Acute adrenal insufficiency after coronary artery bypass grafting.
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Acute Disease↗
Biomedical subjects
D Bitran
Publications and source records attributed to D Bitran.
Ovarian steroids modify the behavioral and neurochemical responses of the central benzodiazepine receptor.
The effect of ovarian steroids on the benzodiazepine receptor was assessed in the elevated plus-maze and, after restraint stress, in benzodiazepine receptor binding assays. Vehicle-treated proestrous rats displayed anxiolytic behavior, relative to diestrus or estrous rats. Anxiolytic behavior was observed after 1 or 2 mg/kg diazepam in diestrus and estrus. However, whereas 4 mg/kg increased open arm exploration in diestrus, a decrease in the same measure was found at estrus. At proestrus, a decrease in anxiolytic behavior was observed after 2 and 4 mg/kg. In ovariectomized vehicle-treated rats, restraint stress increased NaCl-induced potentiation of 3H-flunitrazepam binding in cortical and cerebellar, but not in hippocampal membranes. Estradiol benzoate (2 micrograms) prevented the potentiation of flunitrazepam binding by NaCl in nonstressed and stressed animals, whereas progesterone (0.5 mg) increased the NaCl-induced potentiation of flunitrazepam binding in both nonstressed and stressed animals. Combined estradiol benzoate and progesterone treatment produced effects that were intermediate to those seen after injection of either steroid alone. The potentiation of flunitrazepam binding by NaCl observed in vehicle-treated stressed or progesterone-treated nonstressed animals was mimicked in vitro by addition to reaction test tubes of the neuroactive metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone). These results point to a significant role of ovarian hormones in modifying the stress response of the benzodiazepine receptor.
Animals↗
Chronic anabolic-androgenic steroid treatment affects brain GABA(A) receptor-gated chloride ion transport.
Previous research in this laboratory has shown that chronic treatment of adult male rats with an anabolic-androgenic steroid (AAS) produced anxiolytic behavior and increased the functional response of cortical gamma-aminobutyric acid(A) (GABA(A)) receptors. The experiments reported here were aimed at further characterizing the effect of chronic AAS exposure on cerebral cortical GABA(A) receptors. Adult male rats were injected with dianabol (1,4-androstadien-17alpha-methyl-17beta-ol-3-one; 10 mg/kg/day, SC) for 4 weeks. A significant decrease in ventral prostate gland weight was found after 2 weeks of dianabol, and returned to control levels 3 and 10 days after steroid discontinuation. Testicular weights decreased throughout the treatment period but reached statistical significance only during the withdrawal period. Serum 3alpha-androstanediol level was marginally increased afer 2 weeks of dianabol injection, and was significantly decreased at 3 and 10 days after withdrawal. GABA-stimulated 36chloride (Cl-) influx in cortical synaptoneurosomes was increased in animals treated with dianabol for 2 and 4 weeks, and remained elevated 3 days after dianabol withdrawal, returning to control levels at withdrawal day 10. The increase in receptor efficacy was associated with a transient increase in receptor sensitivity (inverse of EC50), apparent after 2 weeks of AAS treatment and at withdrawal day 3. In a follow-up experiment, metabolites of dianabol were tested for the in vitro efficacy in potentiating GABA-stimulated Cl- transport. Only 3alpha-androstanedial and androsterone were found to have potent stimulatory effects. The 3beta-reduced metabolites were inactive, as were metabolites that contained a methyl group at the 17alpha position. These results point to significant facilitative effects of dianabol treatment on brain GABA(A) receptors via the metabolic formation of neuroactive steroids.
Anabolic Agents↗
Coronary artery bypass surgery during pregnancy.
A 32-year-old woman, in the 22nd week of pregnancy, underwent emergency coronary artery bypass grafting to the left anterior descending artery (LAD). She had suffered an acute myocardial infarction 10 days previously, and continued to suffer from intractable angina pectoris afterwards. Cardiac catheterization revealed spontaneous dissection of the LAD. The left internal mammary artery was used to bypass the LAD, and the operation was performed on a beating heart without the use of cardiopulmonary bypass. The patient's recovery was uneventful, and ultrasound examination and pulse monitoring of the fetus were both normal. She subsequently gave birth to a healthy term baby. To our knowledge this is the second report of coronary artery bypass surgery performed successfully in a pregnant woman. We believe the unique surgical approach avoided the risk of cardiopulmonary bypass to the fetus and placenta.
