title: Beneficial effects of felodipine on myocardial and coronary function during low-flow ischemia and reperfusion.
abstract: An acute coronary occlusion causes severe low-flow ischemia in the occluded region. Calcium antagonists have the potential to reduce the rate of ischemic injury by decreasing myocardial oxygen demand, as well as by other mechanisms, especially when given prior to the onset of ischemia. However, their clinical use may be limited by their negative inotropic effects. The purpose of this study was to assess the effects of felodipine as a potentially protective agent against myocardial ischemia and reperfusion injury, independent of any negative inotropic actions, when given after the onset of low-flow ischemia. Isolated isovolumic (balloon-in-LV), blood-perfused rabbit hearts, paced at a constant heart rate, were subjected to 90 minutes of low-flow ischemia at a coronary perfusion pressure of 10 mmHg, which reduced coronary blood flow to 22-24% of baseline. After 15 minutes of low-flow ischemia, hearts received 2 x 10(-6) M felodipine (n = 7) or no drug (controls, n = 8). Felodipine was given until 15 minutes of reperfusion. During low-flow ischemia both groups of hearts had identical coronary blood flow, heart rate, left ventricular (LV) developed pressure, lactate production, and O2 consumption. However, felodipine markedly protected against ischemic diastolic dysfunction. At the end of low-flow ischemia, LV end-diastolic pressure (LVEDP) had increased from 10 +/- 1 to 28 +/- 5 mmHg in the felodipine group, while in the controls LVEDP increased to 48 +/- 8 mmHg (p < 0.05). During 30 minutes of reperfusion, felodipine had a beneficial effect upon coronary blood flow (initial postischemic hyperemia 245 +/- 38% of baseline in the felodipine group vs. 124 +/- 18% in the controls; p < 0.01) Felodipine markedly improved the recovery of contractile function [LV developed pressure recovered from a baseline of 104 +/- 4 to 75 +/- 6 mmHg (72%) in the felodipine group vs. 34 +/- 10 mmHg (32%) in the control group; p < 0.01], as well as diastolic function (LVEDP = 25 +/- 4 mmHg in the felodipine group vs. 61 +/- 10 mmHg in the controls; p < 0.05), and ATP levels (8.5 +/- 1.4 mumoles/g d.w. in the felodipine group vs. 3.9 +/- 1.4 mumoles/g d.w. in the control group, p < 0.05). Felodipine, given after the onset of low-flow ischemia, protects the myocardium during both ischemia and reperfusion by mechanisms other than reducing myocardial oxygen demand.
authors.affiliation: Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Bernstein
authors.forename: F R
authors.initials: FR
authors.lastname: Eberli
authors.forename: A M
authors.initials: AM
authors.lastname: Silverman
authors.forename: G L
authors.initials: GL
authors.lastname: Horowitz
authors.forename: C S
authors.initials: CS
authors.lastname: Apstein
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015736:Felodipine / Q000494:pharmacology* / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D015736:Felodipine; D010100:Oxygen