Organ preservation
Improved Myocardial Function After Cold Storage With Preservation Solution Supplemented With a Carbon Monoxide–Releasing Molecule (CORM-3)

https://doi.org/10.1016/j.healun.2007.08.005Get rights and content

Background

Carbon monoxide–releasing molecules (CO-RMs) are pharmacologically active as they protect against cardiac graft rejection and cold ischemia–mediated renal dysfunction. We investigated the cardioprotective role of carbon monoxide (CO) released from CORM-3 against cold ischemia–mediated injury in the heart and evaluated its potential application in the clinical setting of cardiac transplantation.

Methods

Isolated rat hearts underwent cold ischemic storage for 4 or 6 hours using St Thomas Hospital solution that was supplemented with either CORM-3 (50 μmol/liter) or its inactive counterpart (iCORM-3), which does not release CO. Hearts were then reperfused. Both functional parameters and release of cardiac enzymes were assessed.

Results

Addition of CORM-3 to the preservation solution resulted in a significant improvement in systolic and diastolic function as well as coronary flow when compared with hearts treated with iCORM-3. In addition, lower levels of the cardiac enzymes creatine kinase and lactate dehydrogenase were measured in the perfusate of hearts stored with CORM-3.

Conclusions

The improved functional recovery and reduced enzyme release after cardiac cold storage with CORM-3, but not iCORM-3, indicate that CO is the main mediator of myocardial protection. Thus, CO-RMs can be used as adjuvants to improve the preservation of hearts for transplantation.

Section snippets

Reagents

CORM-3 was synthesized as described previously.19 Stock solutions of CORM-3 in distilled water were prepared fresh each day. The inactive counterpart (iCORM-3) was prepared by leaving the solution for 24 hours to liberate its entire CO content, and finally bubbled with nitrogen gas for 5 minutes.19 A creatine kinase (CK) kit was supplied by Alpha Laboratories, UK, and a lactate dehydrogenase (LDH) kit supplied by Roche Applied Science, UK. All other reagents were purchased from Sigma.

Isolated Rat Heart Preparation

All

Results

There were no statistically significant differences in baseline LVDP, coronary flow (CF), dP/dtmax and dP/dtmin among the groups studied. The baseline values from these groups were identical to those obtained with freshly isolated hearts (Table 1), as reported previously.30

Discussion

In this study we have examined the potential effects of a novel bioactive compound that releases controlled amounts of CO (CORM-3) to protect the myocardium against the injury associated with cold ischemic storage and reperfusion. Cold preservation of the heart provides a rapid arrest of cardiac metabolism while maintaining structural viability and limiting reperfusion injury.31 A number of preservation solutions containing a variety of protective components, including inhibitors of free

References (44)

  • R. Motterlini et al.

    Regulation of heme oxygenase-1 by redox signals involving nitric oxide

    Antioxid Redox Signal

    (2002)
  • J.E. Clark et al.

    Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

    Biochem J

    (2000)
  • T.S. