Physiology and Pharmacology
Year:2001 | Volume:4 | Issue:2|Papers Count:24

The effect of cysteamine, a somatostatin depletor, on synaptic plasticity induced by tetanic and paired-pulse stimulation was investigated in rat hippocampal CA1. For this purpose, hippocampal slices from saline (1ml/Kg, s.c.) and cysteamine (200 mg/Kg, s.c.)-treated and intact rats were used. Population spikes were recorded following Schaffer collateral stimulation: To induce LTP, primed burst titanic stimulation was used. Paired-pulse stimulation at IPIs of 10, 20, 60, 120, 240, 360, and 480 ms were used and then EPI and PPI of CA1 were calculated. The results showed that the amplitude of population spike (PSA) increased 5, 15, 30, and 60 min after tetanic stimulation and 60 min after primed bursts, PSA increased at all stimulus intensities for all groups. In cysteamine-treated group, the magnitude of LTP was decreased as compared to intact and saline-treated groups. In the latter group, the magnitude of LTP increased as compared to intact and cysteaminetreated group. At IPI of 10ms, mean value of EPI was greater than 1 for intact group and less than 1 for saline- and cysteamine-treated groups. In cysteamine-treated group, the mean value of EPI was significantly less than intact group. At IPIs from 20 to 480 ms, mean value of EPI was greater than or equal to 1 for all of the groups and no s'ign ificant difference was observed among them. At IPI of 10 ms, mean value of PPI was greater than 1 in intact group and less than 1 in saline- and cysteamine-treated groups. In these groups,mean value of PPI was significantly less than intact group. At IPI of 20 ms, mean value of PPI was greater than 1 in intact and saline-treated group and less than 1 in cysteamine-treated group. In the latter group, the mean value of PPI was significantly less than saline-treated and intact groups. At IPIs of 60-680 ms, mean value of PPI was greater than 1 in all of the groups with no significant difference among them.It is concluded that cysteamine can alter susceptibility of hippocampal CA1 for synaptic plasticity induced by tetanic and paired-pulse paradigms.

In this study, the effect of α-adrenoceptor agents on imipramine-induced antinociception was investigated using formalin test. Intraperitoneal (IP) administration of imipramine at different doses (10-80 mg/kg) induced antinociception in both phases of formalin test. In addition, intracerebroventricular (ICV) injection of imipramine (1, 5, and 10 µg/rat) did not elicit any effect, although ICV injection of clonidine, an aradrenoceptor agonist at doses of 0.05-0.8 µg/rat also elicited antinociception in both phases of the test. Furthermore, clonidine increases the antinociception induced by imipramine and yohimbine, an α2-aradrenoceptor antagonist at a dose of 2 µg/rat (ICV) reduced the response to imipramine at a low dose (10 mg/kg, IP) and clonidine (0.05 µg/rat, ICV), but did not alter the response induced by higher doses of imipramine (20 and 40 mg/kg) alone or in combination with clonidine. Yohimbine by itself elicited no response. Meanwhile, phenylephrine (0.07-1.5 µg/rat, ICV), a α1-adrenoceptor agonist induced antinociception in both phases of formalin test, but did not alter the imipramine-induced antinociception. The α1-adrenoceptor antagonist, prazocin neither elicited antinociception nor altered the imipramine response. Yohimbine (2 µg/rat, ICV) in combination with prazocin (0.5 µg/rat, ICV) further inhibited the response for imipramine alone or in combination with clonidine. Taken together, it is concluded that aradrenoceptor-mediated mechanism might be involved in the development of imipramine-induced antinociception.

Ion channels are responsible for control of cell function in excitable tissues such as heart and brain and also in organs and tissues traditionally thought to be nonexcitable including liver and epithelium. In the present research, the effect of lead (Pb2+) on Ca2+-dependent action potential and currents was studied in F77 neuronal soma membrane of Helix aspersa. For this purpose, action potential generation and Ca2+ currents were investigated in the absence and presence of Pb2+using two-electrode voltage clamp and current clamp methods. Two distinct types of-high voltage activated (HVA) calcium currents were recorded. In this respect, one of them was sensitive to nifedipine (1 µM) and the other one was resistant to nifedipine. Extracellular application of Pb2+ at concentrations of 0.6 and 3µM suppressed the firing behavior of F77 neurons. It also decreased the amplitude and the duration of calcium action potentials. The voltage clamp findings demonstrated that lead blocked more than 50% of HVA Ca2+currents. The blocking effect of Pb2+on Ca2+was time-dependent. Therefore, it can be concluded that Pb2+may alter the bioelectrical properties of F77 neuron through blocking high voltage activated Ca2+currents, particularly L-type that are nifedipine sensitive.

