The reduction of myocardial damage and leukocyte polymorphonuclear accumulation following coronary artery occlusion by the tyrosine kinase inhibitor tyrphostin AG 556

Domenica Altavilla, Francesco Squadrito, Giuseppe M. Campo, Antonino Saitta, Giovanni Squadrito, Cristina Quartarone, Barbara Deodato, Mariarita Arlotta, Marcella Ferlito, Letteria Minutoli, Michelangelo Tringali, Giuseppe Urna, Aurora Sardella, Achille P. Caputi

Research output: Contribution to journalArticle

Abstract

We investigated the effects of tyrphostin AG 556, a tyrosine kinase inhibitor, on the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Male anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK) serum Tumor Necrosis Factor (TNF-α) and Interleukin 6 (IL-6), cardiac intercellular adhesion molecule-1 (ICAM-1) and TNF-α expression and myocardial contractility (left ventricle dP/dt(max) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity (196.5 ± 19 U/100 ml, at the end of reperfusion) and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area-at-risk (4.5 ± 0.5 U/g/tissue) and in necrotic area (8.2 ± 1.2 U/g/tissue), reduced myocardial contractility (1,706 ± 52 mmHg/s, at the end of reperfusion) and induced a marked increase in the serum levels of TNF-α (1,950 ± 97 pg/ml, at 1 h of reperfusion) and IL-6 (998 ± 16 U/ml, at the end of reperfusion). Finally, myocardial ischaemia-reperfusion injury also increased cardiac mRNA for TNF-α and ICAM-1 in the myocardium-at risk. Tyrphostin AG 556 (0.5, 1 and 2 mg/kg subcutaneously 5 min after the onset of reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk (1.5 ± 0.2 U/g/tissue, following the highest dose) and in necrotic area (2.9 ± 0.3 U/g/tissue following the highest dose), decreased serum CPK activity (96 ± 9 U/100 ml, at the end of reperfusion), lowered serum TNF-α and IL-6, increased myocardial contractility (2,096 ± 88 mmHg s, at the end of reperfusion) and reduced cardiac mRNA levels for TNF-α and ICAM-1. The present data suggest that tyrosine kinase inhibitors protect against myocardial ischaemia-reperfusion injury by reducing leukocyte accumulation to the ischaemic myocardium. (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)2615-2629
Number of pages15
JournalLife Sciences
Volume67
Issue number21
DOIs
StatePublished - Oct 13 2000

Keywords

  • ICAM-1
  • Myocardial ischaemia reperfusion injury
  • Tyrphostin AG 556

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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  • Cite this

    Altavilla, D., Squadrito, F., Campo, G. M., Saitta, A., Squadrito, G., Quartarone, C., Deodato, B., Arlotta, M., Ferlito, M., Minutoli, L., Tringali, M., Urna, G., Sardella, A., & Caputi, A. P. (2000). The reduction of myocardial damage and leukocyte polymorphonuclear accumulation following coronary artery occlusion by the tyrosine kinase inhibitor tyrphostin AG 556. Life Sciences, 67(21), 2615-2629. https://doi.org/10.1016/S0024-3205(00)00845-6