Laursen J B, Boesgaard S, Poulsen H E, Aldershvile J
Medical Department B, University of Copenhagen, Denmark.
Cardiovasc Res. 1996 May;31(5):814-9. doi: 10.1016/0008-6363(96)00027-2.
Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied.
Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured.
Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance.
The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.
硝酸甘油（NTG）在血管平滑肌细胞中代谢为一氧化氮（NO）。目前尚不清楚长期暴露于NTG及耐受性的产生是否会直接影响体内内源性NO介导的血管舒张。本研究调查了在形成硝酸盐耐受性前后清醒的慢性插管大鼠中NO介导的血管舒张情况。还研究了可能影响NTG反应性的硫醇化合物N-乙酰半胱氨酸（NAC）的作用。
通过72小时静脉输注NTG诱导硝酸盐耐受性，并通过对NTG的降压反应降低65 - 68%来确认（P < 0.05）。在未耐受和硝酸盐耐受的大鼠中检测乙酰胆碱（ACh）和硝普钠（SNP）的降压作用以及NAC介导的对这些化合物反应的可能变化。此外，测量对NO合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）的升压反应。
硝酸盐耐受性与对ACh的降压反应显著减弱相关（之前为24±1 mmHg；之后为17±2 mmHg，n = 7，P < 0.05）。同样，对SNP的反应从32±1 mmHg降至26±3 mmHg（n = 7，P < 0.05）。NTG载体（安慰剂）不影响对ACh和SNP的反应（P > 0.05）。NAC增强了NTG、ACh和SNP在未耐受和硝酸盐耐受动物中的作用（P < 0.05）。诱导硝酸盐耐受性后，对L-NAME的升压反应（n = 8）降低了67%（从34±6 mmHg降至11±1 mmHg，P < 0.05）。
结果表明：（1）体内硝酸盐耐受性与对外源性和内源性硝基血管扩张剂产生的NO介导的血管舒张的交叉耐受性相关；（2）添加NAC也可改善对NTG以外的硝基血管扩张剂的反应。
