title: 5-hydroxytryptamine has an endothelium-derived hyperpolarizing factor-like effect on coronary flow in isolated rat hearts.
abstract: 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 Ca(2+)-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-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 Ca(2+)-activated K(+) channel blockers, 5-HT-induced coronary flow increases in L-NAME-treated hearts were inhibited by TRAM-34 (intermediate-conductance Ca(2+)-activated K(+) channel blocker) and UCL1684 (small-conductance Ca(2+)-activated K(+) channel blocker), but effects of the large-conductance Ca(2+)-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.
  
  
  CONCLUSIONS
  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 Ca(2+)-activated K(+) channel, and intermediate-conductance Ca(2+)-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 Ca(2+)-activated K(+) channel in 5-HT-induced coronary flow increases in L-NAME-treated hearts needs further investigation.
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, 11F No.1 Sec.1, Ren-ai Rd, Taipei, 10051, Taiwan. d95443008@ntu.edu.tw.
authors.forename: Ching-Chia Chang
authors.initials: CC
authors.lastname: Chien
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, 11F No.1 Sec.1, Ren-ai Rd, Taipei, 10051, Taiwan. mingja@ntu.edu.tw.
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009924:Organ Culture Techniques; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000008:administration & dosage*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D011985:Receptors, Serotonin; C411671:TRAM 34; C067410:endothelium-dependent hyperpolarization factor; C104425:serotonin 7 receptor; D012701:Serotonin; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester