5-hydroxytryptamine has an endothelium-derived hyperpolarizing factor-like effect on coronary flow in isolated rat hearts

Journal of Biomedical Science

Ming-Jai Su¹  Ching-Chia Chang Chien¹ 

[1] Institute of Pharmacology, College of Medicine, National Taiwan University, 11F No.1 Sec.1, Ren-ai Rd, Taipei 10051, Taiwan

关键词: NO-independent;    Rat;    Coronary flow;    EDHF;    Endothelium-derived hyperpolarization factor;    NO;    Nitric oxide;    5-HT;    Serotonin;   

Others  :  1213941
DOI  :  10.1186/s12929-015-0149-8

 received in 2015-01-13, accepted in 2015-05-19,  发布年份 2015

【 摘 要 】

Background

5-hydroxytryptamine (5-HT)-induced coronary artery responses have both vasoconstriction and vasorelaxation components. The vasoconstrictive effects of 5-HT have been well studied while the mechanism(s) of how 5-HT causes relaxation of coronary arteries has been less investigated. In isolated rat hearts, 5-HT-induced coronary flow increases are partially resistant to the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) and are blocked by 5-HT₇ receptor antagonists. In the present study, we investigated the role of 5-HT₇ receptor in 5-HT-induced coronary flow increases in isolated rat hearts in the absence of L-NAME, and we also evaluated the involvement of endothelium-derived hyperpolarizing factor (EDHF) in 5-HT-induced coronary flow increases in L-NAME-treated hearts with the inhibitors of arachidonic acid metabolism and the blockers of Ca²⁺-activated K⁺ channels.

Results

In isolated rat hearts, 5-HT and the 5-HT₇ receptor agonist 5-carboxamidotryptamine induced coronary flow increases, and both of these effects were blocked by the selective 5-HT₇ receptor antagonist SB269970; in SB269970-treated hearts, 5-HT induced coronary flow decreases, which effect was blocked by the 5-HT_2A receptor blocker R96544. In L-NAME-treated hearts, 5-HT-induced coronary flow increases were blocked by the phospholipase A₂ inhibitor quinacrine and the cytochrome P450 inhibitor SKF525A, but were not inhibited by the cyclooxygenase inhibitor indomethacin. As to the effects of the Ca²⁺-activated K⁺ channel blockers, 5-HT-induced coronary flow increases in L-NAME-treated hearts were inhibited by TRAM-34 (intermediate-conductance Ca²⁺-activated K⁺ channel blocker) and UCL1684 (small-conductance Ca²⁺-activated K⁺ channel blocker), but effects of the large-conductance Ca²⁺-activated K⁺ channel blockers on 5-HT-induced coronary flow increases were various: penitrem A and paxilline did not significantly affect 5-HT-induced coronary flow responses while tetraethylammonium suppressed the coronary flow increases elicited by 5-HT.

Conclusion

In the present study, we found that 5-HT-induced coronary flow increases are mediated by the activation of 5-HT₇ receptor in rat hearts in the absence of L-NAME. Metabolites of cytochrome P450s, small-conductance Ca²⁺-activated K⁺ channel, and intermediate-conductance Ca²⁺-activated K⁺ channel are involved in 5-HT-induced coronary flow increases in L-NAME-treated hearts, which resemble the mechanisms of EDHF-induced vasorelaxation. The role of large-conductance Ca²⁺-activated K⁺ channel in 5-HT-induced coronary flow increases in L-NAME-treated hearts needs further investigation.

