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OtherCARDIOVASCULAR PHARMACOLOGY

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 and Dipak K. Das
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1274-1279;
Arpad Tosaki
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Nilanjana Maulik
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Gary T. Elliott
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Ingolf E. Blasig
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Richard M. Engelman
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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.

Footnotes

  • Send reprint requests to: Dipak K. Das, Ph.D., Cardiovascular Div., Dept. of Surgery, University of Connecticut, School of Medicine, Farmington, CT 06030-1110.

  • ↵1 This study was supported in part by National Institutes of Health grants HL 22559, HL 33889 and HL 34360, a Grant-in-Aid from the American Heart Association and a grant from Volkswagen Stiftung, Berlin, Germany as well as by a grant from the RIBI ImmunoChem Research Inc.

  • Abbreviations:
    MLA
    monophosphoryl lipid A
    iNOS
    inducible nitric oxide synthase
    l-NAME
    l-ω-nitro-l-arginine methyl ester
    NO
    nitric oxide
    cDNA
    complementary deoxynucleic acid
    VF
    ventricular fibrillation
    VT
    ventricular tachycardia
    HR
    heart rate
    CF
    coronary flow
    AF
    aortic flow
    LVDP
    left ventricular developed pressure
    LVmaxdp/dt
    maximum first derivative of left ventricular developed pressure
    cGMP
    cyclic guanosine monophosphate
    IFN
    interferon
    LPS
    lipopolysaccharides
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    ECG
    electrocardiogram
    • Received September 29, 1997.
    • Accepted February 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherCARDIOVASCULAR PHARMACOLOGY

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 and Dipak K. Das
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1274-1279;

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OtherCARDIOVASCULAR PHARMACOLOGY

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 and Dipak K. Das
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1274-1279;
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