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.