Changes in the renin-angiotensin-aldosterone system in rats of both sexes submitted to chronic hypobaric hypoxia

The effect of moderate chronic hypobaric hypoxia (CHH) on the renin-angiotensin-aldosterone system has been analysed in male and female intact and castrated rats. The experimental animals were submitted to a simulated altitude of 4,400 m during ten weeks. Half of the experimental and half of the control animals were castrated at three weeks of age. Arterial pressure (AP) was measured once a week during the whole experimental period. Blood samples were obtained by decapitation at the end of the study. Red cell volume, plasma renin activity (PRA), plasma angiotensinogen (Ao) and aldosterone concentration (ALDO) were determined in the blood samples. Results have shown that the female animals subjected to CHH had lower levels of AP than the control female rats during all the studied periods whereas the AP of male hypoxic rats was only transiently diminished. All these changes were abolished by castration. PRA was not altered in either sex. The enzymatic complex was higher in male than in female control animals and decreased after castration in both hypoxic and control male rats. Ao was decreased by CHH in both sexes of intact rats and in female castrated animals. The renin substrate was higher in male than in female intact rats and decreased after castration in male animals. ALDO was increased after CHH only in male rats. Control female rats have higher levels of ALDO than male animals. Changes in the renin-angiotensin-aldosterone system related to CHH and also significant differences between sexes suggest that adrenal and gonadal corticosteroids may be involved in the main alterations presently observed.     

Protective effect of oestradiol on the heart of rats exposed to acute ischaemia

Sex-related differences in mortality from ischaemic heart disease are attributed chiefly to difference in the incidence of atherosclerosis. Little attention has been paid to the influence of sex hormones on resistance of the myocardium itself to acute ischaemia. Experiments on rats showed that isolated female hearts were more resistant than male hearts. A period of eight weeks spent at an altitude of 1,350 m raised heart resistance only in males. Conversely, gonadectomy abruptly reduced the resistance of the male heart to ischaemia, especially under conditions of mild altitude hypoxia. The administration of oestradiol to gonadectomized male rats largely abolished the disturbance caused by isolated gonadectomy. Since coronary vasoconstriction and vasospasm lead to temporary ischaemia and even to infarction, the above effect of the sex hormones may play a role in the increased incidence of heart attacks after the gonads have ceased to function.     

Adaptation to chronic hypobaric hypoxia and sexual hormones

The role of the gonads and their hormones on body weight was studied in rats of both sexes submitted to chronic hypoxia and their controls at sea level atmospheric pressure. Intact rats were exposed to either 4 700 or 6 000 m simulated altitude in a hypopressure chamber. Castrated rats and castrated rats daily injected with either 0.5 mg of testosterone or 20 microgram of estradiol or the vehicle, were exposed to the higher altitude. The rat weight was recorded for a period of at least eight weeks. All groups of hypoxic male animals increased their weight significantly less than the controls at sea level. Also in castrated females and in castrated injected with testosterone or the vehicle the same pattern of weight curves was observed. On the contrary, groups of intact females and castrated females injected with estradiol did not show significant differences between hypoxic and control animals. Only in a group of smaller intact females (50-80 g) the body weight increase was significantly diminished by exposure to either 4 700 or 6 000 m simulated altitude.     

DNA synthesis in the ventricular myocardium of young rats exposed to intermittent high altitude (IHA) hypoxia. An autoradiographic study.

Intermittent high altitude (IHA) hypoxia (7000 m) increased the wet weight of the right ventricular myocardium of 30-day-old rats after two 4 h/day exposures. During the same period the number of DNA-synthesizing nuclei of both muscle and non-muscle cell types increased proportionally. After 4 such exposures to hypoxia the number of 3H-thymidine-labelled nuclei in both cell types increased further. In addition, the number of labelled nuclei increased significantly in the yet un-enlarged left ventricle. While there was no difference in the number of DNA-synthesizing cells between the right and left ventricles in control animals, a significant increase in the number of cells involved in DNA synthesis in the right ventricle was found in both groups of animals exposed to IHA hypoxia. These results show that DNA synthesis in myonuclei of the ventricular myocardium can be stimulated in 30-day-old rats, i.e. at the very end of the weaning period.     

Cardiac microstructure in female and male offspring of exercised rat mothers

The microstructure of the cardiac muscle in eight subgroups of female and male rats was investigated: exercised (EE) and control (EC) offspring of exercised mothers, and exercised (CE) and control (CC) offspring of control, inactive mothers. The differences between subgroups were subjected to variance analysis and multiple-range tests according to Duncan. There were no marked differences in total body weight and weight of the heart related to total body weight. A significant difference (highest values) was shown in the density of muscle fibers and capillaries in the offspring of exercised mothers, which was further potentiated by the additional exercise during postnatal life. Diffusion distance was significantly longer in CC animals; the other subgroups did not differ significantly. There were no significant differences in the reaction of female and male offspring both due to prenatal and postnatal exercise.     

Effect of adaptation to altitude hypoxia in early ontogeny on the indices of higher nervous activity]

Newborn male and female Wistar rats were adapted to hypoxia in a pressure chamber. Adaptation was started from the "altitude" of 1000 m, 1 hour daily, and then the time and the intensity of hypoxic actions were gradually increased: beginning from the 17th day the animals were subjected to adaptation to the "altitude" of 5000 m, for 5 hours, 5 days a week. The defence conditioned reflex of active avoidance was provoked in the animals after 2-month adaptation. A tendency to a more rapid elaboration of the reflex and a markedly enhanced degree of its retention in comparison with control was revealed in the adapted males. No significant changes in the elaboration and rentention of the reflex were found in the female animals adapted to hypoxia under analogous conditions.     

Strain and sex differences in the cardiopulmonary adaptation of rats to high altitude

On chronic exposure to hypoxia, the commercially available Hilltop (H) strain of male Sprague-Dawley rats develops severe pulmonary hypertension, right ventricular hypertrophy (RVH), and polycythemia. These signs of chronic mountain sickness are associated with a high mortality rate. In contrast, the Madison (M) strain of Sprague-Dawley rats remains healthy with significantly less severe cardiopulmonary and hematological responses. Breeding experiments under locally controlled conditions were undertaken to determine if the differences between the two strains were genetically determined and to look for possible sex differences. Following 30 to 50 days exposure to a simulated altitude of 18,000 ft, the first generation of male H rats exhibited a higher right ventricular peak systolic pressure (RVPP), a more pronounced RVH, and a greater degree of polycythemia than the male M rats. The H rats had a mortality rate of 40% in contrast to a rate of 0% in the male M rats. The first generation of female H rats also developed a higher RVPP, a greater RVH, and more severe polycythemia than that in the female M rats. There were no differences in RVPP or RVH between the males and females of either strain. Females of both strains tolerated the hypoxic exposure with a 0% mortality rate. The data suggest that the differences between the males of H and M strains in their cardiopulmonary and hematological responses and in their susceptibilities to chronic hypoxia are genetic in nature. They further suggest that the female resistance to hypoxia is not due to milder cardiopulmonary responses. Perhaps female rats tolerate RVH better than male rats, at least of the H strain.     

Sex-related patterns of body tolerance to repeated acute hypobaric hypoxia

The individual differences in the response of male and female rats to repeated exposure to acute hypobaric hypoxia were experimentally studied. The time of attitudinal reflex maintenance and recovery in a rotating decompression chamber as well as the value of hypoxic hypothermia after decompression to a simulated altitude of 11200 m were used to evaluate the tolerance to hypoxia. Males demonstrated a slightly higher reactivity than females. At the same time, a more efficient adaptation to hypoxia conserved the body’s compensatory capacity and rapidly restored the functions affected by repeated exposure to the extreme factor. Such long-term adaptation was observed in initially low-resistant females, which could increase their resistance to repeated exposures to the stress factor.     

Effects of olive, corn, sesame or peanut oil on the body weights and reproductive organ weights of immature male and female rats.

Olive, corn, sesame or peanut oil which have been used as vehicles in the immature rat uterotrophic assay or Hershberger assay, for detection of endocrine disrupting effects of environmental chemicals, was administered to ten immature female rats by subcutaneous injection from postnatal day (PND) 21 for 3 or 7 days, and each oil was also administered to ten male rats from PND 21 for 7 and 10 days. The body weights, and the weights of sex and sex accessory organs in female and male rats were measured. There were no significant differences in body weights of female rats between each oil group and the control group, while the body weight of male rats in the group given peanut or olive oil was significantly increased from 8 or 9 days after administration. There were no changes in the sex and sex accessory organ weights of female or male rats related to the endocrine disrupters. The results of the body weights and organ weights demonstrate that each oil is a suitable vehicle for the immature rat uterotrophic assay. However, each oil is suggested to be unsuitable for the Hershberger assay, because the analysis of changes of sex accessory organ weights in this assay might be confused by the increased body weights.     

