Jun Yamazaki

Stimulatory and inhibitory effects of serotonergic hallucinogens on spinal mono- and polysynaptic reflex pathways in the rat.

The effects of two 5-HT-related hallucinogens on rat spinal mono- and polysynaptic reflex pathways in the rat were investigated. 5-Methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 and 100 micrograms/kg, i.v.), an indolealkylamine agent, produced a dose-dependent decrease in the monosynaptic reflex, whereas 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1-100 micrograms/kg), a phenylalkylamine agent, produced a dose-dependent increase in the monosynaptic reflex. Both agents increased the polysynaptic reflex. The 5-HT2 receptor antagonists ketanserin (100 micrograms/kg) and ritanserin (100 micrograms/kg) blocked the effects of DOI on the monosynaptic reflex but only partially blocked the 5-MeODMT-induced effect on the monosynaptic reflex. These antagonists inhibited the change in polysynaptic reflex, induced by DOI but not by 5-MeODMT. Neither propranolol (1 mg/kg) nor 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, 1 mg/kg) antagonized the effect of either agent. 5-Methoxy-N,N-dimethyltryptamine and DOI increased the excitability of motoneurons and this effect was inhibited by ketanserin. These results indicate that the two types of hallucinogens possess both common and distinct characteristics, with regard to their action on the spinal reflex: (1) both increase the activity of motoneurons through 5-HT2 receptors but (2) only 5-MeODMT has an inhibitory action on the pathway of the monosynaptic reflex.

5-Hydroxydecanoate selectively reduces the initial increase in extracellular K+ in ischemic guinea-pig heart

The aim of the present study was to determine the effect of 5-hydroxydecanoate (5-HD) on extracellular K+ levels during global ischemia for 30 min employing K+-sensitive electrodes in isolated guinea-pig hearts. 5-HD (100 microM) reduced the K+ accumulation during the early period of ischemia, but did not inhibit the elevation of extracellular K+ in the latter half of the ischemic period which was selectively enhanced by ouabain (3 microM). Thus, 5-HD appears to exert a similar mode of action as glibenclamide on extracellular K+ accumulation in the ischemic guinea-pig hearts. The present study also strengthens the previous conclusion that an ATP-sensitive K+ channel contributes only to the initial increasing phase of extracellular K+ accumulation during ischemia in guinea-pig hearts.

Macrolide compounds, ivermectin and milbemycin D, stimulate chloride channels sensitive to GABAergic drugs in cultured chick spinal neurons.

1. The effects of ivermectin (IVM) and milbemycin D (MMD) on cultured embryonic spinal neurons were investigated, using the whole-cell recording technique. 2. IVM and MMD caused Cl- current under voltage-clamp conditions. 3. The reversal potential of the MMD-evoked Cl- current was shifted in a positive direction when half of the external Cl- was substituted by isethionate. 4. The MMD-evoked current was inhibited by picrotoxinin and bicuculline, whereas it was enhanced by diazepam. 5. Different characteristics of desensitization were observed between the MMD- (IVM-) and muscimol-induced effects. 6. These results suggest that IVM and MMD directly activate the Cl- channel through their specific sites modulated by GABAergic drugs.

The actions of ivermectin on cultured chick spinal cord neurons

The effects of ivermectin (IVM) on cultured chick spinal neurons sensitive to GABA agonists were investigated. IVM caused a change of membrane potential which was associated with an increase in membrane conductance, apparently reversed at about -40 mV and weakened by repetitive application. Furthermore, this agent did not have any effects on either the actions of GABA agonists on neurons or [3H]GABA efflux from those cells. These results suggest that IVM increases membrane conductance through sites which are different from GABA recognition sites.