The internal mammary artery (IMA) is currently the preferred conduit for myocardial revascularization. However, pre-operative vasospasm and a hypoperfusion state during maximal exercise may limit its use as a bypass graft. The mechanism of spasm has not been clearly defined. Since ß-adrenoceptor activation plays a major role in vasorelaxation, the present study was carried out to investigate the ß-adrenoceptor responsiveness of human IMA smooth muscle.For this purpose, IMA was obtained from patients with atherosclerosis of coronary artery whom have undergone coronary artery bypass. The endothelium denuded rings of IMA were placed on platinum wires (L-shaped) in a Krebs solution containing tissue bath, and were connected to an isometric transducer. It was found out that Isoproterenol produced a dose-dependent relaxation in endothelium-denuded MA segments, precontracted with phenylephrine (maximal relaxation was 46.33 ±5.45%). Isoproterenol-induced relaxation was inhibited by atenolol (10-6M) and propranolol (2 x 10-7M). While atenolol-induced inhibition was partial, propranolol-induced inhibition was complete in a majority of the segments. BRL 37344, a selective ß3-adrenoceptor agonist, produced a dose-dependent relaxation in phenylephrine precontracted rings of endothelium-denuded IMA (maximal relaxation was 40.35 ±4.07%). Cyanopindolol, a ß-adrenoceptor partial agonist, produced a marked relaxation in endothelium-denuded IMA rings, precontracted with phenylephrine (maximal relaxation was 58.65±6.2%). Cyanopindolol-induced relaxation was resistant to blockade by propranolol (2 x 10-7 M). In addition, spontaneous contractions of IMA rings were observed in some of the cases that were inhibited by isoproterenol and BRL 37344. This observation may indicate the important role of ß3-adrenoceptor activation in prevention of human IMA spasm.Therefore, it is concluded that human IMA smooth muscle possesses both ß1-and ß2-radrenoceptors. The existence of ß3-adrenoceptorip this tissue is also suggested.

The effect of chronic inflammation induced by complete Freund's adjuvant (CFA) on anterior blood vessels of knee joint and its diameter was studied. Blood flow changes in response to phenylephrine (α1-adrenoceptor agonist) in CFA-treated and contra lateral knee joints were observed over a 40-day period, using laser Doppler flowmetery (LDF) technique. Unilateral injection of CFA (0.2 ml) increased the diameter of injected knee at all days post-injection (P<0.001) and reached to its maximum level (49.7 ± 2%) at day 3; Then, the diameter decreased gradually but did not return to its initial value. In control animals, topical application of phenylephrine (10-13-10-17 M) to the exposed joint capsule decreased blood flow in a dose-dependent manner (11.1± 4.4 to 58.2±4.5%, P<0.001). Unilateral injection of CFA attenuated the phenylephrine response in both ipsilateral and contralateral knees compared to the response of control animals (5.2 ± 1.6 to 48.3 ± 6.1% and 1.9±2.2 to 45.3 ±5.6% respectively, P<0.05). The reduction persisted for three weeks after CFA injection (ipsilateral for 21 days; contralateral for 30 days, P<0.001).Then, the above response returned to its normal value. To evaluate the role of nitric oxide (NO) on the observed responses, aminoguanidine (inducible-NO synthase inhibitor) was injected (120 mg/kg/day, I.P.) in other groups of CFA-treated animals. Aminoguanidine potentiated (P<0.001) the vasoconstrictor response to phenylephrine in both CFA injected and contralateral knees at 7, 14, and 21 days post-injection, and the increment of knee joint diameter was also less prominent.These findings may indicate that the vasoconstrictor response to phenylephrine is decreased in chronic inflammation, and increased production of NO during chronic inflammation might be involved.

There is strong evidence that two cerebral hemispheres are differentially involved in emotional memory and that amygdala is a key subcortical structure for emotional experience. The present research investigated the possible involvement of lateralization of basolateral amygdala (BLA) and central amygdala (CEA) in place avoidance memory.For this purpose, male Long-Evans rats (280-320 g) were implanted bilaterally with cannulae aimed at the BLA and CEA. One week later, the rats were trained in place avoidance apparatus as a spatial learning model. During the training session (30 min), the animal learned to avoid and recognize the places with a possibility of shock. One day later, bilateral or unilateral injection of TTX (5 ng/ml/side) were perfumed to inactivate temporarily the BLA and CEA during retrieval of the place avoidance task. Control rats were injected with the same volume of saline. Place avoidance training occurred in a single 30 min session and one day later, the avoidance memory was assessed during a 30-min extinction trial. The time to the first entrance and the number of entrances into the punished sector during extinction were used to measure the avoidance memory. The results indicated that bilateral or only right BLA inactivation significantly impaired retrieval of memory, although inactivation of the CEA and left BLA had no significant effect.Taken together, these results suggested that the right and left BLA make differential contribution to the expression of spatial memory and that the contribution of the right BLA may be more important.

