Glucocorticoid mechanisms may contribute to ECT-induced retrograde amnesia.

RATIONALE: Cortisol levels rise sharply immediately after electroconvulsive therapy (ECT); the resultant stimulation of steroid receptors in the hippocampus may be beneficial or harmful to cognition, depending on the magnitude of the stimulation. Steroid mechanisms may therefore modulate ECT-induced amnesia. OBJECTIVES: Using mifepristone (a glucocorticoid receptor antagonist) as a chemical probe, we sought to examine steroid mechanisms in an animal model of ECT-induced retrograde amnesia. MATERIALS AND METHODS: Adult, male Wistar rats (n = 68) trained in a step-through passive-avoidance task were randomized to receive mifepristone (20 or 40 mg kg(-1) day(-1)) or vehicle (control). These treatments were administered 1 day before the electroconvulsive shock (ECS) course and, again, 1 h before each of five once-daily true (30 mC) or sham ECS. Recall of pre-ECS learning was tested 1 day after the last ECS. RESULTS: Relative to sham ECS, true ECS resulted in significant retrograde amnesia in the vehicle group but not in either of the mifepristone groups. In sham ECS-treated animals, mifepristone did not significantly influence recall. In ECS-treated rats, the higher but not the lower dose of mifepristone was associated with significant protection against the retrograde amnesia evident in the vehicle group. CONCLUSION: Mifepristone administered before the ECT seizure may attenuate ECT-induced retrograde amnesia. This suggests that glucocorticoid mechanisms may contribute to ECT-induced retrograde amnesia.

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats.

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.

BR-16A protects against ECS-induced anterograde amnesia.

BR-16A is an herbal (non allopathic) medication used in India to enhance cognition. In experiment 1, 28 Wistar rats received either BR-16A (200 mg/kg/day) or vehicle alone for 3 weeks. During the third week, the rats were tested for learning in the Hebb Williams complex maze. BR-16A-treated rats showed significantly better learning than did controls. Experiment 2 was conducted identically except that during the second week all of 32 rats additionally received six once-daily electroconvulsive shocks (ECS). An advantage for learning was again demonstrated for the BR-16A group. It is concluded that BR-16A facilitates learning, and that this effect extends to a protection against ECS-induced anterograde amnesia. Cognitive deficits induced by electroconvulsive therapy are a major disadvantage of the treatment and, to-date, no drug has been found to offer satisfactory protection against such deficits. It is suggested that BR-16A may hold promise in the containment of electroconvulsive therapy (ECT)-induced cognitive compromise.

Synthesis and alpha-adrenergic activities of 2- and 4-substituted imidazoline and imidazole analogues.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

Diversity of the pharmacological actions of some tolazoline analogues in human platelets and rat aorta.

Tolazoline and two 4'-substituted benzyl analogues, 2-(4'-aminobenzyl) imidazoline (ABI) and 2-(4'-isothiocyanatobenzyl)imidazoline (IBI) were synthesized and evaluated for adrenoceptor activity in human platelets (alpha 2) and rat aorta (alpha 1), respectively. IBI was prepared as an affinity label for alpha-adrenoceptors and compared with chloroethylclonidine. Tolazoline, IBI, ABI and chloroethylclonidine inhibited the primary and secondary waves of epinephrine-induced human platelet aggregation. In aspirin treated platelets, primary wave aggregatory responses to epinephrine were blocked in a competitive manner by tolazoline, ABI. IBI and chloroethylclonidine giving pA2 values of 6.33, 6.12, 4.71 and 5.70, respectively. Only IBI blocked the aggregation responses to ADP (secondary wave only) arachidonic acid and U46619 (a thromboxane A2 agonist). Arachidonic acid-induced serotonin release and malondialdehyde formation and thrombin-induced release of [3H]arachidonic acid from membrane phospholipids were also blocked by IBI. These data indicate that IBI blocks arachidonic acid release, prostaglandin biosynthesis and the action of thromboxane A2. One hour exposure of aspirin treated platelets with IBI abolished inhibitory effects against epinephrine induced aggregation. In contrast to human platelets, both ABI and IBI produced contractions of rat aorta; however, only the responses to ABI were blocked in a competitive manner by the alpha-antagonists, phentolamine, prazosin, and SKF 104078. Moreover, idazoxan blocked the stimulatory actions of IBI, cirazoline and phenylephrine on rat aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets.

