ITF 296, a new endothelium-independent vasodilator: comparison with nitroglycerin and isosorbide dinitrate.
The effects of a new nitrate ester derivative, ITF 296, on large conductance and small resistance coronary arteries were investigated and compared with those of nitroglycerin and isosorbide dinitrate in chronically instrumented conscious dogs with an intact or with a deendothelialized large coronary artery. In a wide range of doses, ITF 296 (0.3-3 micrograms/kg), nitroglycerin (0.1-0.3 micrograms/kg), and isosorbide dinitrate (0.3-10 micrograms/kg) induced a highly selective dilatation of the large conductance vessels, an effect that was dose-dependent. At 30-fold higher doses, the three drugs also dilated coronary arterioles, an effect that preceded dilatation of large arteries but was transient. Qualitatively, ITF 296 therefore exhibits the same pattern of coronary effects as nitroglycerin and isosorbide dinitrate. Quantitatively, ITF 296 was 6.6-fold less potent than nitroglycerin at dilating large coronary arteries, but its effects on these vessels were of longer duration. Three days after endothelium removal, the vasodilation observed during reactive hyperemia or induced by acetylcholine were almost completely abolished. In contrast, the vasodilating effects of ITF 296 (30-100 micrograms/kg) and nitroglycerin (1 microgram/kg) were not significantly different from those observed before endothelium removal, thus indicating that these two drugs dilate the large conductance coronary arteries through an endothelium-independent mechanism.
Ghaleh
B
B
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin Bicêtre, France.
Dubois-Randé
J L
JL
Hittinger
L
L
Berdeaux
A
A
Giudicelli
J F
JF
D000818:Animals; D048588:Benzoxazines; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009566:Nitrates / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D048588:Benzoxazines; D009566:Nitrates; D010078:Oxazines; D014665:Vasodilator Agents; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate; C091726:sinitrodil