The effect of continuous versus intermittent treatment with transdermal nitroglycerin on pacing-induced preconditioning in conscious rabbits.

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.