title: Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin.
abstract: Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which (-)-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K(+) channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K(+) (KV) channels, and glibenclamide, a selective ATP-sensitive K(+) (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca(2+)-activated K(+) channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80mM K(+), (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca(2+)-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca(2+), interfere with intracellular Ca(2+) release and re-uptake by the sarcoplasmic reticulum.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia. Electronic address: aleksn@pharmacy.bg.ac.rs.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Novakovic
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Marinko
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Vranic
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Jankovic
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Institute for Cardiovascular Diseases "Dedinje", Belgrade, Serbia.
authors.forename: Predrag
authors.initials: P
authors.lastname: Milojevic
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Institute for Cardiovascular Diseases "Dedinje", Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Stojanovic
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Institute for Cardiovascular Diseases "Dedinje", Belgrade, Serbia.
authors.forename: Dragoslav
authors.initials: D
authors.lastname: Nenezic
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
authors.forename: Nenad
authors.initials: N
authors.lastname: Ugresic
authors.affiliation: Academy of Sciences and Arts, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kanjuh
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong; TEDA International Cardiovascular Hospital, Tianjin, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: TEDA International Cardiovascular Hospital, Tianjin, China.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
mesh_terms: D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008323:Mammary Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010656:Phenylephrine; D002392:Catechin; D002118:Calcium
keywords: (-)-Epicatechin; Calcium channels; Human internal mammary artery; Intracellular calcium release; Potassium channels; Vasorelaxation