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

• Published in: British journal of pharmacology Vol. 114; no. 8; pp. 1605 - 1612
• Main Authors: Bohn, Helmut, Brendel, Joachim, Martorana, Piero A., Schönafinger, Karl
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-1995; Nature Publishing
• Subjects: Administration, Oral; Animals; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Blood Pressure - drug effects; cardiovascular effects in dog; cardiovascular effects in pig; Cardiovascular system; CAS 1609; Dogs; Dose-Response Relationship, Drug; Female; furoxan; Guinea Pigs; haemodynamics; heart failure; Heart Rate - drug effects; Hemodynamics - drug effects; Injections, Intravenous; Male; Medical sciences; Microspheres; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; Nitric Oxide - metabolism; NO donor; Oxadiazoles - pharmacology; Oxygen Consumption; Pharmacology. Drug treatments; pulmonary artery; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Time Factors; tolerance; Vasoconstriction - drug effects; Vasodilation - drug effects; Antianginal agent; Heart failure; Vasodilator agent; Intravenous administration; Treatment efficiency; Oral administration; Cardiovascular disease; In vitro; Biological activity; In vivo; Chemotherapy; Heart disease; Animal; Nitrogen monoxide; Intraduodenal administration; Endothelium derived relaxing factor; Acquired tolerance
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb14946.x

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 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).
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 (0.3mgkg−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 ≤ 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.