Reduced hyperpolarization in endothelial cells of rabbit aortic valve following chronic nitroglycerine administration.
This study was undertaken to determine whether long-term in vivo administration of nitroglycerine (NTG) downregulates the hyperpolarization induced by acetylcholine (ACh) in aortic valve endothelial cells (AVECs) of the rabbit and, if so, whether antioxidant agents can normalize this downregulated hyperpolarization. ACh (0.03-3 microM) induced a hyperpolarization through activations of both apamin- and charybdotoxin-sensitive Ca2+-activated K+ channels (K(Ca)) in rabbit AVECs. The intermediate-conductance K(Ca) channel (IK(Ca)) activator 1-ethyl-2-benzimidazolinone (1-EBIO, 0.3 mM) induced a hyperpolarization of the same magnitude as ACh (3 microM). The ACh-induced hyperpolarization was significantly weaker, although the ACh-induced [Ca2+]i increase was unchanged, in NTG-treated rabbits (versus NTG-untreated control rabbits). The hyperpolarization induced by 1-EBIO was also weaker in NTG-treated rabbits. The reduced ACh-induced hyperpolarization seen in NTG-treated rabbits was not modified by in vitro application of the superoxide scavengers Mn-TBAP, tiron or ascorbate, but it was normalized when ascorbate was coadministered with NTG in vivo. Superoxide production within the endothelial cell (estimated by ethidium fluorescence) was increased in NTG-treated rabbits and this increased production was normalized by in vivo coadministration of ascorbate with the NTG. It is suggested that long-term in vivo administration of NTG downregulates the ACh-induced hyperpolarization in rabbit AVECs, possibly through chronic actions mediated by superoxide.
Kusama
Nobuyoshi
N
Department of Cellular and Molecular Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Nagoya, Aichi 467-8601, Japan.
Kajikuri
Junko
J
Yamamoto
Tamao
T
Watanabe
Yoshimasa
Y
Suzuki
Yoshikatsu
Y
Katsuya
Hirotada
H
Itoh
Takeo
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001021:Aortic Valve / Q000166:cytology; D001030:Apamin / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004361:Drug Tolerance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D000975:Antioxidants; D001562:Benzimidazoles; D001685:Biological Factors; D002120:Calcium Channel Agonists; D007476:Ionophores; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013481:Superoxides; D018999:Charybdotoxin; D001030:Apamin; D015759:Ionomycin; D005996:Nitroglycerin; C102635:1-ethyl-2-benzimidazolinone; D000109:Acetylcholine; D001205:Ascorbic Acid; D002118:Calcium