Effects of zopiclone on blood glucose level, serum lipid concentration and clot lysis time in normoglycemic and normolipidemic rats.

In normoglycemic and normolipidemic rats the i.p. injection of zopiclone induced an acceleration of fibrinolysis in a dose-dependent bell shaped manner and various changes of the blood glucose level. Total lipids, total cholesterol and triglyceride serum levels remained unaffected by doses of 1.25, 2.5 and 15.0 mg/kg, with the exception of the medium dose (5.0 mg/kg) and the next dose (10.0 mg/kg) which lowered them very significantly.

The influence of intracerebroventricular administration of (+/-) propranolol and (+/-) verapamil on experimental myocardial ischemia and necrosis in rats.

In albino rats, infarctoid myocardial lesions were produced by intraperitoneal (i.p.) administration of isoproterenol (75 mg/kg, during 3 days). In other groups, the descending anterior left coronary artery was ligated. In both experimental settings, the intracerebroventricular (i.c.v.) administration of (+/-) propranolol (100-200-300 microg/animal/day, during 7 days) or (+/-) verapamil (40-80-160 microg/animal/day, during 7 days) afforded a significant protection (with the exception of the lowest dose) on the investigated parameters: arrhythmias, ischemic zone (in coronary ligated rats), lactate dehydrogenase and aspartate aminotransferase activity of the serum, focal necrosis (in isoproterenol treated rats). This protective activity is lower than that afforded by i.p. administered (+/-) propranolol (5 mg/kg, during seven days) or (+/-) verapamil (5 mg/kg, during seven days). From these data it may be concluded that (+/-) propranolol and (+/-) verapamil have a protective action on the experimental myocardial ischemia and necrosis in rats, not only when the drugs come in direct contact with the heart, but also acting upon the central nervous system.

Effects of ICI 118.551, a selective beta-2 adrenergic blocking agent on the guinea pig cardiac excitability and ventricular fibrillation threshold.

In isolated guinea pig perfused hearts ICI 118.551, a selective beta 2 adrenoceptor antagonist, induced transient ventricular extrasystoles. Following the termination of the perfusion, a very significant increase of both the ventricular fibrillation threshold and the refractory periods were measured. In guanethidine pretreated hearts, ICI 118.551 failed to induce premature beats. At the same time the fibrillation threshold and refractory periods exhibited a very significant decrease. The perfusion of equimolecular concentration of metoprolol, a beta-1-adrenoceptor antagonist, and (+) propranolol, a quinidine-like compound, induced, in most experimental settings, similar results as ICI 118.551. Thus, besides its beta-2-adrenoceptor antagonist properties, ICI 118.551 presented other pharmacological actions.

Acute effects of zopiclone on blood glucose level and serum lipids in hyperlipidemic rats. Interactions with PK 11195 and flumazenil.

UNLABELLED: Intraperitoneal administration of 5 mg/kg zopiclone a cyclopyrolone acting on the central benzodiazepine receptors was found to produce significant reduction of total lipids, total cholesterol and triglyceride in rats randered hyperlipidemic by intraperitoneal injection of Triton W-1339. Blood glucose level was also reduced. Flumazenil (10 mg/kg) potentiated the hypoglicemic effect of zopiclone but had no additional effect on serum lipids. PK 11195 (25 mg/kg) antagonized the hypolipidemic effects of zopiclone. IN CONCLUSION: 1. The central benzodiazepine receptors are not involved in the hypolipidemic activity of zopiclone. 2. The peripheral type benzodiazepine receptors are partly responsible, for the hypolipidemic activity of this cyclopirrolone. 3. The changes of blood glucose level induced by these drugs does not seem to be related to benzodiazepine receptors.

Acute effects of zopiclone on blood glucose level and serum lipids in hyperlipidemic rats.

In rats rendered hyperlipidemic by ip administration of Triton WR-1339, the ip administration of zopiclone at doses of 1.25, 2.5, 5.0, 7.5, 10.0 and 15.0 mg/kg, a cyclopyrrolone acting upon the central benzodiazepine receptors, induces very significant reductions of total lipids, total cholesterol, and triglycerides, at nearly all of the doses. The most active dose was 5.0 mg/kg. The blood glucose level was diminished by doses of 1.25, 2.5, 7.5 and 15.0 mg/kg and it was not changed by the rest of the other doses.