【 授权许可】

   
2015 Chang Chien and Su.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

【 参考文献 】

• [1]McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med. 1991; 324:648-54.
• [2]Golino P, Piscione F, Willerson JT, Cappelli-Bigazzi M, Focaccio A, Villari B et al.. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med. 1991; 324:641-8.
• [3]McFadden EP, Bauters C, Lablanche JM, Leroy F, Clarke JG, Henry M et al.. Effect of ketanserin on proximal and distal coronary constrictor responses to intracoronary infusion of serotonin in patients with stable angina, patients with variant angina, and control patients. Circulation. 1992; 86:187-95.
• [4]Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T et al.. Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol. 1999; 372:49-56.
• [5]Eglen RM, Jasper JR, Chang DJ, Martin GR. The 5-HT7 receptor: orphan found. Trends Pharmacol Sci. 1997; 18:104-7.
• [6]Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL. Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem. 1993; 268:23422-6.
• [7]Lenglet S, Louiset E, Delarue C, Vaudry H, Contesse V. Involvement of T-type calcium channels in the mechanism of action of 5-HT in rat glomerulosa cells: a novel signaling pathway for the 5-HT7 receptor. Endocr Res. 2002; 28:651-5.
• [8]Terron JA. The relaxant 5-HT receptor in the dog coronary artery smooth muscle: pharmacological resemblance to the cloned 5-ht7 receptor subtype. Br J Pharmacol. 1996; 118:1421-8.
• [9]Chang Chien CC, Hsin LW, Su MJ. Activation of serotonin 5-HT(7) receptor induces coronary flow increase in isolated rat heart. Eur J Pharmacol. 2015; 748:68-75.
• [10]Martorana PA, Goebel B, Ruetten H, Koehl D, Keil M. Coronary endothelial dysfunction after ischemia and reperfusion in the dog: a functional and morphological investigation. Basic Res Cardiol. 1998; 93:257-63.
• [11]Bouchard JF, Chouinard J, Lamontagne D. Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart. Cardiovasc Res. 2000; 45:418-27.
• [12]Joyeux M, Bouchard JF, Lamontagne D, Godin-Ribuot D, Ribuot C. Heat stress-induced protection of endothelial function against ischaemic injury is abolished by ATP-sensitive potassium channel blockade in the isolated rat heart. Br J Pharmacol. 2000; 130:345-50.
• [13]Mankad PS, Chester AH, Yacoub MH. 5-Hydroxytryptamine mediates endothelium dependent coronary vasodilatation in the isolated rat heart by the release of nitric oxide. Cardiovasc Res. 1991; 25:244-8.
• [14]Gereliuk IP, Stukal IK. The mechanisms of the effect of serotonin on the prostacyclin synthesis and coronary vascular resistance of the isolated rat heart. Fiziologicheskii zhurnal SSSR imeni I M Sechenova. 1992; 78:55-60.
• [15]Hecker M, Bara AT, Bauersachs J, Busse R. Characterization of endothelium-derived hyperpolarizing factor as a cytochrome P450-derived arachidonic acid metabolite in mammals. J Physiol. 1994; 481(Pt 2):407-14.
• [16]Grgic I, Kaistha BP, Hoyer J, Kohler R. Endothelial Ca + −activated K+ channels in normal and impaired EDHF-dilator responses–relevance to cardiovascular pathologies and drug discovery. Br J Pharmacol. 2009; 157:509-26.
• [17]Garland CJ, Hiley CR, Dora KA. EDHF: spreading the influence of the endothelium. Br J Pharmacol. 2011; 164:839-52.
• [18]Campbell WB, Gauthier KM. Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway. J Cardiovasc Pharmacol. 2013; 61:176-87.
• [19]Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I et al.. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature. 1999; 401:493-7.
• [20]Fleming I. Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol Res. 2004; 49:525-33.
