Since the idea that memory is associated with alterations in synaptic strength was accepted, studies on the cellular and molecular mechanisms responsible for the plastic changes in neurons have attracted wide interest in the scientific community. Recent studies on memory processes have also pointed out some unifying themes emerging from a wide range of nervous systems, suggesting that regardless of the species or brain regions, a common denominator for memory may exist. Thus, the present review attempted to create a hypothetical and universal synaptic model valid for a variety of nervous systems, ranging from molluscs to mammals. The cellular and molecular events leading to short- and long-term modifications of memory have been described in a sequential order, from the triggering signals to the gene expression, synthesis of new proteins and neuronal growth. These events are thought to represent the late phases of memory consolidation leading to persistent modifications in synaptic plasticity, thereby facilitating the permanent storage of acquired information throughout the individual''s life.
We determined the effects of KW-3902 (8-(noradamantan-3-yl)-1, 3-dipropylxanthine), a novel adenosine A1-receptor antagonist, on the development of hypertension in Dahl salt-sensitive (Dahl-S) rats. KW-3902 (0.00017% w/w-0.017% w/w), fed with the diet, prevented the development of hypertension at 2-6 weeks in response to the high (8% w/w) NaCl diet. KW-3902 increased urine volume and sodium excretion and attenuated cardiac hypertrophy. In another series of the experiments employing the clearance method, KW-3902 (0.1 mg/kg, i.v.) increased urine volume, sodium excretion and lithium clearance in anesthetized Dahl-S rats. These results suggest that the antihypertensive effect of KW-3902 in Dahl-S rats is mediated via its natriuretic effect, the site of action being, at least partly, the proximal tubule. The adenosine A1-receptor antagonist may be effective for the treatment of salt-sensitive hypertension.
Since reported experimental models of thrombosis are not suitable for comparison of several drugs by oral administration, we developed a convenient model for this purpose by applying direct current through an intravascular electrode. In conscious rats, which were implanted with anodal electrodes in the abdominal aorta on the day before the experiment, application of 200 μA of direct current induced the formation of a platelet-rich thrombus around the intravascular electrode. Using this model, we studied the antithrombotic effect of the novel antiplatelet agent TA-993, (−)-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-8-methyl-2-(4-methylphenyl)-1, 5-benzothiazepin-4(5H)-one maleate, and compared its effect with other antiplatelet agents. TA-993 at doses of 30 mg/kg, p.o. or more by single administration or at doses of 10 mg/kg or more by repeated administration dose-dependently suppressed the thrombus formation. Aspirin (10 mg/kg, p.o. or more), cilostazol (100 mg/kg, p.o.) and ticlopidine (30 mg/kg, p.o. or more) also suppressed the thrombus formation by single administration. These results suggest that TA-993 has a comparable antithrombotic effect with other antiplatelet agents, and thus it is a possible remedy for thrombotic and embolic diseases.
The purpose of this investigation was to determine if neurally induced vasodilatation is mediated by nitric oxide (NO) in monkey mesenteric veins. Helical strips of the monkey mesenteric vein were exposed to the bathing media for isometric tension recording, and perivascular nerves were stimulated by nicotine. Nicotine produced a contraction, which was potentiated by treatment with NG-nitro-L-arginine, a NO synthase inhibitor, the effect being reversed by L-arginine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was abolished by the NO synthase inhibitor, and it was restored by L-arginine. D-Enantiomers were without effect. The response was not influenced by timolol and indomethacin, but was abolished by hexamethonium and oxyhemoglobin. There were perivascular nerve fibers containing NO synthase immunoreactivity in the monkey vein. Neurally induced venous relaxations appear to be mediated by NO from perivascular nerves, as seen in dog and monkey mesenteric arteries. It is concluded that monkey mesenteric veins are innervated by nitroxidergic and adrenergic nerves, which may balance the vascular tone.
We investigated the comparative effects of ketamine, flunitrazepam, diazepam and midazolam on function and metabolism in reperfused rat hearts. Seventy-two hearts were rapidly excised and perfused with buffer as a Neely''s working model. Whole heart ischemia was induced for 15 min followed by reperfusion for 20 min. Four intravenous anesthetics in 2 different concentrations (10 and 50 times of therapeutic concentrations) were administered during reperfusion. The data were compared to a control group in which intravenous anesthetics were not used. At the end of reperfusion, myocardial metabolites were measured by liquid chromatography. Cardiac outputs in the both groups given lower and higher doses of ketamine and flunitrazepam and in the groups given the higher dose of diazepam and midazolam were significantly lower than that in the control group [at the end of reperfusion: control: 60.4; ketamine: 48.8 (lower) and 14.6 (higher); flunitrazepam: 50.2 (lower) and 50.6 (higher); diazepam: 62.6 (lower) and 42.5 (higher); midazolam: 59.5 (lower) and 51.2 (higher), ml/min]. The levels of ATP in all higher concentration anesthetic groups were significantly lower than those in the control group (control: 23.7, ketamine: 17.8, flunitrazepam: 17.8, diazepam: 17.7, midazolam: 17.7, μmol/g). These results suggest that ketamine and flunitrazepam moderately depress cardiac function more than diazepam and midazolam when they are given during reperfusion.
Effects of GABAergic drugs on the recovery of reflex potentials after spinal cord ischemia were examined in anesthethized spinal cats. Monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials, elicited by electrical stimulation of the tibial nerve in spinal cats, were recorded from the lumbosacral ventral root. The spinal reflex potentials were immediately depressed by occlusion of the thoracic aorta and the bilateral mammary arteries for 10 min. The potentials recovered gradually to the control level within 90 min after reperfusion. Pretreatment with bicuculline (0.3 mg/kg, i.v.), a GABA antagonist, or semicarbazide (200 mg/kg, i.v.), an inhibitor of GABA synthesis, accelerated the recovery of PSR potentials after the removal of the arterial occlusion. In contrast, pretreatment with aminooxyacetic acid (10 mg/kg, i.v.), an inhibitor of GABA degradation, retarded the recovery of PSR potentials, and this effect was overcome by the addition of the opioid antagonist naloxone (10 mg/kg, i.v.). These results suggest that the GABAergic system retards the recovery of PSR potentials after a brief spinal cord ischemia, which can be antagonized by naloxone.
Male SD rats, 7-weeks-old, were used to investigate the changes in the hepatic drug metabolizing system of chronic renal failure (CRF) model rats. Partial nephrectomy (5/6) was performed in a twostage surgical procedure. After nephrectomy, the rats were housed under regular conditions at least 21 days. After confirming the CRF states, trimethadione (TMO, 100 mg/kg, i.p.) was administered for evaluation of the hepatic drug metabolizing capacity; the ratio of dimethadione (DMO: the only metabolite of TMO) to TMO (DMO/TMO) in the serum and the dialysate from the blood microdialysis method were ascertained. The hepatic drug metabolizing enzyme contents and activities were also determined. In the CRF rats, the DMO/TMO ratios decreased significantly; total cytochrome P450 (CYP) contents, aminopyrine N-demethylase activity and δ-aminolevulinic acid synthetase activity also decreased significantly in the CRF rats. The extent of the alterations of these enzyme contents and activities correlated well with the severity of the CRF states evaluated by the serum blood urea nitrogen and creatinine concentrations. With Western blot analysis, the levels of CYP2C6, CYP2C11 and CYP3A2 decreased considerably in the CRF rats. These results suggest that CRF states induce not only a reduction of renal function but also an alternation of hepatic metabolism.
Effects of cholecystokinin octapeptide (CCK-8) on long-term potentiation (LTP) of CA1 synaptic transmission induced by tetanic stimulation of the input fibers were examined in guinea pig hippocampal slices. CCK-8 and a selective agonist for the CCKB receptor, non-sulfated CCK-8, dose-dependently augmented the magnitude of LTP. Concomitant application of a selective antagonist for the CCKB receptor subtype, L-365, 260 (3R(+)-N-(2, 3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-N''-(3-methylphenyl)urea), completely blocked the augmentation of LTP induced by CCK-8, whereas a selective CCKA-receptor antagonist, L-364, 718 (3S(−)-N-(2, 3-dihydro-1-methyl-2-oxo-5-phenyl-IH-1, 4-benzodiazepine)), had little effect. Thus, enhancement of LTP by CCK appears to be mediated by CCKB receptors. Furthermore, CCK-8 enhanced paired-pulse facilitation at a concentration of 10-7 M without affecting the amplitude of the population spike induced by single stimulation. This effect was mimicked by a low dose of tetraethylammonium (TEA), a K+ channel blocker. Moreover, both CCK-8 and TEA reduced the late component of evoked field potentials. This late evoked potential was diminished by increasing the extracellular K+ concentration. It is suggested that CCK-8 reduces the K+ conductance in CA1 pyramidal neurons. This reduction in the K+ conductance might be related to enhancement of the LTP.
We studied the effects of antiallergic drugs, epinastine, ketotifen, oxatomide, mequitazine and cromolyn sodium on superoxide anion (O2-) generation from rat neutrophils. Epinastine, ketotifen, oxatomide and mequitazine dose-dependently prevented the N-formyl-Met-Leu-Phe- and phorbol 12-myristate 13-acetate-induced O2 generation, but cromolyn sodium did not prevent it. When membrane and cytosol fractions were incubated with each drug, epinastine, ketotifen and mequitazine prevented O2- generation. On the other hand, when only the membrane fraction was incubated with each drug, ketotifen and mequitazine prevented O2- generation, but epinastine did not. Epinastine may inhibit the NADPH oxidase system through the obstruction of NADPH oxidase-associated cytosol components.