Role of nitric oxide in radiation-induced initiation of mammary tumorigenesis in rats.

Nitric oxide (NO) and its reaction products have been shown to cause DNA damage and to be mutagenic. To elucidate whether NO produced by irradiation participates in the initiation of mammary tumorigenesis, we performed experiments using the nitric oxide-specific scavenger Fe(2+)-diethyldithiocarbamate complex (Fe(DETC)(2)) or a selective inhibitor for inducible nitric oxide synthase (iNOS), S,S(')-(4-phenylene-bis(1,2-ethanedinyl))bis-isothiourea (1,4-PB-ITU). Mother rats at day 21 of lactation were injected simultaneously with diethyldithiocarbamate intraperitoneally and Fe(2+)-citrate subcutaneously to form Fe(DETC)(2), in vivo, and then irradiated with 1.5Gy gamma-rays immediately after the injection. An additional injection of chemicals followed twice at 8 and 24h after the irradiation in the same manner. Both control and treated rats were then implanted with diethylstilbestrol pellets as a tumor promoter. The mammary tumor incidence in the experimental group was significantly reduced to one-fourth of that in the irradiated-alone group as the control. On the other hand, when mother rats took drinking water containing 0.005% 1,4-PB-ITU for 6 days from 3 days prior to irradiation at day 21 of lactation, a low tumor incidence in the iNOS inhibitor-treated groups was observed in the 1-year period. This report is the first to show that the NO derived from iNOS is an important radical for radiation-induced initiation of tumorigenesis of mammary glands in rats.     

Increased sensitivity to neurotensin in fasted rats

The present study was designed to investigate the influence of fasting on the ability of neurotensin (NT) to produce hypotension in anesthetized rats, to constrict the coronary vessels of perfused rat hearts and to stimulate isolated rat stomach strips and spontaneously beating atria of rats. The hypotensive effects of NT, in contrast to those elicited by bradykinin and isoproterenol, were markedly increased in 24h-fasted and 72h-fasted rats compared to control fed rats. The increase in perfusion pressure provoked by NT in perfused hearts derived from 24h-fasted and 72h-fasted rats was much larger than in hearts derived from control fed animals. On the other hand, the constrictor action of angiotensin in perfused rat hearts was not altered by fasting. The stimulatory effect of NT in stomach strips and atrial preparations derived from fasted rats was not increased when compared to tissues from control fed animals. It is suggested that prolonged period of fasting in rats may contribute to sensitize the cardiovascular system of these animals to the action of NT.     

Angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (ANG II) (200 micrograms/kg sc) to the rat induced a hypothermic response that was characterized within 12 min by a reduction in the rate of O2 consumption, vasodilation of the tail, and a 1.3 degrees C fall in colonic temperature. Administration of ANG II in doses ranging from 10 to 200 micrograms/kg resulted in a decrease in colonic and an increase in tail skin temperature. Angiotensin I (ANG I) (200 micrograms/kg sc) induced a similar hypothermic response which was abolished by pretreatment with the ANG I-converting enzyme inhibitor, captopril (35 mg/kg ip). The interaction of ANG II with cholinergic and adrenergic pathways was evaluated to determine possible mechanisms. Treatment with ANG II (200 micrograms/kg sc) and propranolol, a beta-adrenoceptor antagonist (6 mg/kg ip), resulted in a greater depression of colonic temperature (Tco) than was observed with ANG II alone but did not affect the increase in tail skin temperature (Tsk) accompanying administration of ANG II. When ANG II was administered in combination with the beta-adrenergic agonist, isoproterenol (50 micrograms/kg ip), Tco remained at control levels, whereas an enhancement of the ANG II-induced increase in Tsk occurred. Administration of ANG II in combination with atropine sulfate (6 mg/kg ip), a muscarinic receptor antagonist which crosses the blood-brain barrier, significantly reduced the extent of the fall in Tco without affecting the increase in Tsk. The combined treatment of ANG II and the quaternary analogue, atropine methyl nitrate (3.25 mg/kg ip), which does not cross the blood-brain barrier, failed to affect the hypothermic responses to ANG II. These results suggest that the hypothermic responses to ANG II may be mediated through a central cholinergic pathway and possibly influenced by an adrenergic component. The inability of both adrenergic and cholinergic blockers to affect the vasodilatory response of the tail of the rat to administration of ANG II suggests that the mechanisms subserving heat production can be blocked independently of those subserving heat loss.     

