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 pre conditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatmen t 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 i ndicators of myocardial ischaemia. These changes were significantly at tenuated 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 mu g kg(-1) NG by the a pplication of transdermal NG (approx. 0.07 mg kg(-1) h(-1)) over 7 day s. Furthermore, transdermal NG per se attenuated both RVP-induced ST-s egment elevation and LVEDP-increase over the 7 day period. 4 With inte rmittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), ne ither 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 experi ments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrument ed anaesthetized open-chest rabbits with the same NG-treatment protoco ls. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated anima ls and in those given patches intermittently during both 'patch on' an d 'patch off' periods. However, the preconditioning effect on either c yclic nucleotide was blocked in the tolerant animals. 6 Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the no n-tolerant but not in the tolerant state. The postpacing increase in c yclic AMP content was inhibited by transdermal NG, independent of vasc ular tolerance development, whereas, an increase in 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 mecha nism in the tolerant state. While intermittent NG therapy prevents dev elopment of vascular tolerance and preserves preconditioning, the nitr ate-free periods yield an increased susceptibility of the heart to isc haemic challenges.