Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Jun;89(6):2060–2065. doi: 10.1172/JCI115818

Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic, coronary-perfused heart.

I Amende 1, L A Bentivegna 1, A J Zeind 1, P Wenzlaff 1, W Grossman 1, J P Morgan 1
PMCID: PMC295924  PMID: 1602012

Abstract

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

Full text

PDF
2060

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen D. G., Orchard C. H. Intracellular calcium concentration during hypoxia and metabolic inhibition in mammalian ventricular muscle. J Physiol. 1983 Jun;339:107–122. doi: 10.1113/jphysiol.1983.sp014706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amende I., Simon R., Hood W. P., Jr, Hetzer R., Lichtlen P. R. Intracoronary nifedipine in human beings: magnitude and time course of changes in left ventricular contraction/relaxation and coronary sinus blood flow. J Am Coll Cardiol. 1983 Dec;2(6):1141–1145. doi: 10.1016/s0735-1097(83)80341-6. [DOI] [PubMed] [Google Scholar]
  3. Apstein C. S., Deckelbaum L., Hagopian L., Hood W. B., Jr Acute cardiac ischemia and reperfusion: contractility, relaxation, and glycolysis. Am J Physiol. 1978 Dec;235(6):H637–H648. doi: 10.1152/ajpheart.1978.235.6.H637. [DOI] [PubMed] [Google Scholar]
  4. Blinks J. R., Wier W. G., Hess P., Prendergast F. G. Measurement of Ca2+ concentrations in living cells. Prog Biophys Mol Biol. 1982;40(1-2):1–114. doi: 10.1016/0079-6107(82)90011-6. [DOI] [PubMed] [Google Scholar]
  5. Clark R. E., Christlieb I. Y., Henry P. D., Fischer A. E., Nora J. D., Williamson J. R., Sobel B. E. Nifedipine: a myocardial protective agent. Am J Cardiol. 1979 Oct 22;44(5):825–831. doi: 10.1016/0002-9149(79)90204-2. [DOI] [PubMed] [Google Scholar]
  6. De Jong J. W., Huizer T., Tijssen J. G. Energy conservation by nisoldipine in ischaemic heart. Br J Pharmacol. 1984 Dec;83(4):943–949. doi: 10.1111/j.1476-5381.1984.tb16535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Henry P. D., Schuchleib R., Davis J., Weiss E. S., Sobel B. E. Myocardial contracture and accumulation of mitochondrial calcium in ischemic rabbit heart. Am J Physiol. 1977 Dec;233(6):H677–H684. doi: 10.1152/ajpheart.1977.233.6.H677. [DOI] [PubMed] [Google Scholar]
  8. Kihara Y., Grossman W., Morgan J. P. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res. 1989 Oct;65(4):1029–1044. doi: 10.1161/01.res.65.4.1029. [DOI] [PubMed] [Google Scholar]
  9. Kihara Y., Morgan J. P. Intracellular calcium and ventricular fibrillation. Studies in the aequorin-loaded isovolumic ferret heart. Circ Res. 1991 May;68(5):1378–1389. doi: 10.1161/01.res.68.5.1378. [DOI] [PubMed] [Google Scholar]
  10. Kusuoka H., Koretsune Y., Chacko V. P., Weisfeldt M. L., Marban E. Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning? Circ Res. 1990 May;66(5):1268–1276. doi: 10.1161/01.res.66.5.1268. [DOI] [PubMed] [Google Scholar]
  11. Lee H. C., Mohabir R., Smith N., Franz M. R., Clusin W. T. Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing indo 1. Correlation with monophasic action potentials and contraction. Circulation. 1988 Oct;78(4):1047–1059. doi: 10.1161/01.cir.78.4.1047. [DOI] [PubMed] [Google Scholar]
  12. Lorell B. H., Apstein C. S., Cunningham M. J., Schoen F. J., Weinberg E. O., Peeters G. A., Barry W. H. Contribution of endothelial cells to calcium-dependent fluorescence transients in rabbit hearts loaded with indo 1. Circ Res. 1990 Aug;67(2):415–425. doi: 10.1161/01.res.67.2.415. [DOI] [PubMed] [Google Scholar]
  13. Marban E., Kitakaze M., Kusuoka H., Porterfield J. K., Yue D. T., Chacko V. P. Intracellular free calcium concentration measured with 19F NMR spectroscopy in intact ferret hearts. Proc Natl Acad Sci U S A. 1987 Aug;84(16):6005–6009. doi: 10.1073/pnas.84.16.6005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nayler W. G., 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 Aug;46(2):242–248. doi: 10.1016/0002-9149(80)90064-8. [DOI] [PubMed] [Google Scholar]
  15. Steenbergen C., Murphy E., Levy L., London R. E. Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ Res. 1987 May;60(5):700–707. doi: 10.1161/01.res.60.5.700. [DOI] [PubMed] [Google Scholar]
  16. Steenbergen C., Murphy E., Watts J. A., London R. E. Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res. 1990 Jan;66(1):135–146. doi: 10.1161/01.res.66.1.135. [DOI] [PubMed] [Google Scholar]
  17. Watts J. A., Maiorano L. J., Maiorano P. C. Comparison of the protective effects of verapamil, diltiazem, nifedipine, and buffer containing low calcium upon global myocardial ischemic injury. J Mol Cell Cardiol. 1986 Mar;18(3):255–263. doi: 10.1016/s0022-2828(86)80407-2. [DOI] [PubMed] [Google Scholar]
  18. Watts J. A., Maiorano L. J., Maiorano P. C. Protection by verapamil of globally ischemic rat hearts: energy preservation, a partial explanation. J Mol Cell Cardiol. 1985 Aug;17(8):797–804. doi: 10.1016/s0022-2828(85)80041-9. [DOI] [PubMed] [Google Scholar]
  19. Watts J. A., Whipple J. P., Hatley A. A. A low concentration of nisoldipine reduces ischemic heart injury: enhanced reflow and recovery of contractile function without energy preservation during ischemia. J Mol Cell Cardiol. 1987 Aug;19(8):809–816. doi: 10.1016/s0022-2828(87)80391-7. [DOI] [PubMed] [Google Scholar]
  20. Weisfeldt M. L., Armstrong P., Scully H. E., Sanders C. A., Daggett W. M. Incomplete relaxation between beats after myocardial hypoxia and ischemia. J Clin Invest. 1974 Jun;53(6):1626–1636. doi: 10.1172/JCI107713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. de Jong J. W., Huizer T. Reduced glycolysis by nisoldipine treatment of ischemic heart. J Cardiovasc Pharmacol. 1985 May-Jun;7(3):497–500. doi: 10.1097/00005344-198505000-00013. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES