Effects of Zeneca ZD7288 in comparison with alinidine and UL-FS 49 on guinea pig sinoatrial node and ventricular action potentials.
ZENECA ZD7288 (4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino) pyrimidium chloride) is a novel compound which we compared with alinidine and UL-FS 49 (zatebradine) in guinea pig sinoatrial node (SAN) and papillary muscle preparations, using conventional microelectrode techniques. At low concentrations (1 x 10(-8)-1 x 10(-6) M), ZD7288 caused slowing of the diastolic depolarisation rate of SAN pacemaker cells, thus prolonging the diastolic interval and slowing the beating rate. Alinidine and UL-FS 49 also had qualitatively similar effects on diastolic depolarisation rate, but ZD7288 caused least prolongation of the action potential duration (APD) of SAN cells at the concentrations that had "selective bradycardic actions." ZD7288 affected the APs of ventricular cells in guinea pig papillary muscle only at relatively high concentrations (3 x 10(-6)M-1 x 10(-4) M), which reduced plateau potential duration, although total APD was less affected. Reduced force of contraction (FOC) was also observed at these high concentrations; significant effects on AP Vmax were noted only at concentrations > or = 3 x 10(-5)M. Alinidine also had negative inotropic effects on papillary muscle, but its effects were noted at concentrations similar to those with bradycardic actions; in contrast, UL-FS 49 had marked positive inotropic actions and also increased ventricular APD within the bradycardic concentration range. These data provide a basis for the selective actions of ZD7288 on heart rate (HR).
Briggs
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Cardiovascular Research Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, England.
BoSmith
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Heapy
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology; D012849:Sinoatrial Node / Q000187:drug effects*
D001552:Benzazepines; D002317:Cardiovascular Agents; D011743:Pyrimidines; C082246:ICI D2788; C022192:alinidine; D003000:Clonidine; C043636:zatebradine