Abstract
Background5-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.ResultsIn 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-HT2A 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.ConclusionIn 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.
Highlights
We found that 5-HT-induced coronary flow increases in isolated rat hearts have a LNAME-resistant component [9], and the 5-HT-induced coronary flow increases in Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME)-treated hearts are blocked by 5-HT7 receptor antagonists [9]; the role of 5-HT7 receptor activation in the nitric oxide (NO)-dependent component of 5-HT-induced coronary flow increases was left unevaluated, and the mechanism(s) of the LNAME-resistant component of the coronary flowincreasing effect was not studied
We investigated the role of 5-HT7 receptor in 5-HTinduced coronary flow increases in the absence of LNAME in isolated rat hearts by using selective 5-HT receptor agonist and antagonist, and we evaluated the role of endothelium-derived hyperpolarizing factor (EDHF) in 5-HT-induced coronary flow increases by testing effects of blockers of arachidonic acid metabolism [18, 20] and Ca2+-activated K+ channels [16] on 5-HT-induced coronary flow increases in L-NAMEtreated hearts
5-HT 0.3 and 1 μM induced coronary flow decreases in the presence of SB269970 0.3 μM (Fig. 2b) (n = 5; P < 0.0001 and F = 14.33, one-way ANOVA), which were significantly different from the responses in the control group (P = 0.0007 and F = 33.71, 2-ways ANOVA analyzed with the control group)
Summary
Animals Adult male Sprague Dawley rats aged 2–3 months (weighting 250–350 g) were purchased from BioLasco Co. (Yilan, Taiwan). Animals Adult male Sprague Dawley rats aged 2–3 months (weighting 250–350 g) were purchased from BioLasco Co. Animals were kept in the Laboratory Animal Center of National Taiwan University (Taipei, Taiwan) until the day of experiment. All animal procedures were performed according to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and followed the guidelines of the Animal Welfare Act. The animal studies were approved with a certificate number 20110073 by the Institutional Animal Care and Use Committee of the College of Medicine, National Taiwan University (Taipei, Taiwan). Chemicals and solution 5-HT, adenosine, histamine, indomethacin, tetraethylammonium chloride (TEA), L-NAME, and dimethyl sulfoxide (DMSO) were purchased form Sigma-Aldrich (St. Louis, Missouri, USA). Quinacrine, penitrem A, paxilline, and SKF525A were purchased from Cayman Chemical Co. Quinacrine, penitrem A, paxilline, and SKF525A were purchased from Cayman Chemical Co. (Ann Arbor, Michigan, USA)
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