Vanillin and vanillin analogs relax porcine coronary and basilar arteries by inhibiting L-type Ca²⁺ channels

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-11a,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]), K_Ca (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 K_ATP (glibenclamide), by K_ir (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 Ca²⁺ reintroduction in coronary arteries, and by an opener of L-type Ca²⁺-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 Ca²⁺ or incubation with nifedipine. Thus, in porcine arteries, relaxation from VA (and its analogs) is due to inhibition of L-type Ca²⁺ channels. Hence, these compounds could be used to relieve coronary or cerebral vasospasms due to exaggerated Ca²⁺ influx, but therapeutic efficacy would require exposures that far exceed the current levels obtained by the use of vanillin additives.