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This work discusses both the synthesis of trans-[RuCl2(dinic)4], dinic = 3,5-pyridinecarboxylic acid, and its main characteristics including potentiometric titration, spectroscopic and electrochemical properties, and some biological properties. The complex was synthesized using ruthenium blue solution as the precursor in a synthetic route. The complex was characterized using electronic spectroscopy, vibrational FT-IR spectroscopy, and Raman spectroscopy, as well as 1H and 13C NMR. The results indicated that the complex exhibits a trans-geometry. Cyclic voltammetry carried out in water:acetone 1:1 solution revealed a quasi-reversible process centered on the Ru(II) atom, as well as a dependence of the redox potential, E1/2, on pH. An analysis of the electronic spectra revealed that the MLCT (metal ligand charge transfer) band underwent a hypsochromic shift as the pH increased. Spectroelectrochemical analysis indicated that the visible region band progressively faded out upon oxidation. The equilibrium constants for the eight protons of the complex were determined by potentiometric titration. The complex neither inhibits the activity of nitrogen monoxide synthase nor acts as a scavenger for nitrogen monoxide. Nevertheless, the complex shows antinociceptive properties and acts as a scavenger for hydroxyl radicals.

The relaxant response and the possible contribution of K+ channels to the relaxation caused by both methyl and ethyl gallates, two compounds isolated from the Brazilian medicinal plant Phyllanthus urinaria, were investigated in the guinea pig trachea in vitro. Both methyl and ethyl gallate (0.01-30 microM) caused graded and complete relaxation of the guinea pig trachea without epithelium, pre-contracted by histamine, with mean EC50 values of 1.8 (1.2-2.2) microM and 0.7 (0.6-0.8) microM, respectively, and Emax of both 100+/-0%. Response to ethyl, but not methyl gallate, was significantly shifted to the right, with no change in the maximum effect when the epithelium was removed. The increase in K+ concentration in the medium to 80 mM completely abolished the relaxant response caused by both methyl and ethyl gallate. In addition, tetraethylammonium (10 mM) reduced by 50+/-6% and 43+/-4% the relaxation caused by methyl and ethyl gallates. In contrast, glibenclamide (3 microM) shifted (by about two- and fourfold) the concentration-response curves for both methyl and ethyl gallates, with no changes in the maximum effect. Charybdotoxin (100 nM), but not apamin (100 nM), significantly blocked by 54+/-5% and 59+/-4% the relaxation of both methyl and ethyl gallates. In contrast, SQ 22536 (10 microM; a selective adenylyl cyclase inhibitor), methylene blue (10 microM) or ODQ (1 microM; a guanylyl cyclase inhibitor) did not significantly affect the relaxant response caused by either of the compounds. These results provide evidence that the relaxation caused by both methyl and ethyl gallates in the guinea pig trachea in vitro may involve the activation of large-conductance Ca2+-activated K+ channels, and, to a lesser extent, ATP-sensitive K+ channels. Such results extend our previous observations and are consistent with the notion that methyl and ethyl gallates are mainly responsible for the relaxant action previously demonstrated in the extract of this plant.

This study evaluates the actions of the new ruthenium complexes trans-[RuCl2(nic)4] (Complex I) and trans-[RuCl2(i-nic)4] (Complex II) as antinociceptives, and their interaction with nitric oxide isoenzymes and with acetylcholine-induced relaxation of rat and rabbit aorta. Complex II inhibited, in a graded manner, neuronal and inducible nitric oxide (NO) synthase, and was about two fold more effective in inhibiting the neuronal NO synthase than the inducible form of the enzyme. Complex I was inactive. Both complexes failed to interfere with constitutive endothelial nitric oxide synthase because they did not change the mean arterial blood pressure of rats. The vasorelaxant effect of acetylcholine was markedly antagonised by the Complexes I and II in rings of both rat and rabbit aorta. Complexes I and II, given intraperitoneally, like N(omega)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NOARG), inhibited, in a graded manner, both phases of the pain response induced by formalin. The actions of L-NAME, L-NOARG and Complex II, but not that of Complex I, were largely reversed by L-arginine. Both complexes failed to affect the motor response of animals in the rota-rod test and had no effect in the hot-plate assay. Together, these findings provide indications that the new ruthenium complexes, especially Complex II and its derivatives, might be of potential therapeutic benefit in the management of pain disorders.

This study describes the anti-inflammatory actions of NPC 18884, a non-peptide bradykinin B2 receptor antagonist in bradykinin and carrageenan-induced inflammation in the mouse model of pleurisy. The selectivity of NPC 18884 was assessed in the pleurisy caused by histamine, substance P and des-Arg9-bradykinin. NPC 18884 given intraperitoneally or orally inhibited bradykinin-induced leukocytes influx (ID50 value of 63 nmol/kg and 141 nmol/kg, respectively). The NPC 18884 also inhibited the exudation induced by bradykinin (P < 0.05). NPC 18884 given either intraperitoneally or orally caused dose-dependent inhibition of the exudation and total and differential cell content caused by intrapleural injection of carrageenan (1%, assessed 4 h after), with mean ID50, values of 132 and 295 nmol/kg, respectively. The NPC 18884 actions installs rapidly (0.5 h), lasted for up to 4 h and were selective for the bradykinin B2 receptors; at similar doses it had no significant effect against the inflammatory responses induced by des-Arg9-bradykinin, histamine or substance P. These results indicate that the novel non-peptide bradykinin B2 receptor antagonist, NPC 18884, exhibited selective intraperitoneal and oral anti-inflammatory properties when assessed in the inflammatory reaction induced by bradykinin and carrageenan in the mice model of pleurisy.

Dipyrone injected intraperitoneally (i.p.) or subplantarly into the mouse paw caused dose-related antinociception against the early and the late phases of formalin-induced licking, with mean ID50 values of 154.5 and 263.7 micromol/kg, and 2.6 and 1.2 micromol/paw, respectively. Given either by intracerebroventricular (i.c.v.) or by intrathecal (i.t.) routes, dipyrone produced a similar inhibition of both phases of the formalin-induced licking, with mean ID50 values of 0.4 and 1.3 micromol/site, and 0.4 and 0.9 micromol/site against the early and the late phase of the formalin response, respectively. Dipyrone, given by i.p., subplantar, i.t. or i.c.v. routes, caused dose-related antinociception of capsaicin-induced licking. The mean ID50 values were: 207.6 micromol/kg, 2.2 micromol/paw, 0.4 micromol/site and 0.14 micromol/site, respectively. In addition, dipyrone given i.p. caused a significant increase of the latency both in the hot-plate and the tail-flick assays. Dipyrone, given i.p., i.t. or i.c.v., reversed significantly the hyperalgesia caused by i.t. injection of glutamate, with mean ID50 values of 9 micromol/kg, 29 nmol/site and 94 nmol/site, respectively. The antinociception caused by dipyrone was not influenced by naloxone, L-arginine, phaclofen, glibenclamide, p-chlorophenylalanine methyl ester, pertussis toxin or by adrenal gland hormones, when assessed against the formalin assay. Dipyrone analgesic action was not secondary to its anti-inflammatory effect, nor was it associated with non-specific effects such as muscle relaxation or sedation actions of animals. Dipyrone at a higher concentration caused significant inhibition of [3H]glutamate binding (37%) in cerebral cortical membranes from both mice and rats. However, dipyrone had no significant effect on brain constitutive neuronal nitric oxide synthase activity. It is concluded that dipyrone produces peripheral, spinal and supraspinal antinociception when assessed on formalin and capsaicin-induced pain as well as in glutamate-induced hyperalgesia in mice. Dipyrone antinociception seems unlikely to involve an interaction with the L-arginine-nitric oxide pathway, serotonin system, activation of Gi protein sensitive to pertussis toxin. interaction of ATP-sensitive K+ channels, GABA(B) receptors, or the release of endogenous glucocorticoids. However, a modulatory effect on glutamate-induced hyperalgesia and, to a lesser extent, an interaction with glutamate binding sites, seems to account for its analgesic action.

The H(+)-ATPase from chloroplasts, CF0F1, was isolated, purified and reconstituted into asolectin liposomes. The enzyme was brought either into the oxidized state or into the reduced state, and the rate of ATP synthesis was measured after energisation of the proteoliposomes with an acid-base transition delta pH (pHin = 5.0, pHout = 8.5) and a K+/valinomycin diffusion potential, delta phi (Kin+ = 0.6 mM, Kout+ = 60 mM). A rate of 250 s-1 was observed with the reduced enzyme (85 s-1 in the absence of delta phi). A rate of 50 s-1 was observed with the oxidized enzyme under the same conditions (15 s-1 in the absence of delta phi). The reconstituted enzyme contained 2 ATPbound per CF0F1 and 1 ADPbound per CF0F1. Upon energisation the enzyme was activated and 0.9 ADP per CF0F1 was released. Binding of ADP to the active reduced enzyme was observed under different conditions. In the absence of phosphate the rate constant for ADP binding was 10(5) M-1.s-1 under energized and de-energized conditions. In the presence of phosphate the rate of ADP binding drastically increased under energized conditions, and strongly decreased under de-energized conditions.