模拟高原低氧对不同性别新生大鼠下丘脑 CRF和AVP水平的影响

目的:探讨高原低氧对雌雄新生大鼠下丘脑-腺垂体-肾上腺皮质轴中枢部位肽能神经元发育的影响.方法:在低压氧舱中模拟高海拔低氧,用放免法测定精氨酸加压素(AVP)和下丘脑促肾上腺皮质激素释放激素(CRF)含量.结果:无论是在2 300 m对照海拔,还是在5 000 m模拟海拔,雌雄生后大鼠具相同的发育模式.低氧下发育至21 d时,CRF水平显著低于对照;相反,21 d及28 d时,低氧组AVP水平高于对照.结论:下丘脑CRF和AVP神经元间不同的发育模式可能与它们的功能及发育阶段特性相异有关.     

Influence of housing conditions from weaning to adulthood on the ventilatory, thermoregulatory, and endocrine responses to hypoxia of adult female rats

Housing conditions affect animal physiology. We previously showed that the hypoxic ventilatory and thermoregulatory responses to hypoxia of adult male rats housed in triads during the juvenile period (postnatal day 21 to adulthood) were significantly reduced compared with animals housed in pairs. Because sex hormones influence development and responsiveness to environmental stressors, this study investigated the impact of housing on the respiratory and thermoregulatory physiology of female rats. Since neonatal stress attenuates the hypoxic ventilatory response (HVR) of female rats at adulthood, experiments were performed both on "control" (undisturbed) animals and rats subjected to neonatal maternal separation (NMS; 3 h/day, postnatal days 3-12). At adulthood, ventilatory activity was measured by whole body plethysmography under normoxic and hypoxic conditions [fraction of inspired oxygen (Fi(O(2))) = 0.12; 20 min]. The ventilatory and body temperature responses to hypoxia of female rats raised in triads were reduced compared with rats housed in pairs. Housing female rats in triads did not affect basal or hypoxic plasma corticosterone levels but did increase levels of estradiol significantly. We conclude that modest changes in housing conditions (pairs vs. triads) from weaning to adulthood does influence basic homeostatic functions such as temperature and respiratory regulation. Triad housing can reverse the manifestations of respiratory instability at adulthood induced by stressful neonatal treatments. This should raise awareness of the benefits of increasing social interactions in clinical settings but also caution researchers of the potential impact of such subtle changes on experimental protocols and interpretation of results.     

Effect of hypoxia (6,060 m) and cold (−5°C) on sexual organs of male rabbits

Studies have been carried out on 18 adult male rabbits divided into three groups. One group (hypoxic) was exposed to a simulated altitude (6,060 m for 6 h daily for 21 days), the second group was exposed to the same altitude plus cold (–5°C) for the same duration, and the third acted as control. The results showed no difference in the body weight of the three groups, but the weights of the sex organs in the exposed groups were significantly reduced. In both these groups the number, motility and survival time of spermatozoa decreased significantly; the sex organs showed atrophy on histological examination; and there was an increase in the alkaline and acid phosphatase activity and cholesterol concentration, and a fall in GPC level. These changes were more marked in the cold plus altitude group than in the group exposed to altitude alone. It has been concluded that hypoxia affects not only the testis but also the epididymis and the vas deferens. The spermatozoal quality of rabbits deteriorates. When cold and hypoxia are combined, their effects are additive.     

A masculinized skeletomusculature is not necessary for male-typical patterns of food-protective movement

Although sexual dimorphism in movement has been documented in rodents, the extent to which it relates to dimorphic neural control versus dimorphic body size/structure is unclear. We have shown previously that male and female rats are sexually dimorphic with regards to the lateral movements and hindpaw stepping they use to protect a food item. We addressed the question of whether this sexual dimorphism is due to sex differences in peripheral skeletomusculature or in the CNS by examining the movement composition used during dodging to protect a food item by tfm-affected males and their wild-type male (WTM) and female (WTF) controls. The tfm-affected male, while genetically male, develops internal testes that secrete testosterone, but is phenotypically female due to a failure of androgen receptor-mediated masculinization of the periphery. Masculinization of the CNS of tfm-affected males, however, is primarily accomplished by the actions of testosterone's aromatized metabolite estradiol acting via estrogen receptors. Thus the tfm-affected male provides an assay by which the relative contributions of the skeletomusculature or CNS to sex differences in movement organization can be addressed. We found that female wild-type animals were significantly different from both the tfm-affected and wild-type males. There were no significant differences in dodge patterns used by tfm-affected males and their wild-type male controls. This study provides evidence that the sex differences in dodging patterns are mediated primarily by CNS mechanisms and are not primarily dependent on a male- or female-typical skeletomusculature.     

