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。耐硝酸甘油(NG)的降压作用可阻止兔快速心室起搏(RVP)诱导的预处理。在目前的工作中,在有意识的兔子中研究了经皮硝酸甘油连续或间歇治疗对起搏诱发的预适应现象的影响。 2. RVP(5分钟内每分钟5次搏动)使左心室舒张末期压力(LVEDP)从基线4.1 /-0.9增加到后起搏13.8 /-2.9 mmHg(P <0.001),并且右室ST段抬高。 1.25 /-0.13 mV,是心肌缺血的两个指标。当在RVP周期之前以5分钟的间隔间隔进行相同速度和持续时间的预适应性起搏后,这些变化会大大减弱。 3.当通过在7天内施用透皮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,取消了通过预处理的保护。此外,在7天内,透皮NG本身减弱了RVP诱导的ST段升高和LVEDP升高。 4.间歇性经皮NG治疗(12小时“贴片”与“贴片”),既未观察到血管耐受性的发展,也未观察到NG或预处理引起的抗局部缺血作用的减弱。但是,起搏期间,起搏诱发的心肌缺血的严重程度显着增加。 5.在第二组实验中,通过放射免疫测定法在具有相同NG处理方案的经慢性麻醉的开胸兔中测定心脏循环GMP和循环AMP水平的起搏变化。预处理可以减少循环AMP的起搏后增加,同时在“贴片”和“贴片”期间间歇地给未治疗的动物的心脏和那些间歇给予贴片的动物增加心脏中的循环GMP浓度。然而,在耐受性动物中,对任一环状核苷酸的预处理作用均被阻断。 6.经皮NG增加了非耐受性但非耐受性状态下两个心脏环状核苷酸的静息水平。循环AMP含量的起搏后增加受透皮NG抑制,与血管耐受性的发展无关,而环状GMP含量仅在非耐受性动物中可见。 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。间歇性NG治疗可防止血管耐受性发展并保留预处理,而无硝酸盐治疗期则增加了心脏对缺血性疾病的敏感性。

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