TY - JOUR
T1 - Nitrate tolerance is specific for nitric acid esters and its recovery requires an intact protein synthesis
AU - Hinz, Burkhard
AU - Schröder, Henning
N1 - Funding Information:
This work was supported by the Deutsche Forschungsgemein-schaft (Schr 298/8-2).
PY - 1998/11/9
Y1 - 1998/11/9
N2 - Using cultured LLC-PK1 cells the present study investigates mechanisms leading to nitrate tolerance and its reversal. A 5-h pretreatment with glyceryl trinitrate (GTN, 0.01-100 μM) resulted in desensitization of the intracellular cyclic GMP response to a subsequent 10-min challenge with GTN (1 μM). The spontaneous donor of nitric oxide (NO) spermine NONOate, which releases NO independently of enzymatic catalysis, did not induce tolerance to its own cyclic GMP stimulatory effect and remained fully effective in GTN-tolerant cells. Tolerant cells regained sensitivity to GTN after a 30-h incubation in media. Recovery of the cyclic GMP response was blocked in the presence of cycloheximide (10 μM) suggesting that de novo protein synthesis is necessary for tolerance reversal. Our results demonstrate that nitrate tolerance is specific for nitric acid esters and possibly due to down-regulation of enzymes involved in bioactivation of, and NO generation from, organic nitrates.
AB - Using cultured LLC-PK1 cells the present study investigates mechanisms leading to nitrate tolerance and its reversal. A 5-h pretreatment with glyceryl trinitrate (GTN, 0.01-100 μM) resulted in desensitization of the intracellular cyclic GMP response to a subsequent 10-min challenge with GTN (1 μM). The spontaneous donor of nitric oxide (NO) spermine NONOate, which releases NO independently of enzymatic catalysis, did not induce tolerance to its own cyclic GMP stimulatory effect and remained fully effective in GTN-tolerant cells. Tolerant cells regained sensitivity to GTN after a 30-h incubation in media. Recovery of the cyclic GMP response was blocked in the presence of cycloheximide (10 μM) suggesting that de novo protein synthesis is necessary for tolerance reversal. Our results demonstrate that nitrate tolerance is specific for nitric acid esters and possibly due to down-regulation of enzymes involved in bioactivation of, and NO generation from, organic nitrates.
UR - http://www.scopus.com/inward/record.url?scp=0344074610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0344074610&partnerID=8YFLogxK
U2 - 10.1006/bbrc.1998.9630
DO - 10.1006/bbrc.1998.9630
M3 - Article
C2 - 9813175
AN - SCOPUS:0344074610
SN - 0006-291X
VL - 252
SP - 232
EP - 235
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -