Preconditioning of rat heart with monophosphoryl lipid A: A role for nitric oxide

Arpad Tosaki, Nilanjana Maulik, Gary T. Elliott, Ingolf E. Blasig, Richard M. Engelman, Dipak K. Das

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Abstract

Preconditioning with monophosphoryl lipid A (MLA) protects rabbit hearts from prolonged ischemic reperfusion injury by a mechanism involving inducible nitric oxide synthase (iNOS) activation. This study was undertaken to determine whether MLA also could precondition rat hearts in a similar manner. Rats were injected with two different doses of MLA (300 μg/kg or 450 μg/kg i.v.) or vehicle (control), and after 24 hr the animals were sacrificed for preparation of isolated perfused rat hearts. Hearts were then perfused by working mode, and then made ischemic for 30 min followed by 30 min of reperfusion. Another group of hearts were treated simultaneously with a nitric oxide (NO) blocker, L-nitro-arginine-methyl-ester (L-NAME) (10 mg/kg) and MLA (450 μg/kg). For arrhythmia studies, 12 hearts were used in each group (total, 48 hearts). Cardiac functions were examined in a separate group of 24 hearts (n = 6/group). MLA-treated hearts (either dose) were tolerant to ischemic reperfusion injury as evidenced by improved postischemic ventricular recovery [coronary flow (ml/min) 19.1 ± 0.8 (300 μg/kg MLA), 22.6 ± 1.0 (450 μg/kg MLA) vs. 15.9 ± 0.7 (control); aortic flow (ml/min) 20.7 ± 1.8 (300 μg/kg MLA), 25.8 ± 1.4 (450 μg/kg MLA) vs. 11.0 ± 0.8 (control); left ventricular developed pressure (kPa) 13.3 ± 0.6 (300 μg/kg MLA), 14.6 ± 0.2 (450 μg/kg MLA) vs. 10.3 ± 0.7 (control)]. Incidences of ventricular fibrillation and ventricular tachycardia were decreased compared with the control group only in the 450 μg/kg dose of MLA-treated hearts (92% to 33%). Pretreatment of the hearts with L-NAME inhibited the preconditioning effect of MLA. To examine the induction of the iNOS expression, RNAs were extracted from the control and MLA-treated hearts (after 2, 4,6, 8, 12 and 24 hr of treatment) and Northern blot analyses were performed with a specific cDNA probe for iNOS. A single band of approximately 4.6 kb corresponding to iNOS mRNA was detected after 4 hr of MLA treatment, whereas the maximal iNOS expression was found between 6 and 8 hr of MLA treatment. The results of this study demonstrated that MLA induced the expression of iNOS and protected the myocardium from ischemic reperfusion injury which is blocked by an inhibitor of NO synthesis, which suggests a role of NO in MLA-mediated cardioprotection.

Original languageEnglish
Pages (from-to)1274-1279
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume285
Issue number3
Publication statusPublished - Jun 1 1998

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Tosaki, A., Maulik, N., Elliott, G. T., Blasig, I. E., Engelman, R. M., & Das, D. K. (1998). Preconditioning of rat heart with monophosphoryl lipid A: A role for nitric oxide. Journal of Pharmacology and Experimental Therapeutics, 285(3), 1274-1279.