Calcium channel blockers are an important group of drugs that have been used in the treatment of cardiovascular disorders, especially hypertensive states. In this study we have investigated the effects of three newly synthesized ester analogs of nifedipine on mean arterial blood pressure (MAP), cardiac contractility index (dp/dt) and heart rate (HR) in normal rabbits and in rabbits with hypertension.Animals (n=24) were divided into three groups (n=8) and anesthetized with diazepam (1.7 mg/kg) and sodium pentobarbital (30 mg/kg). The right femoral vein and artery were cannulated for further injections (phenylephrine and sodium pentobarbital) and recording of arterial blood pressure respectively. Right jugular vein was cannulated for injection of test compounds. Another cannula was inserted in right carotid artery and pushed to left ventricle to record intraventricular pressure. Ventricular dp/dt was calculated as an index of cardiac contractility. Test compounds and nifedipine were tested in two groups. In the first group, 1 ml of nifedipine (10-4M) was injected through the jugular vein for one minute. Five minutes later, 1 ml of test compounds was injected. Then, the effects of I ml of nifedipine at a g.oncentrationof 10-3M and test compounds were investigated. In the second group, arterial blood pressure was increased by 20 mmHg/min through infusion of phenylephrine (2 x 10-5 M at a rate of 1.5-2 ml/min) and then experiments of first group were repeated in hypertensive condition.Our results showed that in normotensive conditions, nifedipine (10-3 M) reduced MAP and dp/dt and increased HR by 10, 12.5 and 3% respectively and in hypertensive conditions, nifedipine reduced MAP and dp/dt and increased HR by 16.1, 19.5% and 3.4% respectively. In addition, compound No. 1 reduced the same indices by 4, 8.4, and 1.4% respectively, in normotensive state and by 10, 14.1, and 3% in hypertensive state, compound No. 2 reduced these indices by 14.1, 5.5, and 8.5% in normotensive state and by 16.5, 4.9, and 4.2% in hypertensive state, and compound No. 3 decreased variables by 10.8, 12.7, and 8.6% in normotensive state and by 20.8, 7.9, and 4.9% in hypertensive state respectively. In hypertensive conditions compounds No. 2 and No. 3 reduced heart rate in contrast to nifedipine (P<0.05). The effect of these three compounds (10-4 M) was non-significantly lower than nifedipine at the same concentration.Since compounds No. 2 and No.3 reduced blood pressure and cardiac contractility similar to nifedipine and meanwhile reduced heart rate non-significantly more than nifidipine, therefore they are probably preferred in the treatment of hypertensive patients with coronary artery disease.

It has been reported that neurons in the VL PAG projecting to nucleus raphe magnus (NRM) utilize excitatory amino acids as neurotransmitter. This projection plays an important role in the descending pain modulatory system. In order to determine the role of this pathway in pain perception, male rats received unilateral injection of ibotenic acid stereotaxically. For lesioning VL PAG, unilateral injection of ibotenic acid (0.2 and 0.5µl) (a specific neurotoxin for EAA-containing neurons) was made. After an I-week recovery period, the nociception was evaluated using formalin test for a period of 60 min. At the end of experiments, animals were perfused by formaldehyde 10%.Serial sections (80 µm) were prepared using vibrato me. The sections were then Nissl stained and examined to determine the lesion location. The results revealed a significant increase in the first phase of formalin test. However, in the second phase, only 0.5 µl of the neurotoxin caused a significant decrease in pain perception.It is concluded that NMDA receptors within the PAG are involved in the perception of pain as measured in the formalin test.

Fluoxetine is an inhibitor of serotonin re-uptake with antidepressant properties. Since serotonin reuptake inhibitors have significant effects on processes undedying learning and memory, this study was conducted to investigate the effect of fluoxetine on spatial learning using Morris water maze (MWM). For this purpose, cannulae were inserted bilaterally into the CA1 region and each day 25 minutes before training, fluoxetine at doses of 0, 6, 12, 18 and 24 µg in 0.5 µl of distilled water was injected bilaterally through the cannulae. In spatial learning in MWM (continued for 3 days), the rats must locate an invisible platform with a constant position during this period. On the fourth day, the platform was in a new position and visible to assess visuomotor coordination.The Results showed that fluoxetine caused an increase in latencies to find the invisible platform, traveled distance and heading angles compared to control group in a dose-dependent manner, but had no effect on visuomotor coordination.These finding suggested that spatial discrimination in MWM may be impaired by fluoxetine in a dose-dependent pattern.

