Enhanced nitric oxide release/synthesis in the posterior hypothalamus during nitroglycerin tolerance in rats

We have recently observed that increasing central noradrenergic transmission and sympathomimetic activity is involved with the complex hemodynamic effects during tolerance to nitroglycerin. The present study was to examine the release of nitric oxide (NO) in the posterior hypothalamus during tolerance to depressor responses to nitroglycerin and determine if, during the tolerance, endogenous NO synthesis is induced in the posterior hypothalamus. A microdialysis probe was implanted in the posterior hypothalamus and perfusion fluid was pumped through the probe at 2 microl/min in conscious rats. Tolerance to nitroglycerin was produced by three intravenous (i.v.) injections of 1.3 mg nitroglycerin each within 40 min compared to the same administrations of low dose of the drug, sodium nitroprusside and papaverine. Dialysate samples were collected 1 h before and 1 h each after injections for 8 h. Concentrations of nitrite (NO(2)(-)), nitrate (NO(3)(-)), and total nitrite plus nitrate (NO(x)(-)) were quantified in the samples by using chemiluminescence. The dose-response curve for arterial depressor induced by intravenous injection of the challenge doses of nitroglycerin was markedly shifted to the right at the first hour after nitroglycerin tolerance, lasted 3 to 5 h and reversed at 7 h. The dialysate NO(3)(-) and NO(x)(-) concentrations in the posterior hypothalamus were significantly increased at the first hour following nitroglycerin tolerance but were not altered by low dose of the drug, sodium nitroprusside, and papaverine. Nitroglycerin tolerance predominantly caused an increase in NO(3)(-) release in the posterior hypothalamus with no or small amount of changes in dialysate NO(2)(-) and the response was partially inhibited by pretreatment with N(G)-Propyl-L-arginine (NPLA) (1.0 mg/kg, i.p.), an inhibitor of neuronal NO synthesis. The increase of NO release in the posterior hypothalamus occurred at the first hour, lasted 2 to 3 h and reversed at 5 to 6 h during nitroglycerin tolerance. The results show that systemically administered high dose of nitroglycerin increases NO release in the posterior hypothalamus which matches the time interval of tolerance to arterial depressor response to the drug. Data suggest that there is an enhanced endogenous NO synthesis in the posterior hypothalamus which may affect central sympathetic functions during nitroglycerin tolerance.