氧化震颤素在精氨酸加压素引起大鼠低温中的作用与对行为性体温调节反应的影响

目的:研究氧化震颤素在精氨酸加压素(AVP)引起低温中的作用及其对行为性体温调节反应的影响。方法:无线遥控测温技术记录成年雌性SD大鼠体核温度(Tc)、棕色脂肪组织(BAT)温度和活动的变化。用无线遥测温度梯度仪记录大鼠行为性体温调节反应。分别观察AVP(10μg/kg)和氧化震颤素(0.25 mg/kg)对大鼠Tc、活动、BAT温度(TBAT)、理毛活动和行为性体温调节反应的影响。结果:AVP和氧化震颤素均能引起Tc和TBAT降低,理毛活动增加,引起低温反应的同时动物选择较低环境温度。氧化震颤素能使AVP引起的Tc和TBAT降低,以及理毛活动的增加更明显,并持续更长时间。注射氧化震颤素后立即注射AVP动物亦选择较低环境温度,但与AVP比较无明显差异。结论:AVP引起的低温与体温调定点下移、抑制BAT产热和增加理毛活动有关。氧化震颤素可能通过影响BAT产热和行为性体温调节参与外周给AVP引起的低温过程。     

Enhanced apomorphine-induced hypothermia in alloxan-treated rats

Previous studies have indicated that drug-induced experimental diabetes is associated with increased receptor binding in the rat brain. The purpose of this study was to determine whether the dopamine receptor agonist apomorphine (APO) might produce an accentuated hypothermic response in rats rendered diabetic by alloxan (ALX) treatment. In a previous study, however, the only controls used were ALX-treated rats that failed to develop glycosuria. Therefore, in this study, APO (0.5 mg/kg IP) was administered to ALX-diabetic and non-diabetic as well as saline-treated control rats to ascertain whether the APO responsiveness of ALX-non-diabetic rats was comparable to that of saline control animals. ALX-diabetic rats experienced significantly greater hypothermic response to APO than did the saline control animals. Although ALX-non-diabetic rats were similar to the saline control animals in body weight and blood glucose levels, they too were hyperresponsive to APO. These findings indicate that pancreatic injury from ALX, while not always sufficiently severe to produce overt diabetes, does appear to induce an hyperresponsiveness to APO-induced hypothermia in a manner similar to that observed in severely diabetic animals.     

Bombesin produces hypothermia in hypophysectomized rats

Intracerebroventricular administration of bombesin, a naturally-occurring peptide, produces hypothermia in the rat. To determine whether a pituitary-dependent step is necessary for this effect, the thermoregulatory response was followed in hypophysectomized and intact rats maintained at room temperature. Significant hypothermia was produced in both experimental groups. This study supports an extra-pituitary mechanism for bombesin-induced hypothermia.     

Reversible deep whole-body hypothermia in rats

The effect of deep hypothermia on the rat's organism was investigated without the use of hypercapnic hypoxia or administration of medicine. The possibility of resuscitation and rehabilitation of rats after deep hypothermia depending on different rate of heating have been also studied. It has been observed that the cardiac activity stopped at about 3 degrees C. We supposed that the extremely intensive heating and temperature rise of an organism were both limiting factors. We have discovered that the low intensity of heating was the next factor of limitation which was connected with the duration of clinical death. These experiments showed that the intensive cooling and heating (about 0.4 degrees C per min.) are the best for resuscitation and rehabilitation after deep hypothermia.     

Role of L-glutamate in systemic AVP-induced hypothermia.

It has been reported that systemic injection of arginine vasopressin (AVP) induces a drop in body core temperature (T(c)), but little is known about the mechanisms involved. Because glutamate is an important excitatory neurotransmitter involved in a number of thermoregulatory actions, in the present study, we tested the hypothesis that glutamate plays a role in systemic AVP-induced hypothermia. Wistar rats were pretreated intracerebroventricularly (icv) with kynurenic acid, an antagonist of l-glutamate ionotropic receptors, alpha-methyl-(4-carboxyphenyl)glycine (MCPG), an antagonist of l-glutamate metabotropic receptors, or saline 15 min before intravenous injection of AVP (2 microg/kg) or saline. T(c), brown adipose tissue (BAT) temperature, blood pressure, heart rate, and tail skin temperature were measured continuously. Administration of saline icv followed by intravenous AVP caused a significant drop in T(c) brought about by a reduction in BAT thermogenesis and an increase in heat loss through the tail. MCPG treatment (icv) did not affect the fall in T(c) induced by AVP. Treatment with kynurenic acid (icv) abolished AVP-induced hypothermia but did not affect the AVP-evoked rise in blood pressure or drop in heart rate and BAT temperature. Heat loss through the tail was significantly reduced in animals injected with AVP and pretrated with kynurenic acid. These data indicate that ionotropic receptors of l-glutamate in the central nervous system participate in peripheral AVP-induced hypothermia by affecting heat loss through the tail.     

Role of radioadaptation on radiation-induced thymic lymphoma in mice

Thymic lymphoma (TL) was observed in different stages of development in 46% of male mice (23/50) following exposure to an acute challenge dose of 2 Gy ⁶⁰Co γ-rays. With an adapting dose of 1 cGy 24 h prior to the challenge dose of 2 Gy, similar growth of TL was seen in 42.5% of mice (17/40). TL was not found in unirradiated control mice (0/50) or in the group treated with 1 cGy (0/50). Multiple adapting doses for 5 or 10 consecutive days induced TL in 8/50 and 9/50 mice, respectively (17% in average). When multiple adapting doses were followed by the challenge dose, the yield of TL was much lower, 16% (8/50) and 30% (15/30), respectively. By 15, 30, 60, 90, and 120 days after exposure with 3 Gy of ⁶⁰Co γ-rays, TL developed in 30, 70, 70, 80 and 85% of the female mice, respectively. When mice were conditioned with an adapting dose of 1 cGy 24 h prior to the challenge dose, TL was not found 15 days post-irradiation, while about a 25% reduction in the occurrence of TL was noticed at all other intervals. The results suggested that an adapting dose could play a role in bringing about a change in terms of delay and inhibition of the acute effects of radiation, i.e., the onset of TL in mice.     

Factors affecting angiotensin II-induced hypothermia in rats

Systemic administration of angiotensin II (AII) to the rat has previously been shown to induce a dose-dependent, hypothermic response manifested by a fall in colonic temperature (CT), a decrease in heat production and an increase in tail skin temperature (TST). The factors mediating AII-induced hypothermia and their site of action were the subjects of the present investigation. To this end, intracerebroventricular administration of 1 microgram of AII induced a 0.4 degrees C reduction in CT and a 2.4 degrees C increase in TST. In contrast, SC administration of 200 micrograms angiotensin III/kg induced a slight increase in CT but had no affect on TST. Pretreatment with the AII-receptor antagonist, saralasin, at either 1 or 10 micrograms/kg, SC did not affect either the fall in CT or the increase in TST induced by administration of 200 micrograms AII/kg, SC. However, the administration of 100 micrograms saralasin/kg, SC attenuated both the fall in CT and the increase in TST induced by either 100 or 200 micrograms AII/kg. Since both the presynaptic alpha adrenoceptor agonist, clonidine, and the opioid antagonist, naloxone, modulate the pressor and dipsogenic responses to AII, their effects on AII-induced hypothermia were tested. Both clonidine (25 micrograms/kg, SC) and naloxone (1 mg/kg, IP) enhanced the fall in CT. Clonidine lengthened the duration of the increase in TST while naloxone had no effect. Pretreatment with the presynaptic adrenoceptor antagonist, yohimbine (300 micrograms/kg, SC), did not alter the hypothermic response to administration of AII. To determine whether vasodilation of the tail of the rat was mediated by AII-induced prostaglandin release, indomethacin (4 and 6 mg/kg) was administered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of proteins in protection against radiation-induced damage in membranes

