would be altered when rats were allowed to use behavioral as well as autonomic thermoregulation. Core temperature, oxygen consumption, and ambient temperature were measured in adult rats before and after handling and a sham intraperitoneal injection. Seven rats were studied in a thermocline (gradient of 7 to 42°C) and eight rats were studied in a metabolic chamber (25°C). The rats studied in the thermocline selected a warm ambient temperature following the sham intraperitoneal injection and exhibited an increase in core temperature of shorter latency, greater magnitude, and greater duration than those studied in the metabolic chamber. The rats studied in the metabolic chamber exhibited an oxygen consumption response of greater magnitude and duration than the animals studied in the thermocline. Thus the characteristics in addition to the effector mechanisms of the core temperature response to psychological stress are altered when rats are allowed to use behavioral as well as autonomic thermoregulatory effectors.

AVP mediates the attenuated febrile response to administration of PGE1 in rats near term of pregnancy

Rats have an attenuated febrile response to intracerebroventricular injection of PGE1 near the term of pregnancy, the mechanism of which is unknown. The present experiments were carried out to test the hypothesis that arginine vasopressin (AVP), functioning as an endogenous antipyretic substance in the central nervous system, mediates this attenuated febrile response. The febrile response to intracerebroventricular injection of 0.2 μg PGE1 was determined in pregnant and nonpregnant rats after an intracerebroventricular injection of either vehicle or a vasopressin V1-receptor antagonist. After intracerebroventricular administration of vehicle, intracerebroventricular administration of 0.2 μg PGE1 produced significant increases in core temperature in both nonpregnant and pregnant animals. The increase in core temperature, however, was attenuated both in magnitude and duration in pregnant compared with nonpregnant animals. After intracerebroventricular administration of a vasopressin V1-receptor antagonist, intracerebroventricular administration of 0.2 μg PGE1 produced significant increases in core temperature that were similar in nonpregnant and pregnant animals. Our data support the hypothesis that a pregnancy-related activation of AVP as an endogenous antipyretic substance in the central nervous system attenuates the febrile response to intracerebroventricular administration of PGE1 near term of pregnancy in rats.Rats have an attenuated febrile response to intracerebroventricular injection of PGE1 near the term of pregnancy, the mechanism of which is unknown. The present experiments were carried out to test the hypothesis that arginine vasopressin (AVP), functioning as an endogenous antipyretic substance in the central nervous system, mediates this attenuated febrile response. The febrile response to intracerebroventricular injection of 0.2 microg PGE1 was determined in pregnant and nonpregnant rats after an intracerebroventricular injection of either vehicle or a vasopressin V1-receptor antagonist. After intracerebroventricular administration of vehicle, intracerebroventricular administration of 0.2 microg PGE1 produced significant increases in core temperature in both nonpregnant and pregnant animals. The increase in core temperature, however, was attenuated both in magnitude and duration in pregnant compared with nonpregnant animals. After intracerebroventricular administration of a vasopressin V1-receptor antagonist, intracerebroventricular administration of 0.2 microg PGE1 produced significant increases in core temperature that were similar in nonpregnant and pregnant animals. Our data support the hypothesis that a pregnancy-related activation of AVP as an endogenous antipyretic substance in the central nervous system attenuates the febrile response to intracerebroventricular administration of PGE1 near term of pregnancy in rats.

Arginine vasopressin does not mediate the attenuated febrile response to intravenous IL-1β in pregnant rats

Rats have an attenuated febrile response to intravenous endogenous pyrogen [e.g., interleukin-1beta (IL-1beta)] near the term of pregnancy. The present experiments were carried out on 25 nonpregnant and 32 pregnant rats to test the hypothesis that arginine vasopressin functioning as an endogenous antipyretic substance in the central nervous system mediates this attenuated febrile response. An intravenous injection of recombinant rat IL-1beta (rrIL-1beta) after intracerebroventricular vehicle produced a significant increase in core temperature in both nonpregnant and pregnant animals, the magnitude and duration of which was greater in the nonpregnant rats. In nonpregnant rats, intravenous rrIL-1beta after intracerebroventricular vasopressin V1-receptor antagonist accentuated the core temperature response compared with that observed with intravenous rrIL-1beta after intracerebroventricular vehicle. In pregnant animals, however, intravenous rrIL-1beta after intracerebroventricular vasopressin V1-receptor antagonist produced a decrease in core temperature rather than an increase in core temperature, which was observed with intravenous rrIL-1beta after intracerebroventricular vehicle. Thus our data do not support the hypothesis that a pregnancy-related activation of arginine vasopressin as an endogenous antipyretic substance in the central nervous system attenuates the febrile response to intravenous rrIL-1beta near the term of pregnancy in rats.Rats have an attenuated febrile response to intravenous endogenous pyrogen [e.g., interleukin-1β (IL-1β)] near the term of pregnancy. The present experiments were carried out on 25 nonpregnant and 32 pregnant rats to test the hypothesis that arginine vasopressin functioning as an endogenous antipyretic substance in the central nervous system mediates this attenuated febrile response. An intravenous injection of recombinant rat IL-1β (rrIL-1β) after intracerebroventricular vehicle produced a significant increase in core temperature in both nonpregnant and pregnant animals, the magnitude and duration of which was greater in the nonpregnant rats. In nonpregnant rats, intravenous rrIL-1β after intracerebroventricular vasopressin V1-receptor antagonist accentuated the core temperature response compared with that observed with intravenous rrIL-1β after intracerebroventricular vehicle. In pregnant animals, however, intravenous rrIL-1β after intracerebroventricular vasopressin V1-receptor antagonist produced a decrease in core temperature rather than an increase in core temperature, which was observed with intravenous rrIL-1β after intracerebroventricular vehicle. Thus our data do not support the hypothesis that a pregnancy-related activation of arginine vasopressin as an endogenous antipyretic substance in the central nervous system attenuates the febrile response to intravenous rrIL-1β near the term of pregnancy in rats.

