Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3′,5′-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.

Synthesis, characterization and anti-inflammatory activity of some 1, 3,4 -oxadiazole derivatives

A series of five-membered heterocyclic rings were synthesized by the reaction between benzoyl chloride and various chlolro-nitro-benzoyl chlorides and semi carbazide to form [C[1]-C[7]] compounds and was tested for their anti-inflammatory activity determined by rat-paw-oedema method. All the synthesis compounds have been characterized by [1]HNMR, IR and Mass spectral data. The compounds were purified by column chromatography. All synthesized derivatives were determined by the carrageenan-induced rat-paw-oedema model for anti-inflammatory activity. The entire compound gives good response for the anti-inflammatory activity: [3-Chloro-N-[5-[3-Chloro-phenyl]-[1,3,4] oxadiazole-2yl] benzamide [C[4]], and [4-Nitro-N-[5-[4-Nitro-phenyl]-[1,3,4] oxadiazole-2yl] benzamide [C[7]]. For this activity, indometacin was used as a standard drug and compared to new synthesized drugs. Some new synthesized drugs have shown better activities for the anti-inflammation

Participation of the NO/cGMP/K+ATP pathway in the antinociception induced by Walker tumor bearing in rats

Implantation of Walker 256 tumor decreases acute systemic inflammation in rats. Inflammatory hyperalgesia is one of the most important events of acute inflammation. The L-arginine/NO/cGMP/K+ATP pathway has been proposed as the mechanism of peripheral antinociception mediated by several drugs and physical exercise. The objective of this study was to investigate a possible involvement of the NO/cGMP/K+ATP pathway in antinociception induced in Walker 256 tumor-bearing male Wistar rats (180-220 g). The groups consisted of 5-6 animals. Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. Walker tumor (4th and 7th day post-implantation) reduced prostaglandin E2- (PGE2, 400 ng/paw; 50 µL; intraplantar injection) and carrageenan-induced hypernociception (500 µg/paw; 100 µL; intraplantar injection). Walker tumor-induced analgesia was reversed (99.3% for carrageenan and 77.2% for PGE2) by a selective inhibitor of nitric oxide synthase (L-NAME; 90 mg/kg, ip) and L-arginine (200 mg/kg, ip), which prevented (80% for carrageenan and 65% for PGE2) the effect of L-NAME. Treatment with the soluble guanylyl cyclase inhibitor ODQ (100% for carrageenan and 95% for PGE2; 8 µg/paw) and the ATP-sensitive K+ channel (KATP) blocker glibenclamide (87.5% for carrageenan and 100% for PGE2; 160 µg/paw) reversed the antinociceptive effect of tumor bearing in a statistically significant manner (P < 0.05). The present study confirmed an intrinsic peripheral antinociceptive effect of Walker tumor bearing in rats. This antinociceptive effect seemed to be mediated by activation of the NO/cGMP pathway followed by the opening of KATP channels.

Cinnamyl alcohol attenuates vasoconstriction by activation of K+ channels via NO-cGMP-protein kinase G pathway and inhibition of Rho-kinase

Cinnamyl alcohol (CAL) is known as an antipyretic, and a recent study showed its vasodilatory activity without explaining the mechanism. Here we demonstrate the vasodilatory effect and the mechanism of action of CAL in rat thoracic aorta. The change of tension in aortic strips treated with CAL was measured in an organ bath system. In addition, vascular strips or human umbilical vein endothelial cells (HUVECs) were used for biochemical experiments such as Western blot and nitrite and cyclic guanosine monophosphate (cGMP) measurements. CAL attenuated the vasoconstriction of phenylephrine (PE, 1 microM)-precontracted aortic strips in an endothelium-dependent manner. CAL-induced vasorelaxation was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 10(-4) M), methylene blue (MB; 10(-5) M) and 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10one, (ODQ; 10(-6) or 10(-7) M) in the endothelium-intact aortic strips. Atrial natriuretic peptide (ANP; 10(-8) or 10(-9) M) did not affect the vasodilatory effect of CAL. The phosphorylation of endothelial nitric oxide synthase (eNOS) and generation of nitric oxide (NO) were stimulated by CAL treatment in HUVECs and inhibited by treatment with L-NAME. In addition, cGMP and PKG1 activation in aortic strips treated with CAL were also significantly inhibited by L-NAME. Furthermore, CAL relaxed Rho-kinase activator calpeptin-precontracted aortic strips, and the vasodilatory effect of CAL was inhibited by the ATP-sensitive K+ channel inhibitor glibenclamide (Gli; 10(-5) M) and the voltage-dependent K+ channel inhibitor 4-aminopyridine (4-AP; 2 x 10(-4) M). These results suggest that CAL induces vasorelaxation by activating K+ channels via the NO-cGMP-PKG pathway and the inhibition of Rho-kinase.

