ICI-D7288, A NOVEL SINOATRIAL NODE MODULATOR

We evaluated the cardiovascular effects of the sinoatrial (SA) node modulating agent, ICI D7288, in guinea pig isolated atria and SA node, anaesthetised and exercising dogs, and conscious rats. ICI D7288 (0.1-100 muM) caused a reduction in spontaneous beating rate in guinea pig isolated right atria without affecting the contractile force of paced left atria. The effect was associated with a reduction in the rate of diastolic depolarisation recorded intracellularly from pacemaker cells in the SA node. In anaesthetised dogs, ICI D7288 (0.02-1 mg/kg intravenously, i.v.) caused a dose-related reduction in heart rate (HR) without directly affecting left ventricular (LV) contractility. Exercise tachycardia in dogs was reduced by the compound (0.1-1 mg/kg i.v. and 0.3-10 mg/kg orally, p.o.). The increase in cardiac output (CO) during exercise was well maintained unless the tachycardia was reduced by >30%, when it was attenuated. Administration of ICI D7288 p.o. (3-100 mg/kg) to conscious rats reduced HR by less-than-or-equal-to 40%, but had no effects on blood pressure (BP). We suggest that ICI D7288, through its selective effects on the SA node, may be of use in treatment of ischaemic heart disease to reduce increased HR without impairing cardiac function.