Adult↗
Aortic stenosis in the elderly: result of aortic valve replacement.
Forty-six patients, 24 male and 22 females, with a mean age of 78.4 years (range 75 to 88) underwent aortic valve replacement (AVR) for severe calcific aortic stenosis during a five year period. Twenty-six patients (56.5%) had combined aortic valve replacement/coronary artery bypass (AVR/CABG) procedures. Bovine pericardial or porcine bioprostheses were used in 47.8% of cases. The mean length of stay in the intensive care unit was 2.9 days (range 2-13) with a mean hospital stay of 12.6 days (range 6-41). Operative mortality rate was 6.5% (3 patients), all in the AVR/CABG group. Complications included pneumonia (8.7%), stroke (6.5%), and complete heart block requiring pacemaker insertion (6.5%). Follow-up of survivors from 11-69 months (mean 34.6) shows 92.9% survival, with 87.2% in New York Heart Association (NYHA) Class I and II. Aortic valve replacement in the elderly population has an acceptable mortality rate and is associated with significantly improved quality of life over the intermediate term.
Aged↗
Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors.
Previous studies from this laboratory have shown that progesterone (PROG) treatment in ovariectomized rats produces an anti-anxiety response similar to that observed after the administration of prototypical anxiolytic benzodiazepine (BDZ) compounds. The PROG-induced anxiolytic response was highly correlated with an increased level of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in the blood and brain, and was also associated with a facilitation of GABA-stimulated chloride ion (Cl-) influx in cortical synaptoneurosomes. This correlative evidence suggested that the anxiolytic effect of PROG was a result of its in vivo reduction to the neuroactive steroid, allopregnanolone. In this report, a series of studies was conducted to determine the mechanism(s) by which PROG alters behavior in animal models of anxiety. In the first experiment, ovariectomized rats were injected with PROG (1 mg/0.2 ml, SC) 4 h prior to a test in the elevated plus-maze. Some animals also received an injection of picrotoxin (0.75 mg/kg, IP), a GABAA receptor-gated Cl- channel antagonist, whereas other animals were pretreated with RU 38486 (5 mg/0.2 ml, SC), a progestin receptor antagonist. PROG elicited anxiolytic behavior in the plus-maze, an effect that was blocked by picrotoxin administration. Pretreatment with RU 38486 was not effective in altering PROG-induced anxiolytic behavior in the plus-maze. In a second experiment, the effect of PROG on behavior in the plus-maze was determined in the presence of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; 10 mg/0.2 ml, SC), a 5 alpha-reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Intraaortic balloon rupture: a possible means of prevention.
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Equipment Failure↗
Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat.
The putative psychotropic effect of the anabolic-androgenic steroid, testosterone propionate (TP), was determined in intact adult male rats after 1 or 2 weeks of continued exposure via subcutaneously implanted capsules. Behavior was assessed in a novel open-field arena and in the elevated plus-maze. In addition, gamma-aminobutyric acid (GABA)-stimulated 36chloride (Cl-) influx was determined in cerebral cortical synaptoneurosomes as a function of TP exposure. The weight of the prostate gland was taken and blood serum level of total testosterone (T) was assayed. One week of TP exposure (approximately 3.5-5.0 mg/kg per day) resulted in anxiolytic behavior, as evidenced by an increase in the exploration of the open arms of the elevated plus-maze. The behavioral effect in the elevated plus-maze was not observed in animals exposed to TP for a 2-week period. Ambulation scores in the novel open field did not change as a function of TP exposure. Blood T levels were increased 7-fold by 1 week of exposure, and increased 10-fold in animals with implants for a 2-week period. After 1 week of TP exposure, the concentration of GABA that elicited 50% of the maximal Cl- influx in cortical synaptoneurosomes (i.e., EC50) was significantly decreased; this effect was not seen in animals exposed to TP for 2 weeks. The maximal efficacy of the GABAA receptor-gated Cl- influx was not affected after 1 or 2 weeks of TP treatment. Thus, 1 week of treatment with TP resulted in anxiolytic behavior that was accompanied by an increase in the sensitivity of cortical GABAA receptors. However, the behavioral and neurochemical changes were no longer present after 2 weeks of TP exposure. These results are discussed in terms of the agonist effects of reduced androgen metabolites at the GABAA receptor and the possible development of tolerance to these effects.
Animals↗
Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function.
The effects of a SC injection of progesterone (0, 1, or 4 mg) on locomotor behavior and exploration of an elevated plus-maze were examined in ovariectomized rats. At the completion of the behavioral tests, blood serum and cerebral cortical level of the 3 alpha-hydroxy ring-A metabolite of progesterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone), was also assessed. GABA-stimulated 36Cl- influx was studied in cortical synaptoneurosomes from a subgroup of ovariectomized females treated with vehicle or 4 mg progesterone. Whereas progesterone treatment did not affect ambulation in a novel arena, significant anxiolytic behavior was detected in the plus-maze 4 h after administration of 1 or 4 mg progesterone. A dose-dependent increase in allopregnanolone level was found in serum and cortical homogenates. Studies of GABA-stimulated Cl- influx demonstrated that progesterone treatment increased the sensitivity of cortical synaptoneurosomes to GABA (i.e., decreased the EC50) and increased the maximal efficacy with which GABA stimulated Cl- transport (i.e., increased the Emax). Together, these data support the hypothesis that the psychotropic effects observed after progesterone administration are due to the bioconversion of progesterone to allopregnanolone, which subsequently augments GABAA receptor-mediated function.
Animals↗
Selective effects on CRF neurons and catecholamine terminals in two stress-responsive regions of adult rat brain after prenatal exposure to diazepam.
Earlier work demonstrated that prenatal exposure to diazepam (DZ) selectively affected the noradrenergic (NE) terminals in the hypothalamus, leading to decreased basal NE levels, turnover rate, and release in adult offspring as well as altered responses to stressors in these NE projections. The exposure also affected plasma hormonal responses to stressors. In the present work, we used immunocytochemistry to study the effects of prenatal DZ exposure on NE terminals and on corticotropin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. DZ exposure (2.5 or 10 mg/kg over gestational days 14-20) led to a decrease in dopamine-beta-hydroxylase (DBH)-immunoreactivity (-ir) and a decrease in CRF-ir containing cells within the PVN of adult rats. The exposure also decreased DBH-ir in the ventral portion of the bed nucleus of the stria terminalis (BNST) but did not affect CRF-ir in the oval nucleus of BNST. Therefore, this study provides anatomic evidence that targeting benzodiazepine binding sites prenatally affects two neurotransmitter systems involved in responses to stressors.
Animals↗
Male rat copulation following 6-OHDA lesions of the medial preoptic area: resistance to repeated administration and rapid behavioral recovery.
Dopamine (DA) in the medial preoptic area (MPOA) has been shown to facilitate male rat sexual behavior. However, injections of the catecholamine (CA) neurotoxin 6-OHDA into the MPOA did not impair copulation in tests 3 days after injection. In the present study, three weekly (serial) injections produced no copulatory deficits compared to animals that received a single injection or to preinjection copulatory behavior scores. However, blocking CA synthesis, which did not impair control rats, produced deficits in both single and serial lesion animals, with significantly fewer serial than single lesion animals initiating copulation. Biochemical analysis of tissue punches showed no difference in MPOA concentrations of dopamine, norepinephrine, epinephrine, or the dopamine metabolite DOPAC between the two groups. Additional animals were tested at earlier intervals after 6-OHDA injections into the MPOA. Tests conducted 30 min after an MPOA injection of 6-OHDA revealed that all measures of copulation were impaired, relative to scores 24 h later. However, these scores were not significantly different from animals tested 30 min after a vehicle injection. A final group, tested 4 h after injection, showed impairment of all measures of copulation compared to vehicle injections and to tests 24 h later. Furthermore, in the tests 24 h later, 6-OHDA animals were not different from vehicle animals. Results from all experiments show that 6-OHDA injections into the MPOA impair copulation for at least 4 h, but that behavioral recovery is complete 24 h later. However, deficits can be reinstated by inhibiting DA synthesis, suggesting that increased synthesis in undamaged terminals contributed to behavioral recovery.
Animals↗
Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor.
