• Korean Journal of Veterinary Research
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• v.39 no.6
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• pp.1161-1167
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• 1999

To investigate the effect of diazepam on fetal development in pregnant rats, this experiment was performed in eighty Sprague-Dawley female rats which were 8 weeks old and grouped into two according to different diazepam treatment period during 5-9 days of gestation and 10-14 days of gestation. Both experimental groups were included by saline treated groups (control) and diazepam-treated groups (6mg, 12mg and 24mg), respectively. Diazepam was injected to pregnant rats subcutaneously, which were sacrified on 20 days of gestation and mean litter size, fetal body weight, fetal crown-rump length (CRL) and pathological findings were examined. 1. Concerning mean litter size, diazepam-treated groups showed lower mean litter size than control in both 5-9 days and 10-14 days of gestation groups(p < 0.05) without difference according to dosage of diazepam and day of gestation. 2. Concerning fetal body weight, diazepam-treated groups during 5-9 days of gestation showed lower fetal body weight than control and the other treated group during 10-14 days(p < 0.01) without difference according to dosage of diazepam. Diazepam-treated group during 10-14 days of gestation showed no difference among experimented groups. 3. Concerning fetal crown-rump length (CRL), diazepam-treated groups during 5-9 days of gestation showed shorter CRL than control and the other treated group during 10-14 days of gestation(p < 0.01) without difference according to dosage of diazepam. 4. Reduction of mean litter size, fetal body weight and CRL was shown from when treated by the dosage of 6mg/kg of diazepam. 5. Maternal mortality according to dosage of the 20mg/kg of diazepam were 30% and 20% in the treated group during 5-9 days and 10-14 days of gestation, respectively. These results indicated that diazepam treatment in pregnant rats caused considerable reduction of mean litter size, fetal body weight and fetal crown-rump length when treated during 5-9 days of gestation.

• Journal of Yeungnam Medical Science
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• v.6 no.2
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• pp.13-22
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• 1989

To investigate the effect of diazepam on the contractility of the intestinal smooth muscle, longitudinal muscle strip isolated from rat ileum was prepared for myography in isolated organ bath. 1) Basal tone of ileal muscle was reduced by diazepam concentration-dependently. 2) Higher concentrations(30 and 100 microM) of diazepam inhibited(p<0.05, p<0.001) the carbachol-induced contraction in a concentration-dependent manner ; but lower concentration of diazepam(10 microM) enhanced(p<0.05). 3) Histamine-induced contraction was inhibited by pretreatment with diazepam in a concentration-dependent manner. 4) $Ca^{++}$-induced tension recovery in calcium-free solution was inhibited in the presence of diazepam concentration-dependently. These results suggest diazepam reduces the contractility of the longitudinal muscle isolated from rat ileum via interference with influx of calcium into the muscle cells.

• Journal of Veterinary Clinics
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• v.9 no.1
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• pp.301-309
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• 1992

The present study was carried out to compare xylazine(2.2mg/kg, IV), xylazine/acepromazine(1.1mg/kg. IV : 0.2mg/kg, IV) and xylazine/diazepam(1.1mg/kg, IV :1.0mg/kg, IV) anesthesia, to determine useful method out of three kinds of anesthesia and tr evaluate this selected method at hypovolemic state. In xylazine, kylazine/acepromazine and kylazine/diazepam anesthesia, the heart rate was increases after administration of atropine until 10minutes after administration of anesthetics and then decreased gradually in all types of anesthesia. The respiratory rate was decreased after administration of anesthetics in all types of anesthesia. The body temperature was rarely changed in xyiazine/acepromazine and xylazine/diazepam anesthesia, but decreased continuously in xylazine anesthesia. In xylazine and kylazine/acepromazine anesthesia the pedal and corneal reflex were not disappeared completely, but reactions to pin pricking were disappeared. In xylazine/diazepam anesthesia their reflex and reactions were disappeared together. The time from head-up to standing was shortest(32.00min) in kylazine/diazepam anesthesia in comparision with xylazine and kylazine/acepromazine anesthesia. In xylazine/diazepam anesthesia, the heart rates in hypovolemic dogs were decreased soon after administration of anesthetics but recovered immediately. The changes in systolic and diastolic blood pressure in hypovolemic dogs revealed similar trends to their changes in normal dogs after administration of anesthetics. It is considered that rylazine/diazepam anesthesia is one of the useful anesthetic methods in healthy dogs and also in hypovolemic dogs.