Cu nuclear spin-spin coupling in the dimer singlet state in SrCu2(BO3)2

We report results of nuclear magnetic resonance experiments in SrCu2(BO3)2, a quasi-two-dimensional spin system with a singlet ground state. When magnetic field is applied along the c-axis, each of the quadrupole-split Cu resonance lines splits further into four lines. The spin-echo intensity for some of the split lines oscillates against the separation time between π/2 and π rf pulses. These phenomena are due to strong nuclear spin-spin coupling mediated by the electronic spin system, which exists only within a pair of nuclei. Thus the results provide direct evidence for the dimer singlet ground state in this material.

Direct activation of endothelial NO pathway by Ba2+ in canine coronary artery

1 We have reported that Ba2+ causes endothelium‐dependent relaxation of canine coronary arteries through NO synthesis in Ca2+‐free and depolarizing solution. To determine the cellular mechanisms by which the endothelium‐dependent relaxation occurs, we used fura‐2 fluorometry (F350 and F390; excitation wavelengths, 350 and 390 nm, respectively) and estimated the intracellular Ba2+ concentration in endothelial and vascular smooth muscle cells. 2 Ba2+ (10−3 m) increased the fura‐2 ratio (F350/F390) recorded from a combined preparation of smooth muscle and endothelium (0.445±0.073, n = 4) and contracted the arteries in the presence of 80 mm K+ (0.22±0.06 g, n = 4). 3 Diltiazem (3×10−6 m) blocks Ba2+ entry into vascular smooth muscle cells via l‐type Ca2+ channels. In this condition, Ba2+ increased the fura‐2 ratio in endothelial cells (0.141±0.014, n = 5) and relaxed the underlying smooth muscle (0.08±0.01 g, n = 5) by a mechanism which was sensitive to 10−4 m NG‐methyl‐l‐arginine (l‐NMMA). 4 Ba2+‐induced relaxation was not attenuated with repeated application and was elicited even after endothelium‐dependent relaxations in response to 10−6 m bradykinin were abolished due to tachyphylaxis. Neither 10−2 m caffeine nor 10−6 m thapsigargin had effect upon Ba2+‐induced relaxation. 5 To further rule out changes in intracellular Ca2+ as a mechanism of Ba2+‐induced relaxation, fura‐2 fluorescence was measured at the isosbestic wavelengths for Ca2+ (360 nm) and Ba2+ (370 nm) in endothelium‐intact arteries. Ba2+ altered F360, but not F370, suggesting little or no contribution of intracellular Ca2+ to the phenomenon of Ba2+‐induced relaxation. 6 These results suggest that the Ba2+‐induced relaxation is due to its direct activation of endothelial NO synthesis without mobilization of intracellular Ca2+.

Flow dependence of nitric oxide-mediated pressure change in rat mesenteric beds with different tonus

To investigate the flow-dependent contribution of basally released nitric oxide (NO) to vascular perfusion pressure, we compared the effects of a NO synthesis inhibitor on the pressure changes in some models of rate mesenteric vascular beds. Spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats (13-14-weeks-old) were used. The perfusion pressure at each flow rate was slightly higher in the SHR bed than in the WKY bed when no contractile compounds were applied. NG-Monomethyl-L-arginine (L-NMMA) significantly increased the pressure in WKY at flow rates more than 5 ml/min (8.9 mm Hg at 7 ml/min). L-NMMA increased the pressure in SHR at flow rates of 2-7 ml/min (40.2 mm Hg at 7 ml/min). L-NMMA markedly increased the pressure at each flow rate in both beds which methoxamine (30 microM) had constricted. The effects of L-NMMA were concentration-dependent, and were blocked by L-arginine. Therefore, basal NO release appears to contribute to the vasolidating tone although flow dependence of the effect is different in the absence or presence of an exogeneous tone in both hypertensive and normotensive rats.

