Pharmacological actions of SDZ 218-135, a novel positive inotropic agent.
The effects of the new inotropic agent, SDZ 218-135 [(+)-(S)-4-[3-(4-diphenyl-methyl-1-piperazinyl)-2-hydroxy-propyl]- 6-(2-hydroxyethyl)-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidin-7(4H)-one], were investigated using in vitro and in vivo techniques. In isolated rat atria, SDZ 218-135 elicited a dose-dependent increase in contractile force (+50% at 10 microM), which was paralleled by an increase in functional refractory period. In anesthetized rats SDZ 218-135 enhanced left ventricular (+)dP/dtmax by 100% at 10 mg/kg without influencing heart rate, arterial blood pressure, and cardiac output. In contrast to its predecessor, DPI 201-106, cardiac relaxation remained essentially unimpaired. The positive inotropic action was also maintained in a rabbit model of depressed heart function after myocardial infarction, where SDZ 218-135 increased peak acceleration of blood in the aorta. The prolongation of the effective refractory period in rat atria suggested possible antiarrhythmic effects. Indeed, SDZ 218-135 showed a dose-dependent marked reduction in reperfusion arrhythmias after coronary artery occlusion in rats. This effect was most likely due to a Class III action, since SDZ 218-135 significantly increased action potential duration (+10% at 10 microM/l) of the isolated guinea pig papillary muscle. In conclusion, SDZ 218-135 is a novel positive inotropic agent with an interesting profile of action. It does not impair cardiac relaxation and shows antiarrhythmic effects in a model of reperfusion-induced arrhythmias. The in vivo and in vitro data are consistent with a mechanism of action via sodium channel agonism.
Zierhut
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W
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Salzmann
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R
Bormann
G
G
Rüegg
U T
UT
Hof
R P
RP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D010063:Ovum / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; C089933:SDZ 218135; D014230:Triazoles; D000255:Adenosine Triphosphate; C046261:DPI 201-106; D011433:Propranolol; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium