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

We have recently demonstrated that glyceryl trinitrate (GTN) exerts a direct myocardial anti‐ischaemic effect in both GTN‐tolerant and nontolerant rats. Here 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 ). 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. GTN improved myocardial function and reduced lactate dehydrogenase (LDH) release during coronary occlusion in both GTN‐tolerant and nontolerant hearts. 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. 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. 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. British Journal of Pharmacology (1999) 128 , 1427–1434; doi: 10.1038/sj.bjp.0702929