Effect of corticosteroids on arachidonate induced mortality in male and female mice

Sodium arachidonate (50 mg/kg) given intravenously to male and female mice induces pulmonary emboli followed by respiratory distress and cyanosis. Female mice are significantly more resistant to this treatment than male mice. Cortisone pretreatment for four days to intact mice (10 mg/kg/day/4 days) had a significant protective effect in both males and females against arachidonate toxicity, eliminating the sex difference previously observed. Adrenalectomy four days before arachidonate infusion increased the sensitivity to SA and resulted in 100% mortality in both sexes. Pretreatment of adrenalized animals with cortisone significantly reduced to some degree the mortality rate in both sexes. Castration of male and female mice three weeks before adrenalectomy did not affect the mortality rate seen following adrenalectomy alone. In conclusion, exogenous cortical steroids augment the resistance of even intact mice and are absolutely necessary for survival in adrenalectomized animals. The observed sex differences in untreated intact animals is not seen after treatment with cortisone or adrenalectomy.     

Experimental cardiac necrosis in hypobaric and anemic hypoxia.

Resistance to isoproterenol-induced cardiac necrosis (IPRO) was compared in rats exposed to two types of hypoxia (i.e., hypobaric and anemic). IPRO was induced by two consecutive, subcutaneous injections of isoproterenol (80 mg/kg) at 24-h intervals. The animals were killed on the third day and the severity of the lesion was evaluated on a 0 (no damage) to 4 (severely damaged) scale. White male rats (HA) were exposed in a barometric chamber to a simulated altitude of 7,000 m (307 mmHg) for 4 h/day for 24 days. Two groups of control rats were kept at sea level; one group (SLA) was the same age and one group (SLW) was the same weight as the altitude-exposed rats. The HA rats were significantly more resistant to IPRO with a mean necrogenic rating of 1.8 compared to 3.3 for the SLA and SLW rats. Infant rats (AA) were made anemic by feeding full-cream milk and glucose for 100 days after weaning. Two groups of control animals were fed a standard laboratory diet; one group (AC) was the same age and one group (AW) was the same weight as the AA rats. There was no significant difference in the necrogenic ratings of the AA (3.3), AC (3.5), or WC (3.7) hearts. Thus, hypobaric hypoxia affords some protection against IPRO which is not afforded by anemic hypoxia. Similarities and differences in the two hypoxias are discussed.     

Sex related differences in the response of mice, rats and cats to administration of picrotoxin

Picrotoxin, 2.5 mg/kg, which was subconvulsive in male rats was 92% convulsive in female rats. Four mg/kg of picrotoxin, a dose which did not produce death in the male rats, was 75% lethal in the female rats. Picrotoxin also produced a significantly greater increase in the frequency of the spinal motoneurons discharge in the female than in male rats (444% of control compared to 222% of control). A similar significant difference to the analogous treatment was obtained in the female and male cats (439% of control compared to 368% of control). To counteract the picrotoxin-induced increased frequency of the spinal motoneurons discharge a double dose of diazepam had to be given to females of both species. A sex related difference in the occurrence of convulsions, latency and death following picrotoxin administration was also present in mice. However, mice responded in an opposite direction to rats and cats. Three mg/kg of picrotoxin was 100% convulsive and 27% lethal in male mice, while only 40% convulsive and 0% lethal in female mice. In male mice treated with a 100% lethal dose of picrotoxin, diazepam, 3.0 mg/kg, did not diminish the occurrence of convulsions but reduced the incidence of death to 70%. In equally treated female mice the same dose of diazepam reduced the occurrence of convulsions from 100 to 70% and the incidence of death to 10%. The existence of sex related differences in the response of mice, rats and cats to administration of picrotoxin might have its origin in the dimorphisms of the GABA system in these animal species.     

