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Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery

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Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery J Pharmacol Sci 118, 521 – 530 (2012) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Full Paper Involvement of Guanylate Cyclase and K+ Channels in Relaxation Evoked by Ferulate Nitrate in Rat Aorta Artery Zhan-Qing Wang1,*, Jing-Feng Xu1, Jin-Ping Wang1, Wei-Juan Zhao1, and Ming Zeng1 1Department of Pharmacology, General Hospital of Beijing Military Command, Beijing 100700, China Received September 29, 2011; Accepted February 21, 2012 Abstract. Vasorelaxant properties of N-2-(ferulamidoethyl)-nitrate (ferulate nitrate, FLNT), a newly synthesized nitrate, were compared with those of isosorbide dinitrate, nicorandil, nitro- glycerin, and 8-bromoguanosine 3,5-cyclic monophosphate (8-Br-cGMP) in rat aorta pre-contracted by phenylephrine. FLNT produced vasorelaxation in a concentration-dependent manner (0.1 – 100 μM). The degree of relaxation induced by FLNT was similar to that induced by isosorbide dinitrate. In addition, removal of endothelium did not affect the relaxant effect of FLNT. FLNT caused a rightward shift of the cumulative concentration–response curves of phenylephrine and reduced the maximal efficacy of contraction. 1H-[1,2,4]Oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM) + and K -channel blockers charybdotoxin (CHT, 0.1 μM) and BaCl2 (1 μM) reduced the relaxant effect of FLNT in the endothelium-denuded arteries, whereas glibenclamide (1 μM) and 4-amino- pyridine (1 mM) failed to influence FLNT-induced vasorelaxation. Furthermore, in the presence of ODQ, both CHT (0.1 μM) and BaCl2 (1 μM) still significantly reduced the relaxation evoked by FLNT. Pretreatment of vessels with hydroxocobalamin, a nitric oxide scavenger, abolished the FLNT effect. These findings demonstrate that FLNT induces relaxation of the rat aorta rings en- dothelium-independently. Furthermore, we demonstrated that FLNT-induced vasorelaxation is related to its stimulation of soluble guanylate cyclase and activation of K+ channels. Keywords: organic nitrate, vasorelaxation, guanylate cyclase, K+ channel Introduction (ALDH-2), and possibly esterases in vitro and in vivo (5, 6). Nitric oxide (NO) is an important regulator of vascular A few evidences indicate that vascular smooth muscle smooth muscle. It stimulates soluble guanylyl cyclase is responsible for denitration and release of NO from (sGC), which catalyzes the conversion of guanosine nitrate which in turn activates sGC (7). However, evi- 5-trisphosphate (GTP) to cyclic guanosine monophos- dences have accumulated to support the endothelium- phate (cGMP), and cGMP may induce vasodilation dependent mechanism of nitrate-induced vasorelaxation through activation of myosin light chain phosphatase (1). (8, 9). Moreover, nitrate tolerance has been reported to NO also causes membrane hyperpolarization through be associated with effects of nitrate on the vascular + 2+ K -channel activation, decreasing Ca entry and leads to endothelium leading to NO synthase activation and L- vasodilatation (2, 3). NO is produced either through the arginine depletion (8, 9). In addition, the tolerance was endogenous L-arginine–citrulline–NO pathway or from a also associated with sGC desensitization to NO because pharmacological NO donor. The organic nitrates are the of increased reactive oxygen species production and S- most commonly used NO donors and mimic endogenous nitrosylation of sGC (10 – 12). However, slight or no NO (3, 4). They are suggested to bio-transform into NO tolerance was developed against a nitrate, like nicorandil, by enzymes such as glutathione S-transferase, cyto- with the property of opening K+ channels (13, 14). chrome P-450, mitochondrial aldehyde dehydrogenase Ferulate nitrate (FLNT), N-2-(ferulamidoethyl)-nitrate is a newly synthesized ferulate derivative. Ferulate is an *Corresponding author. [email protected] antioxidant and protects vascular endothelium cells from Published online in J-STAGE being injured by hyperlipidemic serum. We have previ- doi: 10.1254/jphs.11179FP ously demonstrated that FLNT was an orally efficacious 521 522 Z-Q Wang et al antianginal agent (15). FLNT possesses a nitrate moiety g, Certification No. SCHK-JING-2000-0010), purchased in its chemical structure (Fig. 1). So we hypothesize that from Experimental Animal Breeding Center of Chinese FLNT will also possess potential vasorelaxant activity. Medical Institute (Beijing, China), were sedated via an- The aim of the present study was to determine whether esthetic overdose and killed by cervical dislocation and FLNT induces vasorelaxation in rat aorta artery and to exsanguination. Thoracic aortas were dissected free and address whether sGC and different K+ channels are re- surrounding connective tissues were carefully removed. sponsible for the vasorelaxation induced by FLNT. Four aortic rings (2 mm in length) were prepared from each rat and bathed in 10-ml organ baths containing Materials and Methods Krebs solution of the following composition: 116.3 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl2, 1.04 mM NaH2PO4, Chemicals 0.83 mM MgSO4, 19 mM NaHCO3, 5.5 mM glucose, pH FLNT (99.3% purity) was synthesized in our labo- 7.4. The bath solution was constantly gassed with a ratory; phenylephrine hydrochloride, acetylcholine mixture of 95% O2 and 5% CO2 and maintained at 37°C. chloride, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one Before the experiments were carried out, the aortic rings (ODQ), nicorandil, 8-bromoguanosine 3,5-cyclic mono- were allowed to equilibrate under a resting tension of 1.5 phosphate (8-Br-cGMP), hydroxocobalamin hydrochlo- g for 1 h, during which time Krebs solution was replaced ride, glibenclamide (GLM), charybdotoxin (CHT), every 15 min and muscle tensions were readjusted to 1.5 4-aminopiridine (4-AP), and barium chloride (BaCl2) g. Contractions were recorded isometrically by means of were purchased from Superior Chemical & Instrument four-channel JZ101 force transducers (Xin-Hang Instru- Co. (Beijing, China). All drugs were dissolved in Krebs- ment, Gao-beidian, China) and stored on computer using Henseleit solution except for FLNT, ODQ, nicorandil, Medlab-U-4CS software (Mei-Yi Instrument, Nan-jing, and GLM, which were dissolved in dimethyl sulfoxide. China). The endothelium-denuded rings were made by Dimethyl sulfoxide at a final concentration of 0.2% (v/v) rubbing the lumen of the artery with a steel wire. The did not affect phenylephrine-induced contraction. All removal of the endothelium was deemed successful if no drugs were added directly to the bath in a volume of 10 relaxation was induced in response to acetylcholine (10 mL and the concentrations given are the calculated final μM), and if the relaxation response was more than 80%, concentrations in the bath solution. the ring was deemed endothelium-intact, as described previously (16). Preparation of aortic rings All experiments reported here abided by the Guide for Phenylephrine contractions and FLNT relaxation the Care and Use of Laboratory Animals published by In the first set of experiments, the aortic rings were the US National Institutes of Health (NIH publication contracted with cumulative concentration of phenyleph- NO. 85-23, revised 1996). The experiments were con- rine (0.001 – 100 μM). The contraction concentration– ducted with the approval of the Ethics Review Committee response curves of phenylephrine were then conducted. for Animal Experimentation of the General Hospital of Based on the integrated concentration–response curve, Being Military Command. Male Wistar rats (250 – 300 the 80% maximally effective concentration of phenyleph- rine (1 μM) was selected as the concentration used for pre-contraction of the vessel rings in all the subsequent experiments. Cumulative relaxation responses to FLNT were then studied in the endothelium-intact and -denuded rings, with a 2-min exposure to each FLNT concentra- tion. The relaxation induced by FLNT was also compared to those induced by typical vasodilators: isosorbide dini- trate, nicorandil, nitroglycerin, and 8-Br-cGMP in en- dothelium-intact rings. In the second group of experiments, endothelium-intact aorta arteries were pre-incubated for 5 min with FLNT (1, 10, and 100 μM). The effect of FLNT on the contrac- tion concentration–response curves of phenylephrine was studied. During the experiments, aortic rings were washed by changing the Krebs solution four times at 15-min intervals and then allowed to stabilize between Fig. 1. Chemical structure of FLNT. each FLNT concentration pre-incubation. Vasorelaxation Evoked by FLNT 523 + Studies with K -channel blockers and the drug concentration exhibiting 50% of the Emax As described previously (6, 17 – 20), experiments (EC50) were calculated from the fitted concentration– were performed with CHT (0.1 μM), a selective Ca2+- response curves for each ring. Data were expressed as the + activated K -channel (KCa) blocker, as well as the inward mean ± S.E.M.; n refers to the number of rats from which + rectifier K -channel (KIR) blocker BaCl2 (1 μM). Experi- the vessel ring segments were taken. When the data were ments were also performed with the ATP-sensitive K+- distributed normally, statistical analysis was performed channel (KATP) blocker GLM (1 μM) and voltage-depen- using repeated-measures of analysis of variance, fol- + dent K -channel (KV) blocker 4-AP (1 mM). Tissues lowed by Dunnett’s test to analyze the difference between were pre-incubated with the K+-channel blockers 45 min the control group and experiment groups. The difference before contractions with 1 μM phenylephrine, and then was considered
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