title: Positive inotropic effects of milrinone, sulmazole and AR-L100 on isolated normal and infarcted hearts of the rat.
abstract: The recent development of new positive inotropic agents, such as milrinone, sulmazole and AR-L100 might provide new insights for the treatment of congestive heart failure. Although it has been reported that milrinone and sulmazole have cardiac phosphodiesterase III inhibiting properties, the pharmacological action of these drugs cannot be explained by these mechanisms alone. Despite the presence of cardiac phosphodiesterase III in the rat, the effect of milrinone on the rat heart has been reported to be small or even absent. In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction. A perfused heart preparation was used to assess the direct positive inotropic effect of milrinone, sulmazole and AR-L100 as well as their effect on isoprenaline-evoked increase of contractile force. The increase in left ventricular systolic pressure (LVP) in hearts of control animals amounted to 42.0 +/- 3.9 mm Hg, 18.2 +/- 2.4 mm Hg and 8.0 +/- 1.7 mm Hg for AR-L100, milrinone and sulmazole, respectively. The average initial LVP was 70.4 +/- 5.3 mm Hg. In infarcted hearts, the increase in LVP was 25.5 +/- 5.9 mm Hg, 12.6 +/- 2.3 mm Hg and 6.7 +/- 1.2 mm Hg for AR-L100, milrinone and sulmazole, respectively. In infarcted hearts, the average initial LVP was 38.6 +/- 1.6 mm Hg. These data show that these drugs have positive inotropic effects on rat hearts, although the effects of milrinone and AR-L100 on hearts from myocardial infarcted rats are smaller. However, interaction studies with isoprenaline showed a stronger potentiating effect of milrinone and sulmazole in infarcted hearts than in control hearts. Only in this respect sulmazole was more active than milrinone, while AR-L100 had no potentiating effect at all. These results suggest that milrinone and sulmazole are effective agents in conditions where higher levels of circulating catecholamines exist. Therefore, they might be particularly effective in the treatment of congestive heart failure.
authors.affiliation: Department of Biomedical Pharmacy, Faculty of Pharmacy, University of Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Verrijk
authors.forename: W
authors.initials: W
authors.lastname: Vleeming
authors.forename: H H
authors.initials: HH
authors.lastname: van Rooij
authors.forename: J
authors.initials: J
authors.lastname: Wemer
authors.forename: A J
authors.initials: AJ
authors.lastname: Porsius
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000503:physiopathology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; C029759:AR-L 100 BS; C029758:sulmazole; D020105:Milrinone; D007545:Isoproterenol