The effects of intracerebroventricular administration of reduced metabolites of progesterone on locomotor activity and on exploration in the elevated plus-maze were assessed in adult female rats. Allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one; 1.25, 5.0, and 10 micrograms) and pregnanolone (3 alpha-hydroxy-5 beta-pregnan-20-one; 2.5, 5.0, and 10 micrograms) elicited anxiolytic effects and, at the highest dose tested, allopregnanolone resulted in sedation. In contrast, the 3 beta-hydroxy-epimer of allopregnanolone was without effect in either behavioral paradigm. The anxiolytic response to pregnanolone was blocked by picrotoxin (0.75 mg/kg, i.p.), a dose that by itself did not affect behavior in the plus-maze. These data suggest that the anxiolytic effect of 3 alpha-hydroxy metabolites of progesterone is mediated by brain GABAA receptors in a stereospecific manner, and are in good agreement with the well-documented in vitro effects of these steroids as potent modulators of the GABAA receptor.
Animals↗
Gestational exposure to diazepam increases sensitivity to convulsants that act at the GABA/benzodiazepine receptor complex.
Experiments examining seizure sensitivity were conducted on adult male offspring exposed to diazepam at 1.0 or 2.5 mg/kg per day in utero over gestational days 14-20. Threshold dosages to facial clonus, myoclonic jerk, clonic seizure, and extensor tonus were determined via i.v. infusion of bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), picrotoxin, pentylenetetrazol, caffeine and strychnine. Relative to uninjected and vehicle-exposed adult male offspring, prenatal diazepam administration reduced the threshold for bicuculline- and DMCM-induced facial clonus and myoclonic jerk by 40-50%. The threshold dosages to facial clonus, myoclonic jerk and clonic seizure from picrotoxin infusion were similarly reduced in animals exposed to diazepam in utero. In contrast, seizure thresholds to pentylenetetrazol, caffeine and strychnine were not affected by early developmental exposure to diazepam. In parallel biochemical studies, an increased sensitivity to the antagonistic effects of bicuculline methiodide on gamma-aminobutyrate (GABA)-stimulated chloride influx was observed in cortical synaptoneurosomes from adult male progeny of diazepam-treated dams. The results are interpreted to reflect a long-lasting alteration in the function of the GABA/benzodiazepine receptor complex by prenatal diazepam exposure that is manifest at the behavioral and neurochemical level in a pharmacologic specific manner.
Animals↗
Modulation of noise-potentiated acoustic startle via the benzodiazepine--gamma-aminobutyric acid receptor complex.
Diazepam (DZ), an anxiolytic benzodiazepine (BZD) compound, attenuated the facilitation of the acoustic startle response by background noise. In Experiment 1, using a cumulative dosing paradigm, the effect of DZ on noise potentiation was found to be dose related. In Experiment 2, using a between-animals exposure design, the effect of DZ on noise potentiation was attenuated by coexposure to the central-type BZD receptor antagonist RO 15-1788, which itself was without effect. Using a cumulative dosing design in Experiment 3, RO 15-1788 was found to reverse the effect of DZ, whereas the peripheral-type BZD receptor ligand RO 54864 was without effect. The differences in the effect of cumulative exposure versus single dose exposure to RO 15-1788 were interpreted as indicative of either an intrinsic effect of the antagonist after repeated exposure or an influence of background noise itself on the BZD-gamma-aminobutyric acid receptor complex.
Acoustic Stimulation↗
Ovarian endocrine status modulates the anxiolytic potency of diazepam and the efficacy of gamma-aminobutyric acid-benzodiazepine receptor-mediated chloride ion transport.
The effect of ovarian steroid hormones on the behavioral and neurochemical sensitivity of the gamma-aminobutyric acid (GABA)-benzodiazepine (BZD) receptor chloride ion channel complex was studied. Locomotor activity and behavior in the elevated plus maze were examined in female rats of various ovarian states as was the efficacy and potency of GABA-stimulated chloride uptake in cortical synaptoneurosomes from proestrous and ovariectomized rats. A significant increase in the exploration of the open arms of the plus maze was observed in lactating females, in relation to diestrous, proestrous, ovariectomized, and pregnant females. The anxiolytic effect of diazepam (DZ) was decreased in ovariectomized females, in relation to proestrus females. Although 1.0 mg/kg DZ in proestrous females resulted in significant anxiolytic activity, this dose was ineffective in ovariectomized females but was reinstated by injection of estradiol benzoate and progesterone. A reduced efficacy of GABA-stimulated chloride ion transport in cortical synaptoneurosomes from ovariectomized females, in relation to that from proestrous females, was observed. Furthermore, the facilitative effect of DZ on the potency of GABA-stimulated chloride ion influx that was observed in cortical synaptoneurosomes from proestrous females was absent in synaptoneurosomes from ovariectomized females. These results are discussed in terms of the effect of ovarian steroids and reduced metabolites on GABA-BZD receptor-mediated functions.
Animals↗
Sexually dimorphic influence of prenatal exposure to diazepam on behavioral responses to environmental challenge and on gamma-aminobutyric acid (GABA)-stimulated chloride uptake in the brain.
Early developmental exposure to diazepam (DZ) via administration of the drug to the pregnant rat (1.0 or 2.5 mg/kg) over gestational days 14 to 20 altered both behavior of adult progeny on two tests of anxiety and function of the benzodiazepine/gamma-aminobutyric acid (GABA) receptor complex (a neural substrate of anxiety-related behavior) in a sexually dimorphic manner. Adult male rats (60-90 days) exposed in utero to DZ spent significantly more time on the open arm of the elevated plus-maze than male rats exposed to vehicle, whereas plus-maze performance in female rats was unaffected by the early drug exposure. Similarly, early exposure to DZ markedly altered environment-specific social interaction in male rats, leading to increased social interaction in the unfamiliar environment and decreased social interaction in the familiar environment. Social interaction in adult female rats is not normally environment-specific; however, female rats exposed in utero to DZ at 2.5 mg/kg demonstrated a significant effect of the novel environment on social interaction, thus responding like unmanipulated male rats. The sensitivity of GABA-mediated 36chloride uptake to GABA was enhanced in synaptoneurosomes from male rats exposed in utero to DZ at 2.5 mg/kg and early exposure to either dose of DZ prevented the facilitative effect of DZ added in vitro on GABA-mediated chloride uptake. Function of the receptor complex was not altered in female rats by early DZ exposure. Thus, perinatal insults at the molecular level may underlie gender-related behavioral disorders in the young adult.
Animals↗
Spinal block reveals roles for brain and spinal cord in the mediation of reflexive penile erections in rats.
Five experiments were addressed at two questions: (1) is the influence of the brain on spinal control of reflexive erection exclusively inhibitory; and (2) are the effects of copulation on erectile potential mediated by the brain, the spinal cord, or both? After various amounts of antecedent copulation, spinal anesthesia was induced in male rats by tetracaine (TET) injected through chronically implanted cannulae into the thoracic or lumbar spinal subarachnoid space, and the animals were then tested for reflexive penile erections (supine position, penile sheath retracted, no phasic stimulation applied). In sexually rested rats, TET injected at either T4 or T10 reduced reflex latency but also reduced the number and intensity of responses. Penile erection was inhibited by TET injected at L5, the region of the cord receiving sensory and motor projections from the genitalia. In previous studies surgical transection of the thoracic cord facilitated erection latency and production. In the present experiments the divergent effects of intrathecal TET on these variables suggested that they are controlled by separate systems within the spinal cord and that in the sexually rested rat the net influence of the brain is to inhibit the latency system and excite the production system. After rats copulated to sexual satiety, thoracic spinal block did not reverse the complete abolition of reflexive erections, establishing for the first time that copulation has direct inhibitory effects on the spinal cord's intrinsic system. Fewer antecedent ejaculations had less inhibitory effects on reflexive erection, and TET then acted, as in rested males, to reduce the erection latency and the number of erections, indicating that copulation may act on the brain's descending influences on spinal systems. The overall pattern of results suggested that the brain exerts both excitatory and inhibitory influences on separate, interacting spinal mechanisms that regulate the latency to reflexive erection and the number and intensity of erections displayed.
Anesthesia, Spinal↗
Penile desensitization does not affect postcopulatory genital autogrooming in rats: evidence for central motor patterning.
Postcopulatory genital autogrooming was studied in rats following desensitization of the glans penis due to topical application of an anesthetic ointment or to surgical transection of the dorsal penile nerve. These treatments sharply reduced the number of mounts resulting in intromission, but genital autogrooming was largely unaffected. The probability and duration of genital grooming were sensitive to the mount bout status of the copulatory event. The probability of autogrooming was higher, and the duration longer, after mounts that ended mount bouts and after intromissions, than after mounts that were incorporated within a mount bout. These findings suggest that the apparently compulsive genital autogrooming within a copulatory context is not regulated by afferent impulses from the penis, but may largely reflect central motor programing.
4-Aminobenzoic Acid↗