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 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.
Department of Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, collegeville, PA, USA.
L
L
De Garavilla
E D
ED
Pagani
R A
RA
Buchholz
R
R
Dundore
D C
DC
Bode
M L
ML
Volberg
K N
KN
Jackson
P
P
Pratt
P J
PJ
Silver
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D005996:Nitroglycerin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D011688:Purinones; D014665:Vasodilator Agents; D004176:Dipyridamole; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D005996:Nitroglycerin; C011145:zaprinast; D006152:Cyclic GMP