Mechanical and electrophysiological effects of milrinone on the force-frequency relationship in mammalian myocardium.
Isometric force, action potential and current-voltage relation were studied in guinea-pig and ferret papillary muscles. Milrinone (1 microM) increased peak twitch force by 40 +/- 4%, reduced time to peak tension (TPT) by 12.1 +/- 3% (n = 6, P < 0.01) and reduced time to half relaxation by 17.3 +/- 4.1% (n = 6, P < 0.01). The effect of milrinone was potentiated by rolipram, a RI-PDE inhibitor which in itself had no inotropic effect. After the addition of rolipram peak isometric force was increased by 104 +/- 8% (n = 6, P < 0.001), TPT was further reduced whereas time to half relaxation was slightly increased after the addition of rolipram. Action potential duration at 75% repolarization was decreased by 11 +/- 5 ms (n = 6, P < 0.05). Milrinone also potentiated the second inward current (Isi) by 21 +/- 3.2% (n = 6, P < 0.01). Peak twitch force in response to a test stimulus after an interval, i.e. mechanical restitution was increased at all intervals. The onset of restitution was faster and time to full restitution also shortened. Maximum postextrasystolic potentiation was greater in the presence of milrinone, whereas relative potentiation was smaller in presence of milrinone (46 +/- 7%) than in control (74 +/- 7%). The recirculation fraction of activator calcium was enhanced by milrinone from 0.35 +/- 0.04 to 0.48 +/- 0.07. The results support the view that the positive inotropic effect of milrinone is due to a greater inflow of calcium during the action potential and a more efficient intracellular calcium handling.(ABSTRACT TRUNCATED AT 250 WORDS)
Mörner
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SE
Department of Pharmacology, University of Lund, Sweden.
Arlock
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P
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D005289:Ferrets / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011760:Pyrrolidinones; D020105:Milrinone; D020889:Rolipram; D002118:Calcium