Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor.
1. This study examines the cardiovascular effects of CAS 1609 (4-hydroxymethyl-furoxan-3-carboxamide) in vitro as well as in vivo in various animal models. 2. CAS 1609 relaxed guinea-pig pulmonary artery strips without endothelium with IC50-values of 0.9 microM (phenylephrine contracted) and 15 microM (KCl-depolarized). This effect was inhibited by oxyhaemoglobin. In these arteries CAS 1609 significantly increased (+192%) guanosine 3':5'-cyclic monophosphate levels, which indicates that the compound acts as a donor of nitric oxide (NO). 3. In the anaesthetized pig, CAS 1609 (0.3-1.0 mg kg-1, i.d.) significantly lowered blood pressure and left ventricular end-diastolic pressure. Left ventricular contractility was slightly reduced and heart rate remained almost unchanged. 4. In anaesthetized dogs, i.v. or i.d. administration of CAS 1609 (0.3-3.0 mg kg-1) decreased, in a dose-related fashion, preload and afterload of the heart, cardiac output, left ventricular work and myocardial oxygen consumption. This haemodynamic profile is similar to that of known NO-donors. 5. In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3 mg kg-1, i.v.) improved the haemodynamic condition and reduced mortality by 80%. 6. In conscious dogs, oral treatment with a dose of 0.5 mg kg-1 given twice daily at 07 h 00 min and 19 h 00 min (each dose had a duration of action > or = 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug. 7. All these data indicate that CAS 1609 is a potent, long-lasting orally active donor of NO, devoid of tolerance development.
Bohn
H
H
Department of Pharmacology, Cassella AG, Frankfurt/Main, Germany.
Brendel
J
J
Martorana
P A
PA
Schönafinger
K
K
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D008863:Microspheres; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology*; D010101:Oxygen Consumption; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C094475:4-hydroxynethyl-furoxan-3-carboxamide; D010069:Oxadiazoles; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine