Coronary and systemic hemodynamic effects of the putative nitric oxide donor, FK 409, in comparison with nitroglycerin in conscious and anesthetized dogs.
We compared, the hemodynamic profile of FK 409, a new nitric oxide (NO) donor, directly with that of nitroglycerin (NTG) in chloralose-anesthetized dogs and in chronically instrumented conscious dogs. In anesthetized dogs, FK 409 and NTG (each 0.03-30 micrograms kg-1, intravenously, i.v.) both dilated large and small coronary arteries dose dependently. This coronary vasodilation was associated with dose-dependent decreases in blood pressure (BP), total peripheral resistance (TPR), and left ventricular end-diastolic pressure (LVEDP) and with increases in cardiac output (CO), heart rate (HR) and dP/dtmax. FK 409 was equipotent to NTG in dilating large coronary arteries and in reducing cardiac preload, but three times less potent as systemic and coronary arteriolar vasodilator. In general, the effects of FK 409 developed more slowly and lasted longer than those of NTG. With both drugs, dilation of large coronary arteries was sustained as compared with dilation of systemic or coronary arterioles. In conscious dogs, coronary and systemic hemodynamic effects of FK 409 and NTG (each 0.1-10 micrograms kg-1 i.v.) were qualitatively and quantitatively very similar to those observed in anesthetized dogs, except that reflex tachycardia was more pronounced in animals in the conscious state. Administered orally, FK 409 (0.3 mg kg-1) produced a marked and preferential vasodilation of large coronary arteries but had only minor effects on BP and HR. Coronary blood flow (CBF) was unchanged. FK 409 is an orally active vasodilator with a hemodynamic profile similar to that of NTG. FK 409 exhibits a slightly higher selectivity for large epicardial coronary arteries and has a longer duration of action than NTG.
Drieu la Rochelle
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Preclinical Research Department, Synthélabo Recherche, Bagneux, France.
Lainée
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Grosset
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O'Connor
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SE
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D000959:Antihypertensive Agents; D009574:Nitro Compounds; D014665:Vasodilator Agents; C061872:FK 409; D005996:Nitroglycerin