title: A comparison of three phosphodiesterase type III inhibitors on mechanical and metabolic function in guinea pig isolated hearts.
abstract: Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.
authors.affiliation: Department of Anaesthesia, ZARI, University of Goettingen, Goettingen, Germany. yzausig@zari.de
authors.forename: York A
authors.initials: YA
authors.lastname: Zausig
authors.forename: David F
authors.initials: DF
authors.lastname: Stowe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zink
authors.forename: Christoph
authors.initials: C
authors.lastname: Grube
authors.forename: Eike
authors.initials: E
authors.lastname: Martin
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Graf
mesh_terms: D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017335:Enoximone / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D020105:Milrinone / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D017335:Enoximone; D020105:Milrinone; D000676:Amrinone