ICI-D7288, A NOVEL SINOATRIAL NODE MODULATOR

We evaluated the cardiovascular effects of the sinoatrial (SA) node mo dulating agent, ICI D7288, in guinea pig isolated atria and SA node, a naesthetised and exercising dogs, and conscious rats. ICI D7288 (0.1-1 00 muM) caused a reduction in spontaneous beating rate in guinea pig i solated right atria without affecting the contractile force of paced l eft atria. The effect was associated with a reduction in the rate of d iastolic depolarisation recorded intracellularly from pacemaker cells in the SA node. In anaesthetised dogs, ICI D7288 (0.02-1 mg/kg intrave nously, i.v.) caused a dose-related reduction in heart rate (HR) witho ut directly affecting left ventricular (LV) contractility. Exercise ta chycardia 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 e xercise was well maintained unless the tachycardia was reduced by >30% , when it was attenuated. Administration of ICI D7288 p.o. (3-100 mg/k g) 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 is chaemic heart disease to reduce increased HR without impairing cardiac function.