Omeprazole, a selective H+/K+ ATPase (a molecule located within gastric parietal cells) inhibitor, is widely used in ulcerative diseases of gastrointestinal tract. Omeprazole is extensively metabolized by the liver and its two major plasma metabolites are omeprazole sulphone and hydroxy-omeprazole. Cytochrome P450 enzymes are involved in metabolism of omeprazole and ethnical variations in its metabolism have been reported. In this study, through investigating the metabolism of omeprazole in a group of healthy Iranian volunteers, a metabolite was found that has not been reported already in plasma. The present study was undertaken to further characterize this metabolite. After administration of omeprazole (40 mg), plasma concentration of omeprazole and its metabolites were determined by HPLC using solid-phase extraction procedure. The fractions of eluent related to the unknown metabolite were collected, 'pooled, lyophilized and mass spectrum of it was obtained. On the basis of the mass spectroscopy data, two suggestions were made. The suggested compounds were synthesized and injected to the HPLC system.According to the mass spectroscopy data and retention times in HPLC, it seems that the unknown metabolite might be hydroxy-omeprazole sulphone that has been already reported as a secondary metabolite of omeprazole.

In the present study, the effect of GABA (γ-aminobutyric acid) receptor agonists III and antagonists on morphine-induced antinociception was investigated in formalin test in rats. Intraperitoneal (i.p.) injection of different doses of morphine (1, 3, 6 and 9 mg/kg) and intracerebroventricular (i.c.v.) injection of different doses of muscimol (0.5, 1 and 2 µg/rat) or baclofen (0.25, 0.5 and 1 µg/rat) induced a dose-dependent antinociception in both phases of formalin test. The responses induced by muscimol or baclofen in both phases reduced by bicuculline or CGP35348 respectively. Morphine in combination with different doses of muscimol or baclofen tends to elicit higher response. The opioid receptor antagonist reduced the response induced by both GABA receptor agonists.It can be concluded that stimulation of GABAA and GABAB receptors are responsible for antinociception in formalin test. However, at least part of the antinociception is due to the opioid receptor mechanism.

Adenosine 3', 5'-cyclic monophosphate (cAMP)-mediated pulmonary vascular smooth muscle relaxation is a principal mechanism of pulmonary vasomotor control. The purpose of this study was to compare the potency and efficacy of the following receptor-linked pathway for pulmonary vasorelaxation which are mediated by cAMP. The experiments were performed on the rat pulmonary artery rings using vasorelaxants including isoproterenol (ISO, ß2-adrenoceptoragonist), adenosine (AD, P1-purinoceptor agonist), adenosine 5' -diphosphate (ADP, P2-purinoceptor agonist), adenosine 5'- triphosphate (ATP, P2-purinoceptor agonist), and histamine (HIST, H2-histamine receptor agonist). All of these drugs induced dose-dependent relaxation in the rat artery rings precontracted with phenylephrine (100 nM) (PE, EC75). Dose-response curves for rat pulmonary artery rings were recorded isometrically with Grass FT03 transducers and displayed on a Grass model 7 polygraph. The results showed that ISO (100 pM to 10 µM), AD (30 µM to 100 µM), ADP and ATP (10 nM to 10 µM) and HIST (1 µM to 100 µM) induced dose-dependent relaxation in rat pulmonary artery rings. The maximum responses were for ISO, ADP and A1P (10 µM), AD (10 µM) and HIST (1 mM). In the preparations The maximum relaxant responses were for ISO (93.04±1.25%), ADP (78.39±2.68%), ATP (80.48±1.93%), AD (72.22±3%), and HIST (69.52±4.02%) respectively. The median effective concentrations (EC50) were 0.01 µM Physiology and Pharmacology Volume 4, Number 2 Fall & Winter 2000-2001 for ISO, 0.5 µM for ADP, 0.6 µM for ATP, 70 µM for AD, and 100 µM for HIST. These data revealed that although receptor-linked pathways and their activation of adenylate cycles and ensuing increased level of cAMP are responsible for relaxation in the artery rings, but there existed significant differences regarding potency and efficacy.