Influence of the acute intraperitoneal administration of tetrazepam on blood glucose level and serum lipids in normoglycemic and normolipidemic rats.

The acute i.p. administration of tetrazepam (5, 7.5, 15 mg/kg) in normoglycemic and normolipidemic rats induced an increase in blood glucose level, a delay of fibrinolysis (when administered at the first two doses) and variable changes of serum lipids. These results are different from those obtained in hyperlipidemic rats treated with tetrazepam.

Effects of acute intraperitoneal administration of tetrazepam on blood glucose level and serum lipids in hyperlipidemic albino rats.

In rats rendered hyperlipidemic by the i.p. injection of Triton WR-1339, the i.p. administration of tetrazepam, a benzodiazepine (BZD) used mainly as a central myorelaxant, evoked significant reductions of serum lipids and blood glucose level. The dose-response curve was bell-shaped for serum lipids changes, whereas no clear dose-response relationship for blood glucose level modifications could be established. Tetrazepam was less active on serum lipids than other BZDs as diazepam or midazolam.

The effects of the intraperitoneal administration of midazolam on blood glucose level and serum lipids in streptozotocin-induced diabetes in rats.

In male Wistar rats rendered diabetic by streptozotocin administration, the intraperitoneal (i.p.) injection of midazolam (2.5-5.0 and 10 mg/kg) induced a significant reduction of hyperglycemia and hyperlipidemia. The plasma immunoreactive insulin level was slightly, but significantly increased. The lethality was diminished.

Effects of lormetazepam on glycemia and serum lipids in hyperlipidemic rats.

Lormetazepam (N-methyllorazepam) administered intraperitoneally to rats rendered hyperlipidemic by Triton WR-1339 induced an elevation of blood glucose level at all investigated doses. It brought about significant reduction of serum total lipids, total cholesterol and triglycerides. The dose-response relationship was bell-shaped. However, it presented two peaks, differing from the responses to other benzodiazepines (BZD) which were characterized by only one peak.

Effects of administration of temazepam on blood glucose and serum lipid levels in hyperlipidemic rats.

In rats rendered hyperlipidemic by the administration of Triton WR-1339 temazepam induced significant reductions of serum lipids. The effects was more reduced than of diazepam. The blood glucose level failed to be affected by most of the doses.

Effects of midazolam on glycemia and serum lipids in rats.

Midazolam administered ip. in albino rats (each group consisted from 10 animals rendered hyperdyslipidemic by the administration of Triton WR-1339) induced at most doses a significant reduction of glycemia (p < 0.001). However, the reduction of blood glucose level was outside of the dangerous level. Midazolam elicited also very significant decrease of the elevated serum lipids (p < 0.001). The pharmacological analysis of these phenomena by using the peripheral type benzodiazepine (BZD) receptors antagonist PK 11105, the central BZD receptor antagonist flumazenil and the purinergic P1 receptors antagonist aminophylline has shown that the effects on serum lipids were due, very probably to the stimulation of the peripheral type BZD receptors. Aminophylline seems to have the property to block the peripheral type BZD receptors. The effects on blood glucose level were very variable.

Effects of 4'-chlordiazepam on glycemia and serum lipids in hyperlipidemic rats: interactions with PK 11195 and flumazenil.

In rats rendered hyperlipidemic by the interperitoneal injection of Triton WR-1339, the administration of 4'-chlorodiazepam, a selective agonist of the peripheral type of benzodiazepine (BZO) receptors evoked significant reductions of serum lipids. PK 11195, a specific antagonist of these receptors, partially inhibited these effects. Flumazenil, a selective antagonist of the central BZD receptors, enhanced the lipid lowering activity of 4'-chlorodiazepam.

Effects of the intracerebroventricular administration of ketamine on centrogenic arrhythmias in anesthetized rats.

In urethane anesthetized rats the icv (lateral cerebral ventricle) administration of ketamine, at the highest utilized doses, induced bradypnea and sinus bradycardia in spontaneously breathing rats. Moreover, it partially antagonized the arrhythmogenic activities of sodium glutamate and sodium aspartate, as well as desipramine and ouabain. From these results, we conclude that ketamine had an inhibitory effect on the centrogenic arrhythmias not only acting at the level of NMDA subtype receptor, but also at beta 1 adrenergic central receptors. Moreover at high doses, ketamine can also induce centrogenic arrhythmias in spontaneously breathing rats.

Effects of flumazenil (Ro15-1788) on blood glucose and serum lipids in normoglycemic and normolipidemic rats.

The intraperitoneal administration of flumazenil, an imidazoldiazepine with selective antagonistic properties on the central benzodiazepine receptors, induced in normoglycemic-normolipidemic rats a significant increase in blood glucose levels and significant decreases in the serum lipids.

Effects of some benzodiazepines on glycemia in albino rats.

The acute administration of some benzodiazepines in normoglycemic rats induced only minor changes of the blood glucose levels. In Triton WR-1339 administered rats, the benzodiazepines brought about minor modifications of this parameter. However, in diabetic rats (streptozotocin-induced diabetes), diazepam administered subacutely elicited very significant diminutions of glycemia. This was due, at least partly, to an increase of the glucose uptake by the skeletal muscle.

Central arrhythmogenic effects of N-methyl-D-aspartate (NMDA) in anesthetized rats: influence of the denervation of the carotid-sinus baroreceptors on the susceptibility to arrhythmias.

The intracerebroventricular (i.c.v.) administration of NMDA into urethane anesthetized rats could induce centrogenic cardiac arrhythmias. There were some important differences between sodium glutamate- and NMDA-induced arrhythmias which rendered it difficult to accept the assumption that glutamate-induced arrhythmias were due to the stimulation of only NMDA receptors. Denervation of the carotid-sinus baroreceptor zones enhanced the central arrhythmogenic activity of both sodium glutamate and NMDA.

Effects of gadolinium on N-methyl-D-aspartate (NMDA)-induced centrogenic arrhythmias.

In urethane-anesthetized rats, the intracerebroventricular (i.c.v.) administration of N-methyl-D-aspartate (NMDA)-induced central arrhythmias. These cardiac rhythm disorders could be prevented by the i.c.v. microinjection of gadolinium, an inhibitor of exocytosis. These findings suggest that inhibition of central neurotransmitter exocytosis could protect against centrogenic arrhythmias.

Inhibitory role of somatostatin on calcitonin secretion.

Calcitonin (CT) secretion is not exclusively controlled by calcemia, but the secretory tonus is maintained by the beta-stimulatory adrenergic system Somatostatin (SMS) plays a neuromodulatory role with the reduction of CT secretion by its interference at the central and peripheral level of the beta adrenergic receptors. The experiments were carried out on groups of rats in which the effect of SMS on CT content of the thyroid gland was followed up. Thus, SMS administered i.c.v. significantly reduced the basal CT secretion without blocking the stimulatory effect of calcium. The results were comparable with those obtained after the blockade of the sympatho-adrenergic system by chemical sympathectomy with 6HODA or propranolol. Central blockade of alpha receptors with phentolamine determined a significant rise of CT. This effect was annihilated by SMS. The i.v. administration of SMS did not induce a change in CT content of the thyroid, but blocked the stimulatory action of hypercalcemia. The results are identical with those obtained by blocking the beta-receptors with propranolol. SMS also blocked the stimulatory effects of isoproterenol on CT secretion. The data obtained revealed the fact that SMS lowers CT secretion by the central and peripheral interference of the sympatho-adrenergic path, maintaining the secretory tonus of the thyroid C cells.

Effects of peripheral type benzodiazepine antagonist PK 11195 on the lipid-lowering activity of diazepam in albino rats.

The i.p. administration of PK 11195, a peripheral type benzodiazepine receptor antagonist in a dose of 1 mg/kg/day antagonized the action of u.p. injection of diazepam (5 mg/kg/day, 5 days) on serum triglycerides. It seems that the effects of diazepam on serum lipids were due to the stimulation of the peripheral type benzodiazepine receptors.