Doxofylline, an adenosine-nonblocking xanthine, does not induce cardiostimulant effects

Abstract

Doxofylline (ANSIMAR) is a new adenosine-nonblocking anti-asthmatic drug with potent bronchodilator activity that does not display the typical extrapulmonary side effects of theophylline--a potent adenosine antagonist. The cardiac activity of doxofilline and theophylline was investigated in guinea pig right and left atrial preparations and in anestetized cat. In spontaneously beating right atria doxofylline slightly increased the atrial rate only at 0.3 mM, while theophylline induced a concentration-dependent positive chronotropic effect starting at 0.03 mM. The contractile force of electrically stimulated left atria was affected by doxofylline starting at 0.3 mM. Theophylline induced the same effect already at 0.03 mM. In the anesthetized cat, doxofylline (1-30 mg/kg.i.v.) did not affect the diastolic blood pressure, but the heart rate increased slightly at a dose of 30 mg/kg i.v. On the contrary, theophylline induced a marked dose-dependent hypotensive and positive chronotropic effect. Doxofylline was 10 times less potent that theophylline is its ability to antagonize the cardiodepressant activity induced by adenosine in isolated guinea pig atria. The pharmacodynamic differences between doxofylline and theophylline may bring new insights to the understanding of the mechanisms underlying the positive chronotropic effects of xanthines, and the functional importance of endogenous adenosine. Additionally, the lack of cardiostimulant effects makes doxofylline highly suitable for the treatment of chronic obstructive lung disease particularly in combination with beta 2-adrenergic agonists.