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 microM) 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 < or = 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.
Marshall
P W
PW
ICI Pharmaceuticals, Bioscience Department II, Macclesfield, Cheshire, England.
Rouse
W
W
Briggs
I
I
Hargreaves
R B
RB
Mills
S D
SD
McLoughlin
B J
BJ
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D005082:Physical Exertion / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012849:Sinoatrial Node / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects
D002316:Cardiotonic Agents; D011743:Pyrimidines; C082246:ICI D2788