Rapid tolerance to the hypotensive effects of glyceryl trinitrate in the rat: prevention by N-acetyl-L- but not N-acetyl-D-cysteine.
1. A new model of tolerance to the hypotensive effect of organic nitrates has been developed in the rat. 2. The fall in mean arterial pressure (MAP) in response to bolus doses of sodium nitroprusside (NP) (4 micrograms kg-1) and glyceryl trinitrate (GTN) (10 micrograms kg-1) was recorded both before and after a 60 min infusion of either 0.9% saline, NP (20 micrograms kg-1 min-1) or GTN (40 micrograms kg-1 min-1). 3. The hypotensive effects of NP or GTN were unchanged following saline infusion, but were reduced in both cases by approximately 40% following the infusion of NP. 4. Infusion of GTN for 60 min virtually abolished the hypotensive effect of a GTN bolus (i.e. nitrate tolerance), whilst the effect of a NP bolus was reduced only to a similar extent (30%) as after an infusion of NP. This latter effect is attributed to a degree of non-specific cross-tolerance between GTN and NP. 5. Co-treatment of a group of rats with N-acetyl-L-cysteine (L-NAC) prevented the development of nitrate tolerance, confirming the role of thiols in this phenomenon, whereas N-acetyl-D-cysteine (D-NAC) did not. 6. The stereospecificity in the effect of NAC in preventing this specific tolerance to GTN suggests that the interaction between GTN and NAC and/or cysteine involves an enzyme-dependent step. 7. NAC was unable to prevent the non-specific cross-tolerance to NP which followed infusion of GTN, suggesting that the mechanism does not directly involve NAC and/or cysteine.
Newman
C M
CM
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London.
Warren
J B
JB
Taylor
G W
GW
Boobis
A R
AR
Davies
D S
DS
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004361:Drug Tolerance; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D009599:Nitroprusside; D005996:Nitroglycerin; D000111:Acetylcysteine