Summary
To assess whether the administration of felodipine protects the myocardium in a dose-dependent manner against ischemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of felodipine: 10-10, 10-9, and 10-8 M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP), and calcium were determined. The occurrence of oxidative stress during ischemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutathione. Treatment with felodipine at 10-10 and 10-9 M had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 ± 2.6 to 30.0 ± 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of developed pressure was 100% at 10-8 M, 55% at 10-9 M, and 46% at 10-10 M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also significantly reduced. The effects of felodipine were dose dependent. Felodipine inhibited the initial rate of ATP-driven calcium uptake but failed to affect the initial rate of mitochondrial calcium transport. It is concluded that felodipine infusion provides dose-dependent protection of the heart against ischemia and reperfusion. Because this protection also occurred at 10-9 M and 10-10 M in the absence of a negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy-sparing effect or to improvement in oxygen delivery. From our data we can envisage two other major mechanisms—(1) membrane protection and (2) reduction in oxygen toxicity. The ATP-sparing effect occurring at 10-8 M is likely to be responsible for the further protection.
Similar content being viewed by others
References
Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987;59:84B-89B.
Nayler WG. Calcium antagonists and the ischaemic myocardium. Int J Cadiol 1987;15: 267–274.
Opie LH. Calcium channel antagonists, part I: Fundamental properties: Mechanisms, classification, sites of action. Cardiovasc Drugs Ther 1987;1:411–430.
Kirkels JH, Ruigrok TJC, VanEchteld CJA, Meijler FL. Protective effect of pretreatment with the calcium antagonist anipamil on the ischaemic-reperfused rat myocardium: A phosphorus-31 nuclear magnetic resonance study. J Am Coll Cardiol 1988;2:1087–1093.
Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischaemic myocardium: Results of the NHLBI cooperative study comparison of unconscious and conscious dog models. Circ Res 1985;56:651–655.
Klein HH, Schubothe M, Nebendahl K, Kruezer H. The effects of two different treatments with diltiazem on infarct size in ischaemic, reperfused porcine hearts. Circulation 1984;69:1000–1005.
DeJong JW, Huizer T. Reduced glycolysis by nisoldipine treatment of ischaemic heart. J Cardiovasc Pharmacol 1985;7:497–500.
Lavanchy N, Martin J, Rossi A. Effects of diltiazem on the energy metabolism of the isolated rat heart submitted to ischemia: A phosphorus-31 nuclear magnetic resonance study. J Mol Cell Cardiol 1986;18:931–941.
Hoff PY, Tamura Y, Lucchesi BR. Cardioprotective effects of amlodipine in the ischemic-reperfused hearts. Am J Cardiol 1989;64:1011–1019.
Drake-Holland AJ, Noble MIM. Myocardial protection by calcium antagonist drugs. Eur Heart J 1983;4:823–825.
Ferrari R, Boffa GM, Ceconi C, et al. Effect of D-600 on ischemic and reperfused rabbit myocardium: Relation with timing and modality of administration. Basic Res Cardiol 1989;84:606–622.
Chaudhry A, Vohra MM. Depletion of cardiac noradrenaline stores by the calcium-channel blocker D-600. Can J Physiol Pharmacol 1984;62:640–644.
Brezinski ME, Darius H, Lefer AM. Cardioprotective action of a new calcium channel blocker in acute myocardial ischaemia. Drug Res 1986;36:464–466.
Higgins AJ, Blackburn KJ. Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists. J Mol Cell Cardiol 1984;16:427–438.
Dunselman PHJM, Kuntze CEE, VanBruggen A, et al. Efficacy of felodipine in congestive heart failure. Eur Heart J 1980;10:354–364.
Sangiorgio P, DiPasquale G, Savonitto S, et al. Felodipine in chronic stable angina: A randomized, double-blind, placebo-controlled, cross-over study. Eur Heart J 1990;10: 1011–1017.
Agostoni P, Doria E, Riva S, Polese A. Acute and chronic efficacy of felodipine in congestive heart failure. Int J Cardiol 1991;30:89–95.
Fariello R, Boni E, Corda L, et al. Extended release felodipine in essential hypertension. Variations in blood pressure during whole-day continuous ambulatory recording. Am J Hypertens 1991;4:27–33.
Wester A, Lorimer AR, Westberg B. Felodipine extended release in mild to moderate hypertension. Curr Med Res Opin 1991;12:275–281.
Ferrari R, Curello S, Ceconi C, Cargnoni A, Pasini E, Visioli O. Cardioprotection by nisoldipine: Role of timing of administration. Eur Heart J 1993;14:1258–1272.
Ferrari R, Ceconi C, Curello S, et al. Oxygen mediated myocardial damage during ischaemia and reperfusion: Role of the cellular defences against oxygen toxicity. J Mol Cell Cardiol 1985;17:937–945.
Oliver TA. A spectrophotometric method for the determination of creatine phosphokinase and myokinase. Biochem J 1955;61:116–122.
Ceconi C, Condorelli E, Quinzanini M, Rodella A, Ferrari R, Harris P. Effect of cardiac failure in rats on myocardial concentrations of noradrenaline and on atrial ANP-bombesin and neurotensin-like immunoreactivity. Adv Myochem 1987;1:428–429.
Tietze F. Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Application to mannalian blood and other tissue. Anal Biochem 1969;27:502–522.
Ferrari R, Williams AJ. The role of mitochondria in myocardial damage occurring on post-ischaemic reperfusion. J Appl Cardiol 1986;1:501–519.
Sordahl LA, McCollum WB, Wodd WG, Schwartz A. Mitochondria and sarcoplasmic reticulum function in cardiac hypertrophy and failure. Am J Physiol 1973;244:497–502.
Peng GF, Rane JJ, Murphy ML, Straub KD. Abnormal mitochondrial oxidative phosphorylation of ischaemic myocardium reversed by calcium chelating agents. J Mol Cell Cardiol 1987;9:897–908.
Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle for protein binding. Anal Biochem 1978;72:248–254.
Lamprecht W, Trautschold E. Adenosine-5′-triphosphate determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Methods of Enzymatic Analysis. Bergmeyer HU, ed. New York: Academic Press, 1974:2021–2105.
Reed KL, Bygrave FL. Methodology for in vitro studies of calcium transport. Anal Biochem 1975;67:44–51.
Ferrari R, Boraso A, Cargnoni A, Pasini E, Raddino R, Albertini A. Effects of anipamil on myocardial sarcolemmal and mitochondrial calcium transport, comparison with verapamil and nifedipine. Eur J Pharmacol 1990;189:149–161.
Sillen LS, Martell AE. Stability constants of metal-ions complexes. Chem Soc (Lond) Special Publication, 1981;17.
St. Louis PJ, Sulake PV. Isolation of sarcolemmal membranes from cardiac muscle. Int J Biochem 1976;7:547–583.
Bernocchi P, Ceconi C, Cargnoni A, Pedersini P, Curello S, Ferrari R. Extraction and assay of creatine phosphate, purine and pyridine in cardiac tissue by reversed-phase high-performance liquid chromatography. Anal Biochem 1994;222:374–379.
Sedlack J, Lindsay RH. Estimation of total protein-bound, and on protein sulphydryl groups in tissue Ellman's reagent. Anal Biochem 1968;25:192–205.
Schaper W, Lewi P, Flameng W, Gijpen L. Myocardial steal provided by coronary artery occlusion. Basic Res Cardiol 1973;68:3–20.
Bush LR, Li YP, Shlafer M, Jolly SR, Lucchesi BR. Protective effects of diltiazem during myocardial ischemia in isolated cat hearts. J Pharmacol Exp Ther 1981;218:653–661.
DeJong JW, Huizer T, Tijseen JPG. Energy conservation by nisoldipine in ischaemic heart. Br J Pharmac 1984;83: 943–949.
Holt WW, Wendland MF, Derucin N, Wolfe C, Saeed M, Higgins CB. Effects of nicardipine, a calcium antagonist, on myocardial salvage and high energy phosphate stores in reperfused myocardial injury. J Am Coll Cardiol 1990;16: 1736–1744.
Boraso A, Cargnoni A, Comini L, Gaia G, Bernocchi P, Ferrari R. Effect of lacidipine on ischaemic and reperfused isolated rabbit hearts. Mol Cell Biochem 1993;125:73–86.
Ferrari R, Pedersini P, Bongrazio M, Gaia G, Bernocchi P, DiLisa F, Visioli O. Mitochondrial energy production and cation control in myocardial ischaemia and reperfusion. Basic Res Cardiol 1993;88:495–512.
Henry PD, Shuchleib R, Davis J, Weiss ES, Sobel BE. Myocardial contracture and accumulation of mitochondrial calcium in ischemic rabbit heart. Am J Physiol 1977;233: H677.
Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine, and propranolol on mitochondrial function in the ischemic and reperfused myocardium. Am J Cardiol 1980;46:242–248.
Bourdillon PDV, Poole-Wilson PA. The effects of verapamil, quiescence and cardioplegia on calcium exchange and mechanical function in ischemic rabbit myocardium. Circ Res 1982;50:360–368.
Henry PD, Wahl AM. Diltiazem and nitrendipine suppress hypoxic contracture in quiescent ventricular myocardium. Eur Heart J 1983;4:819–822.
duToit EF, Opie LH. Modulation of severity of reperfusion stunning in the isolated rat heart by agents altering calcium flux at onset of reperfusion. Circ Res 1992;70:960–967.
Park S-W, Tang X-L, Qiu Y, Sun J-Z, Bolli R. Nisoldipine attenuates myocardial stunning induced by multiple coronary occlusions in conscious pigs and this effect is independent of changes in hemodynamics or coronary blood flow. J Mol Cell Cardiol 1996;28:655–666.
Melin JA, Becker LC, Hutchins GM. Protective effect of early and late treatment with nifedipine during myocardial infarction in the conscious dog. Circulation 1984;69: 131–141.
Reibel DK, Rovetto MJ. Myocardial ATP synthesis and mechanical function following oxygen deficiency. Am J Physiol 1978;234:H620-H626.
Opie LH. Post-ischaemic stunning-the case for calcium as the ultimate culprit. Cardiovasc Drugs Ther 1991;5: 895–900.
Opie LH. Proposed role of calcium in reperfusion injury. Int J Cardiol 1989;23:159–164.
Sperelakis N. Cyclic AMP and phosphorylation in regulation of Ca influx into myocardial cells, and blockade by calcium antagonists drugs. Am Heart J 1984;107:347–357.
Nayler WG, Sturrock WJ. Inhibitory effect of calcium antagonists on the depletion of cardiac norepinephrine during post-ischaemic reperfusion. J Cardiovasc Pharmacol 1985; 7:581–587.
Mak II, Beglicki WB. Comparative antioxidant activities of propranolol nifedipine, verapamil and diltiazem against sarcolemmal membrane lipid peroxidation. Circ Res 1990; 66:1449–1452.
Opie LH. Reperfusion injury and its pharmacological modification. Circulation 1989;80:1049–1062.
Hearse DJ. Reperfusion-induced injury: A possible role for oxidant stress and its manipulation. Cardiovasc Drugs Ther 1991;5:225–236.
Author information
Authors and Affiliations
Additional information
Cattedra di Cardiologia, Universita' degli Studi di Brescia
Rights and permissions
About this article
Cite this article
Ferrari, R., Cargnoni, A., Bernocchi, P. et al. Effects of felodipine on the ischemic heart: Insight into the mechanism of cytoprotection. Cardiovasc Drug Ther 10, 425–437 (1996). https://doi.org/10.1007/BF00051107
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00051107