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (alpha 1) and platelets (alpha 2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference alpha 1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher alpha 1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vacular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the alpha 1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no alpha 1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the alpha 2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. Iodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the alpha 2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockers of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

Relaxation of arterial smooth muscle: a new function of a water-soluble degradation product of coenzyme Q (ubiquinone).

Treatment of coenzyme Q with ozone yielded a degradation product having unmodified ring that retained its spectral characteristics and a truncated side-chain that made it water-soluble. This derivative, but not the intact lipid-quinone, showed relaxation of phenylephrine-contracted rat arterial rings. This effect offers an explanation for the known hypotensive action of exogenous coenzyme Q regardless of its side-chain length.

Effect of Maharishi AK-4 on H2O2-induced oxidative stress in isolated rat hearts.

Oxidative damage to crucial biomolecules due to excess generation of reactive oxygen species has been implicated as a major cause of organ damage and hence compounds capable of negating such damage have potential benefits. Using hydrogen peroxide (H2O2) as a model pro-oxidant to induce oxidative stress, we have examined the ability of natural food supplement Maharishi Amrit Kalash (MAK-4) to decrease oxidative damage in potassium-arrested isolated rat hearts. The protocol was that hearts isolated from male Sprague-Dawley rats were retrograde-perfused with Krebs-Henseleit (K-H) solution for 30 min for equilibration. After this period, the hearts were subjected to cardioplegia with high potassium (26-30 mM), followed by reperfusion with K-H solution in the presence or absence of 200 microM H2O2. As expected, H2O2 treatment following cardioplegia induced a high degree of oxidative stress as assessed by release of lactate dehydrogenase (LDH, a marker of plasma membrane damage) and total glutathione (GSH + GSSG). H2O2 also impaired the ability of heart to regain developed tension during the testing period. However, addition of MAK-4 in the perfusate containing H2O2 decreased oxidative stress in terms of release of LDH and glutathione. In parallel with these biochemical studies, in a few experiments the cardiac function was assessed by measuring developed contractile tension. These preliminary studies also showed that in the presence of MAK-4 the H2O2-treated hearts were able to regain better developed tension. Further in vitro studies to examine the possible mechanisms of MAK-4 action reveal that this formulation contains H2O2 binding activity which resulted in the decreased availability of H2O2 itself. Our studies hence reveal that the ayurvedic food supplement MAK-4 may have potential benefits in reducing oxidative stress.

Felodipine potentiates morphine analgesia in control and streptozotocin diabetic female rats.

Tolerance to morphine analgesia was seen in diabetes. Calcium channel blockers potentiate opioid analgesia while calcium agonists antagonize. Therefore, the present study using thermal pain threshold was taken up to find out, whether felodipine, altered morphine analgesia in experimental diabetes. From the end of 6th week of streptozotocin-diabetes, felodipine was administered po for 2 week to half of the control and diabetic female rats. Morphine analgesia was recorded 1 hr after the first (acute effect) and last dose (chronic effect) of felodipine. Significant elevation of pain threshold was seen in the first 6 weeks in diabetic rats compared to controls. No tolerance was seen to morphine (2 mg/kg, sc) analgesia in diabetic rats. In both control and diabetic rats acute administration of felodipine produced significant analgesia while both acute and chronic administration of felodipine produced significant potentiation of morphine analgesia in control diabetic rats. The results suggest that prior felodipine may enhance morphine analgesia, and that this needs to be explored further in various types of pain.

Analgesic activity of new synthetic thiazolidine-4-ones derivatives.

Ten new synthetic thiazolidine-4-ones derivatives (5 chlorothiazolidine-4-ones, 3 methoxythiazolidine-4-ones and 2 hydoxythiazolidine-4-ones) having different substituents at R1, R2 and R3 were evaluated for their analgesic activity using different animal models and their structure activity relationship was also elucidated. Chlorothiazolidine-4-ones and methoxythiazolidine-4-ones exhibited analgesic activity in tail flick test, tail immersion test and acetic acid writhing test. C-III (chloride substituents at R1 and R2) produced higher latencies than any other compounds in tail flick test and C-I (no substituents at R1 and R2) was not effective in acetic acid writhing test. Hydroxythiazolidine-4-ones did not show analgesic activity in any of the animal models used. In conclusion, the character of substituents at R3 of thiazolidine moiety position may have an effect on the analgesic activity of thiazolidine-4-ones and either chloride or methoxy substitution may be necessary to produce analgesic activity. Two chloride substituents in a compound may increase the central analgesic activity of the compound.

Effect of felodipine on cholinergic responses of the colonic smooth muscle of streptozotocin induced diabetic rats.

In streptozotocin induced diabetic rats, irrespective of felodipine treatment (5 mg/kg/day po for 4 weeks), a reduction in contractile response of colonic smooth muscle in vitro was observed. Similarly, in both control and diabetic rats treated with felodipine, contractile response was reduced. However, in felodipine treated diabetic rats there was a significant increase in response to exogenous acetylcholine. It may be of interest to study the effect of felodipine, on gastro-intestinal motility in vivo in diabetic rats, to enable extrapolation of the present results to the effect of felodipine on gastrointestinal complications of diabetes mellitus.

Effect of felodipine on myocardial function and cholinergic responses in short term streptozotocin diabetes in rats.

Cardiovascular complications of diabetes mellitus account for 80% of deaths among diabetics. Autonomic neuropathy increases the susceptibility of the diabetic myocardium to arrhythmias. Decreased contractility of diabetic myocardium is associated with intracellular calcium overload. However, the relationship between calcium levels and myocardial cholinergic responses is not known. This study was undertaken to observe the effect of felodipine 5 mg/kg on myocardial function and cholinergic responses of the spontaneously working isolated heart of rats with short term streptozotocin-diabetes. Felodipine was administered (po) for 4 week to rats with streptozotocin-diabetes of 4 week duration. Felodipine did not alter the blood glucose levels. The increased cardio-somatic ratio in diabetic rats was attenuated by felodipine. Diabetic status was associated with decreased coronary flow and felodipine increased coronary flow in diabetic rat hearts both before and after ACh. It may be concluded that felodipine favourably altered the adverse myocardial pathology in experimental diabetes, and this strengthens its use as an antihypertensive in diabetics.

Effect of inhalation of insecticide spray on learning and memory in rats.

Acute exposure to insecticide (Baygon-spray; 5 ml/animal/5 min) inhalation in rats did not affect the learning process but produced a significant loss of memory (P less than 0.01 less than 0.001) whereas chronic exposure (one exposure per day for three weeks) produced a significant delay in learning (P less than 0.05) and memory (P less than 0.01). Acetylcholinesterase activity in brain after acute and chronic exposure declined significantly (P less than 0.01) during the learning process but returned to normal after 24 hr.

Effect of felodipine on serum lipid profile in short term streptozotocin-diabetes in rats.

Lipid lowering effect of calcium antagonists is well documented in high fat fed rats and in hypertensive patients. In order to study their effect on lipid profile in experimental diabetes, felodipine 5 mg/kg/day per oral for 4 week was given to rats with streptozotocin-diabetes of 8 week duration. Serum total cholesterol and triglycerides were estimated in non-fasting rats at the end of the study period using Ranbaxy diagnostic kits. Diabetic rats had a significant elevation of both total cholesterol and triglycerides. In diabetic rats felodipine treatment produced a significant reduction of the serum triglycerides while there was no change in the serum total cholesterol. In control rats the drug did not produce any significant alteration in the levels of both total cholesterol and triglycerides.