• Biomolecules & Therapeutics
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• v.7 no.3
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• pp.242-248
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• 1999

Diazepam, a benzodiazepine (BDZ) agonist, produces sedation and flumazenil, a BDZ antagonist, blocks these actions. The aim of this study was to examine the effects of BDZs on cortical electroencephalogram (EEG) in rats. The recording electrodes were implanted over the frontal and parietal cortices bilaterally, and the reference and ground electrodes over cerebellum under ketamine anesthesia. To assess the effects of diazepam and flumazenil, rats were injected with diazepam (1 mgHg, i.p.) and/or flumazenil ( 1 mg/kg, i.p.), and the EEG was recorded before and after drugs. Normal awake had theta peak in the spectrum and low amplitude waves, while normal sleep showed large amplitude of slow waves. The powers of delta, theta and alpha bands were increased during sleep compared with during awake. Diazepam reduced the mobility of the rat and induced sleep with intermittent fast spindles and large amplitude of slow activity, and it produced broad peak over betaL band and increased the power of gamma band, which were different from EEG patterns in normal sleep. Saline injection awakened rats and abolished fast spindles for a short period about 2-5 min from EEG pattern during diazepam-induced sleep. Flumazenil blocked both diazepam-induced sleep and decreased the slow activities of delta, theta, alpha and betaL, but not of gamma activity for about 10 min or more. This study may indicate that decrease in power of betaL and betaH bands can be used as the measure of central action of benzodiazepines, and that the EEG parameters of benzodiazepines have to be measured without control over the behavioral state by experimenter.

• Korean Journal of Bronchoesophagology
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• v.4 no.1
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• pp.64-72
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• 1998

This study aimed at observing the effect of diazepam on the contractility of trachealis muscle isolated from canine trachea, possible involvement of central or peripheral type benzodiazepine receptor, and the calcium related mechanism of action of diazepam. Trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiologic salt solution maintained at $37^{\circ}C$, and aerated with 95% $O_2$ /5% $CO_2$. Isometric myography was performed. Diazepam reduced the basal tone concentration dependently, and this inhibitory action was not affected by neither flumazenil, a central benzodiazepine receptor antagonist, nor PK11195, a peripheral benzodiazepine receptor antagonist. Pretreatment with diazepam showed the inhibitory effect on the concentration-response curves to agonists such as bethanechol, 5-hydroxytryptamine and histamine. Diazepam also caused concentration-related inhibition of contraction with potassium chloride 30 mM. The effect of diazepam on the basal tone and potassium chloride-induced contraction with calcium channel blockers were compared. Similar results were obtained in canine trachealis with verapamil, nifedipine and diltiazem. These results suggest that diazepam relax an airway muscle not via specific receptors but by a similar action as calcium channel blockers in canine trachealis muscle.

• Journal of Life Science
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• v.19 no.8
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• pp.1009-1015
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• 2009

The beneficial use of sedatives is often required for medically ill patients. This study examined the effect of plant flavonoids and diazepam peripheral-type benzodiazepine receptor (PBR) activation and glucose utilization in breast cancer cells, along with their interactions. In estrogen receptor negative MDA-MB-231 cells, the anti-proliferative activity of fisetin (3,7,3',4'-tetrahydroxyflavone) and diazepam was more prominent than in estrogen receptor positive MCF-7 cells. Unlike PBR ligands, treatment with $10^{-6}$ M concentration of diazepam for 3 days exhibited anti-proliferative effects, while similar to apigenin (4',5,7-Trihydroxyflavone) and fisetin, diazepam hardly affected the PBR mRNA expression by MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 3 days inhibited the glucose utilization of MDA-MB-231 cells. Treatment with $10^{-6}$ M concentration of flavonoids and diazepam for 6 days showed increased cytotoxicity and reduced the PBR mRNA expression of the MDA-MB-231 cells. Apigenin enhanced diazepam-induced anti-proliferative effects on the MDA-MB-231 cells as well. All together, this study showed the in vitro anti-proliferative activity of flavonoids and diazepam on MDA-MB-231 breast cancer cells, plus additive enhancements. In conclusion, this study provides experimental basis for advanced trials in the future.