• [21]Lovell PJ, Bromidge SM, Dabbs S, Duckworth DM, Forbes IT, Jennings AJ et al.. A novel, potent, and selective 5-HT(7) antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl) phen ol (SB-269970). J Med Chem. 2000; 43:342-5.
• [22]Ogawa T, Sugidachi A, Tanaka N, Fujimoto K, Asai F. Pharmacological profiles of R-96544, the active form of a novel 5-HT2A receptor antagonist R-102444. Eur J Pharmacol. 2002; 457:107-14.
• [23]Hinschen AK, Rose’Meyer RB, Headrick JP. Age-related changes in adenosine-mediated relaxation of coronary and aortic smooth muscle. Am J Physiol Heart Circulatory Physiol. 2001; 280:H2380-9.
• [24]Zifa E, Fillion G. 5-Hydroxytryptamine receptors. Pharmacol Rev. 1992; 44:401-58.
• [25]Bauersachs J, Hecker M, Busse R. Display of the characteristics of endothelium-derived hyperpolarizing factor by a cytochrome P450-derived arachidonic acid metabolite in the coronary microcirculation. Br J Pharmacol. 1994; 113:1548-53.
• [26]Gwozdz P, Drelicharz L, Kozlovski VI, Chlopicki S. Prostacyclin, but not nitric oxide, is the major mediator of acetylcholine-induced vasodilatation in the isolated mouse heart. Pharmacol Reports. 2007; 59:545-52.
• [27]Harrison GJ, Jordan LR, Willis RJ. Deleterious effects of hydrogen peroxide on the function and ultrastructure of cardiac muscle and the coronary vasculature of perfused rat hearts. Can J Cardiol. 1994; 10:843-9.
• [28]Harrison GJ, Jordan LR, Selley ML, Willis RJ. Low-density lipoproteins inhibit histamine and NaNO2 relaxations of the coronary vasculature and reduce contractile function in isolated rat hearts. Heart Vessel. 1995; 10:249-57.
• [29]Van de Voorde J, Brochez V, Vanheel B. Heterogenous effects of histamine on isolated rat coronary arteries. Eur J Pharmacol. 1994; 271:17-23.
• [30]Mishra RC, Belke D, Wulff H, Braun AP. SKA-31, a novel activator of SK(Ca) and IK(Ca) channels, increases coronary flow in male and female rat hearts. Cardiovasc Res. 2013; 97:339-48.
• [31]Dunn PM. UCL 1684: a potent blocker of Ca2 + − activated K+ channels in rat adrenal chromaffin cells in culture. Eur J Pharmacol. 1999; 368:119-23.
• [32]Asano S, Bratz IN, Berwick ZC, Fancher IS, Tune JD, Dick GM. Penitrem A as a tool for understanding the role of large conductance Ca(2+)/voltage-sensitive K(+) channels in vascular function. J Pharmacol Exp Ther. 2012; 342:453-60.
• [33]Sanchez M, McManus OB. Paxilline inhibition of the alpha-subunit of the high-conductance calcium-activated potassium channel. Neuropharmacology. 1996; 35:963-8.
• [34]Rees DD, Palmer RM, Moncada S. Effect of SKF 525A on the release of nitric oxide and prostacyclin from endothelial cells. Eur J Pharmacol. 1988; 150:149-54.
• [35]Cocks TM, Angus JA. Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. Nature. 1983; 305:627-30.
• [36]Ellwood AJ, Curtis MJ. Involvement of 5-HT(1B/1D) and 5-HT2A receptors in 5-HT-induced contraction of endothelium-denuded rabbit epicardial coronary arteries. Br J Pharmacol. 1997; 122:875-84.
• [37]Saxena PR, Villalon CM. Cardiovascular effects of serotonin agonists and antagonists. J Cardiovasc Pharmacol. 1990; 15 Suppl 7:S17-34.
• [38]Lai FM, Tanikella T, Cervoni P. Characterization of serotonin receptors in isolated rat intramyocardial coronary artery. J Pharmacol Exp Ther. 1991; 256:164-8.
• [39]Maguire JJ, Davenport AP. PD156707: a potent antagonist of endothelin-1 in human diseased coronary arteries and vein grafts. J Cardiovasc Pharmacol. 1998; 31 Suppl 1:S239-40.
• [40]Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, Filippelli A. Adrenoreceptors and nitric oxide in the cardiovascular system. Front Physiol. 2013; 4:321.
• [41]Gielen S, Sandri M, Erbs S, Adams V. Exercise-induced modulation of endothelial nitric oxide production. Curr Pharm Biotechnol. 2011; 12:1375-84.
