ZAPRINAST, BUT NOT DIPYRIDAMOLE, REVERSES HEMODYNAMIC TOLERANCE TO NITROGLYCERIN IN-VIVO

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 mu g/kg i.v., and ex vivo in isolated, denuded aortic vascula r rings by exposure to ascending concentrations of nitroglycerin of 0. 0003-100 mu M. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Go-incubation o f tolerant aortic rings and pretreatment of tolerant SHR with 10 mu M and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinas t partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 mu M) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/ kg. Following a 100-mu g/kg i.v. challenge dose of nitroglycerin, aort ic cyclic guanosine monophosphate (cGMP) levels were lower in nitrogly cerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP lev els to nitroglycerin to that seen in non-tolerant SHR. Conversely, dip yridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tole rance in vivo is related to restoration of changes in vascular cGMP le vels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effecti vely reverses tolerance and dipyridamole, a rather non-selective inhib itor, does not.