1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.

译文

1。对硝酸甘油 (NG) 的降压作用的耐受性阻断了兔快速心室起搏 (RVP) 引起的预处理。在本工作中,在清醒的兔子中研究了经皮硝酸甘油连续治疗与间歇治疗对起搏诱导的预处理现象的影响。2. RVP (500搏动min-1超过5分钟) 使左室舒张末期压 (LVEDP) 从基线4.1 +/- 0.9增加至起搏后13.8 +/- 2.9 mmHg (P <0.001),右室ST段抬高1.25 +/- 0.13 mV,心肌缺血的两个指标。当在RVP期之前进行相同速率和持续时间的预处理起搏并间隔5分钟时,这些变化会显着减弱。3.当通过在7天内应用透皮NG (约0.07 mg kg-1 h-1) 使动物耐受30微克kg-1 NG的血管舒张作用时,取消了预处理的保护。此外,透皮NG本身在7天内减弱了RVP诱导的ST段抬高和LVEDP升高。4.间歇性经皮NG治疗 (12 h “贴剂” vs “贴剂”),既没有观察到血管耐受性的发展,也没有观察到NG或预处理诱导的抗缺血作用的减弱。然而,在 “修补” 期间,起搏引起的心肌缺血的严重程度显着增加。5.在第二组实验中,通过放射免疫分析法确定了具有相同NG治疗方案的慢性仪器麻醉开胸兔的心脏循环GMP和循环AMP水平的起搏后变化。预处理在未处理的动物心脏和给定的补片中,在 “补片” 和 “补片” 期间间歇性地减少了循环AMP的起搏后增加,循环GMP浓度增加。然而,在耐受性动物中,对任一环核苷酸的预处理作用均被阻断。6.透皮NG在非耐受状态下增加了两个心脏环核苷酸的静息水平,但在耐受状态下不增加。经皮NG抑制了循环AMP含量的起搏后增加,与血管耐受性的发展无关,而在非耐受性动物中仅观察到循环GMP含量。7.我们得出结论,在耐受状态下,NG的抗缺血作用与循环GMP机制无关。尽管间歇性NG疗法可防止血管耐受性的发展并保留预处理,但无硝酸盐期会增加心脏对缺血性挑战的敏感性。

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