• Journal of Yeungnam Medical Science
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• v.9 no.2
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• pp.359-381
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• 1992

This study was designed to investigate the effect of diazepam on the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus. Female rat(Sprague-Dawley) pretreated with oophorectomy and 4 days administration of estrogen, weighing about 200 g, was sacrificed by cervical dislocation, and the uteruses were isolated. A longitudinal muscle strip was placed in temperature controlled($37^{\circ}C$) muscle chamber containing Locke's solution and myographied isometrically. Diazepam inhibited the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus in a concentration-dependent manner. GABA, muscimol, a GABA A receptor agonist, bicuculline, a competitive GAGA A receptor antagonist, picrotoxin, a non competitive GABA A receptor antagonist, baclofen, a GABA B receptor agonist, and delta-aminovaleric acid, a GABA B receptor antagonist, did not affect on the spontaneous and oxytocin induced contraction of the isolated rat uterus. The inhibitory actions of diazepam on the spontaneous and oxytocin induced contraction were not affected by all the GABA receptor agonists and antagonists, but exceptionally potentiated by bicuculline. This potentiation-effect by bicuculline was not antagonized by muscimol. In normal calcium PSS, addition of calcium restored the spontaneous contraction preinhibited by diazepam and recovered the contractile of oxytocin preinhibited by diazepam. A23187, a calcium inophore, enhanced the restoration of both the spontaneous and oxytocin induced contraction by addition of calcium. In calcium-free PSS, diazepam suppressed the restoration of spontaneous motility by addition of calcium but allowed the recovery of spontaneous motility to a considerable extent. Diazepam could not inhibit some development of contractility by oxytocin in calcium-free PSS, but inhibited the increase in contractility by subsequent addition of calcium. These results suggest that the inhibitory action of diazepam on the rat uterine motility does not depend on or related to GABA receptors and that diazepam inhibits the extracellular calcium influx to suppress the spontaneous and oxytocin induced contractilities.

• The Korean Journal of Pharmacology
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• v.19 no.1
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• pp.115-122
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• 1983

The influences of diazepam and naloxone on the increase of plasma corticosterone level induced by morphine, pentazocine, ACTH, or picrotoxin were investigated in male mice. The results obtained were summarized as follows: 1) The increase induced by morphine or pentazocine of plasma corticosterone level was not affected by naloxone pretreatment but markedly suppressed by diazepam pretreatment. 2) The increase induced by ACTH of plasma corticosterone level was not affected by diazepam or naloxone pretreatment. 3) The picrotoxin markedly increased plasma corticosterone level, and the inceease was not affected by diazepam or naloxone pretreatment. This above results suggest that the increase induced by opioids of plasma corticosterone level seems to be rather related with other than opiate- or GABArerecptor.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.5
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• pp.555-563
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• 1998

The renal function is under regulatory influence of central nervous system (CNS), in which various neurotransmitter and neuromodulator systems take part. However, a possible role of central GABA-benzodiazepine system on the central regulation of renal function has not been explored. This study was undertaken to delineate the renal effects of diazepam. Diazepam, a benzodiazepine agonist, administered into a lateral ventricle (icv) of the rabbit brain in doses ranging from 10 to 100 ${\mu}g/kg,$ elicited dose-related diuresis and natriuresis along with improved renal hemodynamics. However, when given intravenously, 100 ${\mu}g/kg$ diazepam did not produce any significant changes in all parameters of renal function and systemic blood pressure. Diazepam, 100 ${\mu}g/kg$ icv, transiently decreased the renal nerve activity (RNA), which recovered after 3 min. The plasma level of atrial natriuretic peptide (ANP) increased 7-fold, the peak coinciding with the natriuresis and diuresis. Muscimol, a GABAergic agonist, 1.0 ${\mu}g/kg$ given icv, elicited marked antidiuresis and antinatriuresis, accompanied by decreases in systemic blood pressure and renal hemodynamics. When icv 0.3 ${\mu}g/kg$ muscimol was given 3 min prior to 30 ${\mu}g/kg$ of diazepam icv, urinary flow and Na excretion rates did not change significantly, while systemic hypotension was produced. These results indicate that icv diazepam may bring about natriuresis and diuresis by influencing the central regulation of renal function, and that the renal effects are related to the increased plasma ANP levels, not to the decreased renal nerve activity, and suggest that the effects may not be mediated by the activation of central GABAergic system.

• Archives of Pharmacal Research
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• v.6 no.1
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• pp.7-16
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• 1983

A methadone-diazepam interaction study in rats was performed in which conjugated metabolites of methadone were analyzed using deuterated biosynthetic internal standards. Diazepam (5mg/kg) was given to rats through a cannulate djugular vein and a subcutaneous dose of methadone (10mg/kg) was given. Bile was collecte through the cannulate dbile duct over a period of 24 hours. The deuterium label of the internal standards was found to be stable under conditions of the prolonged incubation. There was no significant difference in the excretion of the metabolites between the control and the diazepam treated rats. Feasibility of using biosynthetic internal standards with selected ion monitoring was established for the drug metabolism and kinetic studies.