Atropine and ODQ antagonize tetanic fade induced by L-arginine in cats

Although it has been demonstrated that nitric oxide (NO) released from sodium nitrite induces tetanic fade in the cat neuromuscular preparations, the effect of L-arginine on tetanic fade and its origin induced by NO have not been studied in these preparations. Furthermore, atropine reduces tetanic fade induced by several cholinergic and anticholinergic drugs in these preparations, whose mechanism is suggested to be mediated by the interaction of acetylcholine with inhibitory presynaptic muscarinic receptors. The present study was conducted in cats to determine the effects of L-arginine alone or after pretreatment with atropine or 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ) on neuromuscular preparations indirectly stimulated at high frequency. Drugs were injected into the middle genicular artery. L-arginine (2 mg/kg) and S-nitroso-N-acetylpenicillamine (SNAP; 16 µg/kg) induced tetanic fade. The Nw-nitro-L-arginine (L-NOARG; 2 mg/kg) alone did not produce any effect, but reduced the tetanic fade induced by L-arginine. D-arginine (2 mg/kg) did not induce changes in tetanic fade. The tetanic fade induced by L-arginine or SNAP was reduced by previous injection of atropine (1.0 µg/kg) or ODQ (15 µg/kg). ODQ alone did not change tetanic fade. The data suggest that the NO-synthase-GC pathway participates in the L-arginine-induced tetanic fade in cat neuromuscular preparations. The tetanic fade induced by L-arginine probably depends on the action of NO at the presynaptic level. NO may stimulate guanylate cyclase increasing acetylcholine release and thereby stimulating presynaptic muscarinic receptors

Synthesis and antimicrobial activity of 3,5-bis- [1-3,4-oxadiazol-5-yl] -, [1,3-thiazolo] hydrazony1-and [7H] s-Triazolo- [3,4-b] -1,3,4 Thiadiazinyl] pyridine derivatives

Different 3, 5-bis [oxadiazolyl] pyridine derivatives 3-5 have been obtained from 1 depending on the reaction condition. Reaction of 5 with amines or alkylhalides afforded the corresponding Mannich bases 6 or s-alkyl derivatives 7. The latter derivatived were treated with ammonium acetate to give 9 and with hydrazine hydrate affording bis bicyclic pyridine derivatives 10. Preliminary antimicrobial tests showed products 6e and 8 to possess higher activity when compared with oxytetracycline

Synthesis of some 1, 3, 4-oxadiazole derivatives having pyridazinyl-moiety as antimicrobial agents

Some derivatives of pyridazine are reported to exhibit broad spectrum biologic effect [1,2]. Moreover substituted 1,3,4-oxadiazoles have been mentioned to exert wide variety of application in medicine and agriculture[3,4]. On the basis of these findings we wish to report here the synthesis of some substituted [pyridazin-3-yl] thiomethyl, -1,3,4-oxadiazole derivatives and the evaluation of some of their antimicrobial activity. The starting material in this work is ethyl S-[substituted- pyridazin-3-yl] thioglycolate [II] which was obtained either by the reaction of the corresponding 3-thiopyridazine [I[a]] with ethyl chloroacetate [5] or the reaction of the corresponding 3-chloropyridazine [I[b]] with ethyl thioglycolate[6]. II [Ar = Ph, 'Ar = H] showed i.r. absorption bands at 1740 cm[-1] [ester c=o] and 1445 cm[-1] [S-CH2]. The [1] H-NMR spectrum of [II] showed signals at sigma1.2 [CH[3],t, 3H], sigma 4,2 [CH[2]m,4H] and sigma 7.5-8. 2 [Ar-H, m, 7H]. The hydrazides III were prepared by treating the ethyl ester [II] with hydrazine hydrate. Ill [Ar=Ph, R=H] showed i.r absorption bands at 3400-3210 cm[-1] [NH], 1660 cm[-1] [CONH amide 1] and 1390 cm[-1] [S-CH[2]]. The [1]H-NMR spectrum of compound III [Ar=Ph, R=H] showed signals at sigma 4.0 [CH[2],s, 2H], sigma 4.4 [NH, bs, 2H], sigma 7.5-8.2 [Ar-H, m, 7H] and sigma 9.4 [NH, s, 1H]. Mass spectrum of III [Ar=Ph, R=H] showed the following ion fragments m/z [Peak/relative abundance]: 260/20.3 [M[+]], 243/3.8, 201/3.16, 147/7.59, 105/14.87, 103/17.6, 77/100, 73/17.09, 56/29.11, 55/31.01 and 51/14.56