L-arginine in the development and reversal of tolerance to nitroglycerin

Nitroglycerin (GTN) and sodium nitroprusside (SNP) have different vasodilator profiles and tolerance is evident clinically only with GTN. Our purpose was to determine mechanistic differences between these two agents and any relationship of differences to the development of tolerance. Tolerance to the relaxation of rat aortic rings to GTN was evident after 2 hours of exposure to GTN followed by a 1 hr drug free interval. The ability of L-arginine to reverse tolerance to GTN was determined. Tissue content of L-arginine was assayed before and after exposure to GTN for 2 hours. Concentration-relaxation curves were constructed for GTN with and without L-arginine. cGMP production was measured in aortic rings. Tolerance developed in aorta incubated with GTN as evident by a 71 fold rightward shift of the dose response curve. This shift was associated with a 40% reduction in L-arginine tissue levels. Adding L-arginine to aortic tissue was associated with a significant reduction in rightward shift (9 × fold). SNP induced tolerance immediately after 2hr exposure, but responses normalized over a 1 hr drug free period. Addition of GTN to stimulate production of cGMP revealed that L-arginine potentiated the action of GTN. In summary, L-arginine reverses tolerance to GTN in isolated vascular tissues. The actions of GTN are dependent on L-arginine which decreases in tissues at the point of development to tolerance to GTN. The mechanism by which GTN depletes L-arginine is being investigated.