Contractions and relaxations accompanied by endothelial nitric oxide production induced in the porcine coronary artery by Ca2+, Ba2+ and Sr2+

In order to investigate the effects of Ca2+, Ba2+ and Sr2+ on vascular endothelial nitric oxide (NO) production, contractile and relaxant responses of porcine depolarized coronary arteries to these divalent cations were compared. In the presence of diltiazem, Ba2+ induced NO-dependent relaxation, Sr2+ did slightly and Ca2+ did not; however all three cations increased cGMP levels in endothelium-intact arteries to similar extents. In the absence of diltiazem, these cations evoked contractions: the EC50 of Ca2+ for endothelium-denuded arteries was lower than those of Ba2+ and Sr2+. The IC50 of diltiazem for arteries precontracted with Ca2+ was higher than for arteries precontracted with Ba2+ and Sr2+. These results suggest that Ba2+ and Sr2+, as well as Ca2+, activate coronary arterial NO production, and also that the different responses of coronary arteries to these divalent cations can be explained, in part, by the different sensitivities of the smooth muscle to these cations and by the different potencies of diltiazem to inhibit the contractions the cations induced.

Magnetism, structure, and superconductivity of Cd2Re2O7 pyrochlore: Cd and Re NMR

Abstract We present Cd and Re NMR results on Cd2Re2O7, the first and as yet the only superconductor (T c ≃1 K ) among pyrochlore oxides. Re spin-lattice relaxation rate below Tc exhibits a pronounced coherence peak and follows the weak-coupling BCS with nearly isotropic energy gap. Cd NMR points to moderate ferromagnetic enhancement at high temperatures followed by rapid decrease of the density of states below 200 K , and to strong suppression of spin fluctuations below ∼75 K . Cd and Re NMR spectra reveal two structural phase transitions, one at 200 K and another at 120 K . Re NQR rules out any magnetic or charge order.

Actions of avermectins on cultured neurons

The avermectins (AVM) are macrocyclic lactone derivatives produced by Streptomyces avermitilis, which have potent anthelmintic as well as insecticidal activities (Egerton et al., 1979; Ostlind et aL, 1979; Putter et al., 1981). These compounds consist of four major components (A~a, A:a, Bl~, B2a) and four minor components (A~b, AEb, Bmb, BEb) but it is presumed that all avermectins share a common mechanism of action (Campbell et al., 1983). Ivermectin is a synthetic derivative of BI (22,23-dihydroavermectin B~), consisting of 80% Bla and 20% Bib. On the other hand, milbemycin D, which is structurally related to ivermectin, is one of milbemycins with insecticidal activity, which are derived from Streptomyces hygroscopicus subsp, aureolacrimosus (Takiguchi et al., 1980) (Fig. 1). AVM BI~, one of the major and most potent components of AVM, has been shown to rapidly paralyze nematodes without causing hypercontraction or flaccid paralysis (Kass et al., 1980). Electrophysiological experiments on nematodes have shown that AVM B~a acts by blocking transmission from interneurons to excitatory motoneurons and that washing with a GABA receptor-coupled chloride channel blocker, picrotoxin, reverses it (Kass et al., 1980). In addition, in the lobster neuromuscular junction, which is known to be regulated by excitatory (glutamatergic) transmission and inhibitory (GABAergic) transmission (Gershenfeld, 1973), AVM Bla inhibits both excitatory and inhibitory transmission and these effects of AVM B~ are restored by picrotoxin (Fritz et al., 1979). Thus, it is likely that the basic mechanism of action of AVM could be its interaction with the GABA receptor complex, and that AVM activates the chloride channels coupled to the GABA receptor (Wang and Pong, 1982; Campbell et al., 1983; Wang, 1986; Wright, 1986). On the other hand, because of the low densities of GABAergic synapses in Ascaris and lobsters, most biochemical studies have been done with vertebrate (mammalian) or invertebrate brains, which are a rich source of GABAergic synapses, to biochemically investigate the action of AVM on the GABA receptor complex. Such in vitro studies have shown that AVM specifically binds to vertebrate and invertebrate brain tissue with high affinity (Drexler and Sieghart, 1984; Huang et al., 1986; Min et al., 1986). In the mammalian brain, it is known that AVM can allosterically