Kukovetz W R, Holzmann S
Department of Pharmacodynamics and Toxicology, University of Graz, Austria.
J Cardiovasc Pharmacol. 1989;14 Suppl 11:S40-6.
The molecular mechanism of tolerance development to nitrovasodilators, most prominent with nitroglycerin, associated with desensitization of guanylate cyclase is still unclear. Nitric oxide (NO) appears to be the common denominator of this group of drugs that leads to guanylate cyclase activation, followed by increases in levels of cyclic GMP and relaxation. It was therefore decided to study whether NO itself, which causes some tolerance, interferes with the actions of (a) SIN-1 and sodium nitroprusside, both of which are thought to act directly by NO formation, which explains why they cause little tolerance; and (b) with the actions of nitroglycerin, which stimulates cyclic GMP formation only in the presence of cysteine and causes pronounced (large) tolerance. Experiments were performed in circular strips of isolated de-endothelialized bovine coronary artery by measuring isotonic changes in length and cyclic GMP determined by radioimmunoassay. When the strips were treated with submaximal effective concentrations of NO, some tolerance was observed, as shown by moderate attenuation of the rises in cyclic GMP, and a rightward shift of the dose-response curve of the relaxing effects by a dose factor of 10 (DF = 10). Exposure to nitroglycerin, SIN-1, or sodium nitroprusside rendered the strips cross-tolerant to NO to a comparable extent as NO itself, suggesting that under these conditions the NO component of all of these drugs that caused similar tolerance is displayed. When the strips were treated with NO and subsequently challenged with nitroglycerin, SIN-1, or sodium nitroprusside, the NO cross-tolerance was uniformly lower than the tolerance to the challenging agent.(ABSTRACT TRUNCATED AT 250 WORDS)
对硝基血管扩张剂产生耐受性的分子机制，在硝酸甘油中最为显著，与鸟苷酸环化酶脱敏相关，目前仍不清楚。一氧化氮（NO）似乎是这类导致鸟苷酸环化酶激活、随后环磷酸鸟苷水平升高和血管舒张的药物的共同特征。因此，决定研究导致一定耐受性的NO本身是否会干扰（a）SIN-1和硝普钠的作用，这两种药物都被认为通过形成NO直接起作用，这也解释了它们为何很少引起耐受性；以及（b）硝酸甘油的作用，硝酸甘油仅在存在半胱氨酸时刺激环磷酸鸟苷的形成，并导致明显（较大）的耐受性。实验在分离的去内皮牛冠状动脉环形条上进行，通过测量长度的等张变化和用放射免疫测定法测定环磷酸鸟苷。当用次最大有效浓度的NO处理条带时，观察到了一定的耐受性，表现为环磷酸鸟苷升高的适度减弱，以及舒张作用剂量反应曲线向右移动一个剂量因子10（DF = 10）。暴露于硝酸甘油、SIN-1或硝普钠使条带对NO产生交叉耐受性，程度与NO本身相当，这表明在这些条件下，所有这些引起相似耐受性的药物的NO成分都表现出来了。当条带先用NO处理，随后用硝酸甘油、SIN-1或硝普钠进行挑战时，NO交叉耐受性始终低于对挑战剂的耐受性。（摘要截短于250字）