Effects of ECT-dothiepin combination on learning in rats.

Electroconvulsive therapy (ECT) and antidepressant drugs are each known to impair learning and memory. No information is available on their effects on cognition when used concurrently in the treatment of depression, as is frequent in India. In the present study, therefore, the effects of electro-convulsive shocks (ECS) and dothiepin, separately and in combination, were studied in an animal model employing a complex maze operant learning paradigm. ECS were given on alternate days (3/week) for 2 weeks. Dothiepin (10 mg/kg, ip) was administered once daily for 2 weeks. Learning was assessed on days 2-10 post-treatment ECS produced greater initial impairment in learning while dothiepin produced a more sustained impairment. While impairment was maximum in the combined treatment group, the statistical significances that emerged to proscribed the combination were but weak.

Species variation in the specificity of cholinesterases in human and rat blood samples.

Acetylthiocholine iodide (ATC) as a common substrate in the combined assay of red blood cell cholinesterase (RBC ChE) and butyrylcholinesterase (BuChE) do not provide the accurate individual enzyme activities. Hence, in the present study the two enzyme activities in the same sample were assayed with the help of two different substrate, ATC and butyrylthiocholine iodide (BTC). Specificity of BTC towards BuCHE was found in blood, plasma and serum, while ATC is nonspecifically hydrolysed by both RBC ChE and BuChE. ATC gives significantly higher enzyme activity (P < 0.001) in rat plasma/serum and significantly lower enzyme activity (P < 0.0001; P < 0.001) in human plasma/serum. The possible reasons are discussed for substrate specity in various species in the assay of ChEs.

A perspective of smooth muscle contractility through actions of vanadium compounds.

Smooth muscle contraction has a characteristic step-response with successive additions of stimulating compounds, and instant reversal on withdrawing the stimulus, indicative of an equilibrium situation wherein continuous, rapid reactions are occurring. Vanadium compounds, ortho- and meta-vanadates, decavanadate and peroxovanadate, were found to contract a variety of smooth muscles. Their actions were analyzed with respect to activation of receptors, increase in the intracellular calcium concentration, and increase in calmodulin-dependent myosin light chain phosphorylation leading to contraction. A new perspective of smooth muscle contractility has emerged from the studies with vanadium compounds suggesting control mechanisms involving phosphorylation for contraction and redox for relaxation.

Variations in brain and heart acetylcholine content in rat: cervical dislocation vs guillotine technique.

The stress induced in animals due to handling prior to sacrifice has been shown to produce changes in total acetylcholine (Ach) content of the brain and heart of adult rats. Two methods of killing the animals were compared viz. cervical dislocation and decapitation by a guillotine technique; the former method producing more handling stress than the latter. Ach levels were significantly lower both in brain and heart when the animals were killed by cervical dislocation.

Acetylcholinesterase activity of rat brain and heart in starvation and protein restriction.

AChE activity was determined in the brain and heart of normal, acute totally starved, chronically semi-starved and chronically protein restricted groups of adult male rats. Neither acute total starvation nor chronic semi-starvation produced significant changes in AChE activity and protein content of the brain, while AChE activity and protein content in the heart were significantly decreased (P less than 0.01) after semi-starvation. Protein restriction, however, produced a significant decrease in AChE activity and protein content of both brain (P less than 0.01) and heart (P less than 0.001).

Acetylcholine levels of rat brain and heart in starvation and protein restriction.

Acetylcholine (ACh) levels and protein content in brain and heart were determined in normal, acutely starved, chronically semi-starved and chronically protein restricted groups of adult male rats. The only change observed in acute starvation and chronic semi-starvation was an increase in ACh level with a decrease in protein content in the heart, no change was observed in the brain. Protein restriction, however, produced a significant rise in ACh levels with a decrease in protein content of both brain and heart.