Gender influences the core temperature response to a simulated open field in adult guinea pigs

The induction of psychological stress is often accompanied by a transient increase in core temperature, commonly referred to as stress induced hyperthermia. Although stress-induced hyperthermia occurs when rats, mice, and pigs are exposed to a novel stimulus (e.g., a simulated open field, restraint, etc.), whether or not it occurs in guinea pigs has not been investigated. The present experiments were therefore carried out to investigate the thermoregulatory responses of both male (n = 7) and female (n = 7) adult guinea pigs when they were exposed to a simulated open field. Unexpectedly, neither the male nor female guinea pigs developed stress-induced hyperthermia. To the contrary, female but not male guinea pigs significantly decreased their core temperature during an open field experiment. The mechanism of the gender-specific thermoregulatory response of the adult guinea pig to psychological stress is presently unknown.

Interleukin‐1β‐Induced Fever Does not Alter the Ability of 5‐ to 6‐Day‐Old Rat Pups to Autoresuscitate from Hypoxia‐Induced Apnoea

Experiments were carried out to determine if endogenous pyrogen‐induced fever impairs protective responses of newborn rats to hypoxia. Twenty‐seven 5‐ to 6‐day‐old conscious rat pups received a subcutaneous injection of 0.20 μg of recombinant rat interleukin‐1β (rrIL‐1β) per kilogram of body weight to induce fever, or an equal volume of vehicle. They were then either exposed to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N2‐3% CO2) and their time to last gasp was determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnoea was determined. Core temperature increased significantly following administration of rrIL‐1β but did not change following administration of vehicle (i.e. vehicle, 0.0 ± 0.1 °C; rrIL‐1β, 0.7 ± 0.3 °C; P < 0.001) before exposure to hypoxia. IL‐1β‐induced fever did not alter the time to last gasp when the pups were exposed to a single period of hypoxia or the number of successful autoresuscitations upon repeated exposure to hypoxia. Thus, our data do not support the hypothesis that endogenous pyrogen‐induced fever impairs the protective responses in newborns that may prevent death during hypoxia as may occur during single or repeated episodes of prolonged sleep apnoea.

Mifepristone (RU38486) influences the core temperature response of term pregnant rats to intraperitoneal lipopolysaccharide

Pregnancy alters the cytokine, prostanoid and core temperature responses of rats to infectious stimuli at a time when blood levels of the endogenous glucocorticoid corticosterone are elevated. Given that glucocorticoids attenuate bacterial pyrogen‐induced fever in rats, the present experiments were carried out to test the hypothesis that administration of RU38486, a glucocorticoid type II receptor antagonist, would restore the febrile response to E.coli lipopolysaccharide (LPS) in pregnant rats on day 21 of gestation. Pregnant rats were randomly allocated to one of four experimental groups depending upon whether they received RU38486 (20 mg kg−1 intragastric) or vehicle followed by E. coli LPS (160 μg kg−1i.p.; a minimal dose that elicits maximal febrile response in non‐pregnant rats) or vehicle. Basal core temperature was not altered by intragastric administration of RU38486 or vehicle. Following intragastric administration of vehicle, intraperitoneal administration of E.coli LPS produced a significant hypothermia with latency, duration and magnitude of 0.5 h, 2 h and −1.3°C, respectively. Following intragastric administration of RU38486, however, intraperitoneal administration of E.coli LPS elicited only a minimal decrease in core temperature which was not significantly different from control values. Thus, our data provide evidence that endogenous glucocorticoids play a role in modulating the early core temperature response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.

Oxygen Transport and Utilization during Feeding in the Young Lamb

1 Five lambs (19–27 days old) were studied to determine the effects of feeding on cardiorespiratory function. 2 Each lamb was instrumented to record cardiac output, aortic and pulmonary artery pressure and arterial and mixed venous oxyhaemoglobin saturations (Sa,O2 and Sv,O2). 3 During feeding, arterial haemoglobin desaturated and resaturated sequentially during the periods of sucking and non‐sucking. The nadir of these Sa,O2 desaturations (83 ± 2%, mean ±s.e.m.) was significantly lower than the baseline value (92 ± 2%, P≤ 0.05, ANOVA). Sa,O2 returned to the baseline level between periods of sucking. Sv,O2 also decreased (55 ± 3% baseline, 46 ± 3% sucking, P≤ 0.05) but, in contrast to Sa,O2, it remained significantly lower than baseline levels in the pauses between periods of sucking. 4 Arterial pressure increased during feeding (94 ± 4 mmHg baseline, 113 ± 6 mmHg feeding, P≤ 0.05), while heart rate and cardiac index did not change. 5 Total body oxygen consumption rose during the pauses between sucking periods (10.9 ± 1.1 ml O2 min−1 kg−1 baseline, 13.9 ± 1.2 ml O2 min−1 kg−1 non‐sucking, P≤ 0.05) and was provided for by a significant increase in total body oxygen extraction as systemic oxygen transport was unchanged. 6 Our results reveal that during feeding in young lambs oxygen consumption increases and body stores of oxygen (e.g. Sv,O2) become depleted; this combination may promote rapid arterial desaturation and cyanosis during feeding.