Anti-inflammatory, antinociceptive, and vasorelaxant effects of a new pyrazole compound 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole: role of NO/cGMP pathway and calcium channels.

Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1H-[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl2-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.

Hypotensive and vasorelaxant effects of (E) - methyl isoeugenol: a naturally occurring food flavour.

Application of naturally occurring (E) - methyl isoeugenol (MIE) as food flavour has been widely accepted despite the growing concerns over cardiovascular issue. Hence, we sought to investigate hypotensive property of MIE and the involvement of central and/or peripheral mechanism (s). Variation in mean arterial pressure (MAP), heart rate (HR), systolic blood pressure (SBP), baroreflex sensitivity of normotensive rats and vascular reactivity were recorded. MIE (1.11, 2.25 or 4.50mg/kg, iv) elicited dose-related decrease in MAP (-16.9±1.13; -19.0±4.18 or -27.2±3.65mmHg, respectively) and an increase in HR (17.4±1.79; 24.4±5.11 or 29.9±6.62 bmp, respectively). MIE 25 or 50mg/kg (p.o) reduced the SBP (-13.6±4.18 or -16.6±5.60mmHg, respectively) without altering baroreflex sensitivity. The hypotensive effect of MIE remained unaltered by WAY100635 (antagonist of 5-HT1A) and L-NAME (NO synthase inhibitor). Intracerebroventricular injection of MIE did not change MAP. MIE elicited endothelium independent vasorelaxation (endothelium-intact vessels, Emax 92.5±1.75%; Endothelium-denuded vessels, Emax 91.4±2.79%). MIE blocked CaCl2 or BAY K8644 (L-type voltage gated calcium channel activator)-induced vascular contractions. Our findings showed evidence of hypotensive and vasorelaxation effects of MIE with involvement of calcium channel.

Efferent pathways in sodium overload-induced renal vasodilation in rats.

Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. The present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. In anesthetized rats (n = 6), OT infusion (0.03 µg • kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml • kg(-1) b.wt., i.v.) was infused over 60 s. In sham rats (n = 6), hypertonic saline induced renal vasodilation. The OXTR antagonist (AT; atosiban, 40 µg • kg(-1) • h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. The combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.