Conditional Reflex Reaction of the Passive Avoidance in Female and Male Rats Exposed to Hypoxia at Different Terms of Prenatal Development

Elaboration of the conditional reflex reaction of passive avoidance was studied in the 42–46-day old offsprings of two groups of female rats: intact (control) and exposed to action of hypoxia at the 13th, 16th or 19th day of pregnancy. The parameter of learning was the time of stay of the rats in a dark camera, in which they obtained an electroshock. It is shown that the prenatal hypoxia has different effect on the ability to elaborate the conditional reflex reaction of passive avoidance in female and male rats. By this parameter, no differences were revealed in the male group between the control and the animals exposed to hypoxia at different terms of intrauterine development. In female exposed to hypoxia at the 19th day of gestation, it was not possible to elaborate the conditional reflex reaction of passive avoidance. In females exposed to hypoxia at the 13th day of gestation the parameters of learning were lower, whereas in the females exposed to hypoxia at the 16th gestation day they were higher than in control animals.     

Transient hypobaric hypoxia improves spatial orientation in young rats

To achieve a better understanding of learning and declarative memory under mild transient stress, we investigated the effect of brief hypobaric hypoxia on spatial orientation in rats. Young male Wistar rats aged 30 days were exposed for 60 min to hypobaric hypoxia, simulating an altitude of 7,000 m (23,000 ft) either shortly prior to attempting or after mastering an allothetic navigation task in the Morris water maze with a submerged platform. The post-hypoxic group performed significantly better in the navigation task than the control animals (the mean difference in escape latencies was 11 seconds; P=0.0033, two-way ANOVA with repeated measures, group x session). The experimental group also achieved a remarkably higher search efficiency (calculated as a percentage of successful trials per session), especially during the first four days following hypoxic stress (P=0.0018). During the subsequent training, the post-hypoxic group performed better than the control animals, whilst the efficiency levels of both groups progressively converged. Spatial memory retention and recall of well-trained rats were not affected by the transient hypobaric hypoxia. These results indicate that brief hypobaric hypoxia enhances rats' spatial orientation. Our findings are consistent with several studies, which also suggested that mild transient stress improves learning.     

Activation of glycogen synthase in myocardium induced by intermittent hypoxia is much lower in fasted than in fed rats

Obstructive sleep apnea is characterized by intermittent obstruction of the upper airway, which leads to intermittent hypoxia. Myocardial glycogen is a major energy resource for heart during hypoxia. Previous studies have demonstrated that intermittent hypoxia rapidly degrades myocardial glycogen and activates glycogen synthase (GS). However, the underlying mechanisms remain undefined. Because sleep apnea/intermittent hypoxia usually happens at night, whether intermittent hypoxia leads to GS activation in the postabsorptive state is not known. In the present study, male adult rats were studied after either an overnight fast or ad libitum feeding with or without intermittent ventilatory arrest (3 90-s periods at 10-min intervals). Hearts were quickly excised and freeze-clamped. Intermittent hypoxia induced a significant decrease in myocardial glycogen content in fed rats and stimulated GS in both fasted and fed rats. However, the portion of GS in the active form increased by approximately 38% in fasted rats compared with a larger, approximately 130% increase in fed rats. The basal G-6-P content was comparable in fasted and fed animals and increased approximately threefold after hypoxia. The basal phosphorylation states of Akt and GSK-3beta and the activity of protein phosphatase 1 (PP1) were comparable between fasted and fed control rats. Hypoxia significantly increased Akt phosphorylation and PP1 activity only in fed rats. In contrast, hypoxia did not induce significant change in GSK-3beta phosphorylation in either fasted or fed rats. We conclude that hypoxia activates GS in fed rat myocardium through a combination of rapid glycogenolysis, elevated local G-6-P content, and increased PP1 activity, and fasting attenuates this action independent of local G-6-P content.     

The effect of essential fatty acid deficiency on hepatic bile salt sulphotransferase in rats.

Hepatic bile salt sulphotransferase (BSS) activity and the contents of unconjugated oestradiol-17 beta (E2) and conjugated oestrone (cE1) in liver tissue was significantly lower in young essential fatty acid (EFA) deficient female rats than in female control rats. No corresponding differences were found between male EFA deficient and control rats. A significant sex difference, with higher values in females, was found for BSS activity and E2 and cE1 contents in control rats but not in EFA deficient rats. The decrease in hepatic BSS activity in female rats caused by EFA deficiency may be mediated via a decreased estrogenic action on the liver.