Direct myocardial anti-ischaemic effect of GTN in both nitrate-tolerant and nontolerant rats:: a cyclic GMP-independent activation of KATP

1 We have recently demonstrated that glyceryl trinitrate (GM) exerts a direct myocardial antiischaemic effect in both GTN-tolerant and nontolerant rats. Hers we examined if this effect is mediated by GTN-derived nitric oxide (NO) and involves guanosine 3'5' cyclic monophosphate (cyclic GMP) and ATP-sensitive K+ channels (K-ATP). 2 Rats were treated with 100 mg kg(-1) GTN or vehicle s.c, three times a day for 3 days to induce vascular GTN-tolerance or nontolerance. Isolated working hearts obtained from either GTN-tolerant or nontolerant rats were subjected to 10 min coronary occlusion in the presence of 10(-7) M GTN or its solvent. 3 GTN improved myocardial function and reduced lactate dehydrogenase (LDH) release during coronary occlusion in both GTN-tolerant and nontolerant hearts. 4 Cardiac NO content significantly increased after GTN administration in both GTN-tolerant and nontolerant hearts as assessed by electron spin resonance. However, cardiac cyclic GMP content measured by radioimmunoassay was not changed by GTN administration. 5 When hearts from both GTN-tolerant and nontolerant rats were subjected to coronary occlusion in the presence of the K-ATP-blocker glibenclamide (10(-7) M), the drug itself did not affect myocardial function and LDH release, however, it abolished the anti-ischaemic effect of GTN. 6 We conclude that GTN opens K-ATP via a cyclic GMP-independent mechanism, thereby leading to an anti-ischaemic effect in the heart in both GTN-tolerant and nontolerant rats.