Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor

Abstract

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. CAS 1609 relaxed guinea‐pig pulmonary artery strips without endothelium with IC50‐values of 0.9 μm (phenylephrine contracted) and 15 μ (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). 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. 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. In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3mgkg−1, i.v.) improved the haemodynamic condition and reduced mortality by 80%. 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 ≤ 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug. All these data indicate that CAS 1609 is a potent, long‐lasting orally active donor of NO, devoid of tolerance development. 1995 British Pharmacological Society