NITRATE TOLERANCE IN-VIVO IS NOT ASSOCIATED WITH DEPLETION OF ARTERIAL OR VENOUS THIOL LEVELS

Results from in vitro experiments suggest that development of nitrate tolerance is due to a depletion of vascular thiol compounds tie, cyste ine and glutathione [GSH]) necessary for the bioconversion of organic nitrates. However, it is unknown whether in vivo tolerance development is associated with changes in thiol levels. This study measures plasm a and vessel tissue GSH and cysteine levels in nontolerant rats, nitra te-tolerant rats, and rats treated with the two characteristically dif ferent thiol donors N-acetyl-L-cysteine and L-2-oxothiazolidine-4-carb oxylic acid (OXO). Chronically catheterized conscious rats received an intravenous infusion of either nitroglycerin (NTG, 0.2 mg/h) or match ing placebo for 3 days. At day 3, the hypotensive effect of 2.5 mg NTG /kg was decreased by 74 +/- 6% (mean +/- SEM, P < .05) in the NTG-trea ted group (n = 7), indicating the development of tolerance. No change in the hypotensive effect of NTG was seen in the placebo group (n = 6, P < .05). Hemodynamic tolerance is not associated with changes in aor ta cysteine or GSH levels as compared with the placebo group (cysteine , 77 +/- 14 versus 57 +/- 11 [mean +/- SEM] nmol/g; GSH, 414 +/- 62 ve rsus 399 +/- 89 nmol/g; P > .05). However, the increase in vascular th iol levels seen after OXO treatment in nontolerant rats is completely absent in nitrate-tolerant animals. The results suggest that (1) deple tion of vascular cysteine and/or GSH is apparently not the mechanism u nderlying development of nitrate tolerance in vivo, and (2) the metabo lic handling of thiol compounds and/or the activity of enzymes that ac t on these thiols is altered during the development of nitrate toleran ce in vivo.