• [42]Zeldin DC. Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem. 2001; 276:36059-62.
• [43]Kukovetz WR, Holzmann S, Wurm A, Poch G. Prostacyclin increases cAMP in coronary arteries. J Cyclic Nucleotide Res. 1979; 5:469-76.
• [44]Yamamoto Y, Imaeda K, Suzuki H. Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles. J Physiol. 1999; 514(Pt 2):505-13.
• [45]Edwards G, Feletou M, Gardener MJ, Thollon C, Vanhoutte PM, Weston AH. Role of gap junctions in the responses to EDHF in rat and guinea-pig small arteries. Br J Pharmacol. 1999; 128:1788-94.
• [46]Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 1998; 396:269-72.
• [47]Shimokawa H. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pflugers Arch - Eur J Physiol. 2010; 459:915-22.
• [48]Liu Y, Bubolz AH, Mendoza S, Zhang DX, Gutterman DD. H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles. Circ Res. 2011; 108:566-73.
• [49]Feher A, Rutkai I, Beleznai T, Ungvari Z, Csiszar A, Edes I et al.. Caveolin-1 limits the contribution of BK(Ca) channel to EDHF-mediated arteriolar dilation: implications in diet-induced obesity. Cardiovasc Res. 2010; 87:732-9.
• [50]Moroe H, Honda H. Comparison of endothelial function in the carotid artery between normal and short-term hypercholesterolemic rabbits. Comp Biochem Physiol Toxicol Pharmacol. 2006; 144:197-203.
• [51]Dong H, Waldron GJ, Galipeau D, Cole WC, Triggle CR. NO/PGI2-independent vasorelaxation and the cytochrome P450 pathway in rabbit carotid artery. Br J Pharmacol. 1997; 120:695-701.
• [52]Mori A, Suzuki S, Sakamoto K, Nakahara T, Ishii K. BMS-191011, an opener of large-conductance Ca2 + −activated potassium channels, dilates rat retinal arterioles in vivo. Biol Pharm Bull. 2011; 34:150-2.
• [53]Edwards G, Niederste-Hollenberg A, Schneider J, Noack T, Weston AH. Ion channel modulation by NS 1619, the putative BKCa channel opener, in vascular smooth muscle. Br J Pharmacol. 1994; 113:1538-47.
• [54]Shukla P, Ghatta S, Dubey N, Lemley CO, Johnson ML, Modgil A et al.. Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries. Am J Physiol Heart Circ Physiol. 2014; 307:H134-42.
• [55]Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol. 1995; 268:C799-822.
• [56]Tammaro P, Smith AL, Hutchings SR, Smirnov SV. Pharmacological evidence for a key role of voltage-gated K+ channels in the function of rat aortic smooth muscle cells. Br J Pharmacol. 2004; 143:303-17.
• [57]Kryshtal DO, Nesin VV, Shuba MF, Kryshtal DO, Nesin VV, Shuba MF. Effect of paxilline on Ca(2+)-dependent K+ current in smooth muscle cells isolated from rat vas deferens. Fiziolohichnyi zhurnal (Kiev, Ukraine : 1994). 2007; 53:67-74.
• [58]Asano S, Tune JD, Dick GM. Bisphenol A activates Maxi-K (K(Ca)1.1) channels in coronary smooth muscle. Br J Pharmacol. 2010; 160:160-70.
• [59]Borbouse L, Dick GM, Payne GA, Payne BD, Svendsen MC, Neeb ZP et al.. Contribution of BK(Ca) channels to local metabolic coronary vasodilation: Effects of metabolic syndrome. Am J Physiol Heart Circ Physiol. 2010; 298:H966-73.
• [60]Adeagbo AS. 1-Ethyl-2-benzimidazolinone stimulates endothelial K(Ca) channels and nitric oxide formation in rat mesenteric vessels. Eur J Pharmacol. 1999; 379:151-9.
• [61]Olanrewaju HA, Gafurov BS, Lieberman EM. Involvement of K+ channels in adenosine A2A and A2B receptor-mediated hyperpolarization of porcine coronary artery endothelial cells. J Cardiovasc Pharmacol. 2002; 40:43-9.
• [62]Li G, Cheung DW. Effects of paxilline on K+ channels in rat mesenteric arterial cells. Eur J Pharmacol. 1999; 372:103-7.
• [63]Lang DG, Ritchie AK. Tetraethylammonium blockade of apamin-sensitive and insensitive Ca2(+)-activated K+ channels in a pituitary cell line. J Physiol. 1990; 425:117-32.