title: Vanillin and vanillin analogs relax porcine coronary and basilar arteries by inhibiting L-type Ca2+ channels.
abstract: Vanillin (VA) and vanillyl alcohol (VAA), components of natural vanilla, and ethyl vanillin (EtVA; synthetic analog) are used as flavoring agents and/or as additives by the food, cosmetic, or pharmaceutic industries. VA, VAA, and EtVA possess antioxidant and anti-inflammatory properties, but their vascular effects have not been determined. Therefore, we compared in isolated porcine coronary and basilar arteries the changes in isometric tension caused by VA, VAA, and EtVA. VA and its analogs caused concentration-dependent relaxations of both preparations during contractions from U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α, a thromboxane A2 receptor agonist), and of coronary arteries contracted with KCl or endothelin-1. The order of potency was VAA < VA < EtVA. The relaxations were not inhibited by endothelium removal, by inhibitors of NO synthases (N(ω)-nitro-l-arginine methyl ester hydrochloride), cyclooxygenases (indomethacin), soluble guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ]), KCa (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole [TRAM-34], 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo[b,n][1,5,12,16]tetraazacyclotricosine-5,13-diium ditrifluoroacetate hydrate [UCL-1684], or iberiotoxin), by KATP (glibenclamide), by Kir (BaCl2), by transient receptor potential receptor vanilloid 3 (TRPV3) channels (ruthenium red), or by antioxidants (catalase, apocynin, tempol, N-acetylcysteine, tiron). VA and its analogs inhibited contractions induced by Ca(2+) reintroduction in coronary arteries, and by an opener of L-type Ca(2+)-channels (methyl 2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate [Bay K8644]) in coronary and basilar arteries. They inhibited contractions of coronary rings induced by the protein kinase C activator phorbol 12,13-dibutyrate to the same extent as the removal of extracellular Ca(2+) or incubation with nifedipine. Thus, in porcine arteries, relaxation from VA (and its analogs) is due to inhibition of L-type Ca(2+) channels. Hence, these compounds could be used to relieve coronary or cerebral vasospasms due to exaggerated Ca(2+) influx, but therapeutic efficacy would require exposures that far exceed the current levels obtained by the use of vanillin additives.
authors.affiliation: Department of BIN Fusion Technology, Department of Polymer Nano Science & Technology, Chonbuk National University, Jeonju, South Korea (G.R., G.K., P.M.V.); and Key State Laboratory of Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong SAR, People's Republic of China (P.M.V.) graffai@hotmail.com gskhang@jbnu.ac.kr.
authors.forename: Gábor
authors.initials: G
authors.lastname: Raffai
authors.affiliation: Department of BIN Fusion Technology, Department of Polymer Nano Science & Technology, Chonbuk National University, Jeonju, South Korea (G.R., G.K., P.M.V.); and Key State Laboratory of Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong SAR, People's Republic of China (P.M.V.) graffai@hotmail.com gskhang@jbnu.ac.kr.
authors.forename: Gilson
authors.initials: G
authors.lastname: Khang
authors.affiliation: Department of BIN Fusion Technology, Department of Polymer Nano Science & Technology, Chonbuk National University, Jeonju, South Korea (G.R., G.K., P.M.V.); and Key State Laboratory of Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong SAR, People's Republic of China (P.M.V.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D013329:Structure-Activity Relationship; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001547:Benzaldehydes; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; C100058:vanillin; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D002118:Calcium