The effect of gamma irradiation on liposomes in the presence of a large number of commercially available proteins has been studied. Experiments were designed to demonstrate that the configuration of both acyl chain and cis C = C bonds created by lipid-protein associations are crucial in autocatalyzed radiation-induced lipid peroxidation. Raman spectroscopy was used to characterize these states. Raman spectra in the C-C stretching region show three prominent bands at 1064, 1090, and 1125 cm-1, assigned to trans, gauche, and trans C-C bonds, respectively. A single symmetrical C = C stretching band assigned to the cis isomer occurs at 1660 cm-1. The intensity ratios (I1064/I1090) and (I1660/I1440) are used as Raman probes to define the conformational states of acyl chains and C = C bonds, respectively. Our data show that the ratio (I1064/I1090) decreases in the presence of proteins, indicating that these proteins induce more gauche structures. Upon irradiation, the ratio (I1064/I1090) increases by about 30% in the absence of proteins and by about 15% in the presence of proteins. This shows that proteins retain the gauche structures in irradiated samples. The ratio (I1660/I1440) decreases in liposomes containing proteins, showing that proteins modify the configuration of cis C = C bonds. Upon irradiation, this ratio decreases by about 45-50% in samples without proteins and by about 10% in samples with proteins. These data show that proteins inhibit the radiation-induced configurational changes in the cis C = C bonds. The determination of radiation-induced peroxides (as malondialdehyde equivalents) in liposomes reveals that proteins inhibit the formation of peroxide products at low molar ratio and that the preventive capacity of different proteins is different. We conclude that proteins alter the conformation of both acyl chains and cis C = C bonds in liposomes and that these altered states are less sensitive to radiation-induced peroxidation.     

Role of adenosine in the hypoxia-induced hypothermia of toads

The concept that hypoxia elicits a drop in body temperature (T(b)) in a wide variety of animals is not new, but the mechanisms remain unclear. We tested the hypothesis that adenosine mediates hypoxia-induced hypothermia in toads. Measurements of selected T(b) were performed using a thermal gradient. Animals were injected (into the lymph sac or intracerebroventricularly) with aminophylline (an adenosine receptor antagonist) followed by an 11-h period of hypoxia (7% O(2)) or normoxia exposure. Control animals received saline injections. Hypoxia elicited a drop in T(b) from 24.8 +/- 0.3 to 19. 5 +/- 1.1 degrees C (P < 0.05). Systemically applied aminophylline (25 mg/kg) did not change T(b) during normoxia, indicating that adenosine does not alter normal thermoregulatory function. However, aminophylline (25 mg/kg) significantly blunted hypoxia-induced hypothermia (P < 0.05). To assess the role of central thermoregulatory mechanisms, a smaller dose of aminophylline (0.25 mg/kg), which did not alter hypoxia-induced hypothermia systemically, was injected into the fourth cerebral ventricle. Intracerebroventricular injection of aminophylline (0.25 mg/kg) caused no significant change in T(b) under normoxia, but it abolished hypoxia-induced hypothermia. The present data indicate that adenosine is a central and possibly peripheral mediator of hypoxia-induced hypothermia.     

Dexamethasone blocks morphine-induced hypothermia in restrained rats

Rats restrained in small plexiglass restraining cages responded to morphine, 30mg/kg, with a pronounced $\text{hypo}$thermia. However, when this same dose of morphine was administered to unrestrained freely moving rats a marked $\text{hyper}$thermia resulted. The absolute magnitude and time course for body temperature changes after morphine were similar in both groups. When restrained rats pretreated with dexamethasone were administered morphine the hypothermic response was not only prevented but a subsequent hyperthermia occured. Morphine injected into unrestrained dexamethasone pretreated rats, however, still elicited a hyperthermia although of slightly lesser magnitude. These findings indicate that restraint is a potent modifier of morphine's effects on thermoregulation and that this effect most probably results from a stress-related activation of anterior pituitary hormone release. The possibility that ACTH or ß-endorphin released by the stress of restraint are responsible for this modification is discussed.