Endothelial modulation and tolerance development in the vasorelaxant responses to nitrate of rabbit aorta.
We investigated the endothelial modulations in nitrate tolerance in isolated rabbit aorta. Nitrate tolerance was induced by a 72-h treatment with transdermal nitroglycerin (NTG, 0.4 mg/h) in conscious rabbits, which was verified by a 20-fold increase in the EC50 values [NTG tolerance (6.1 +/- 0.8) x 10(-7) M vs control (3.0 +/- 0.6) x 10(-8) M]. The relaxations to NTG in tolerant and nontolerant aortic strips were enhanced when their endothelia were denuded [E(-)]. In the presence of endothelium [E(+)], NTG-tolerant vessels were not tolerant to acetylcholine (ACh), which can release endothelial nitric oxide (NO), exogenous NO or 8-bromo (Br)-cGMP. In NTG-tolerant and nontolerant vessels with endothelium, concentration-response curves for NO were the same as those in endothelium-absent tolerant vessels. In both NTG-tolerant and nontolerant vessels, treatment with superoxide dismutase (SOD, 20 units/ml), an O2-. scavenger, unaffected the responses to NTG reduced in the presence of endothelium, but treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), an NO synthase (NOS) inhibitor, reversed these reductions. Thus, our data did not indicate that an increased endothelial superoxide O2-. production contributes to nitrate tolerance. Our study suggested that (i) an impaired biotransformation process from NTG to NO is responsible for the occurrence of nitrate tolerance and (ii) vascular response to NTG enhanced by endothelial removal is related to blocked endothelial NO release.
Nakae
Ichiro
I
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan.
Matsumoto
Tetsuya
T
Omura
Tomoko
T
Takashima
Hiroyuki
H
Ohira
Naoto
N
Tarutani
Yasuhiro
Y
Yasuda
Yo
Y
Matsuo
Shinro
S
Koh
Terue
T
Nakaura
Yasuyuki
Y
Kinoshita
Masahiko
M
Horie
Minoru
M
D000109:Acetylcholine / Q000494:pharmacology; D000279:Administration, Cutaneous; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D005996:Nitroglycerin / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D005996:Nitroglycerin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester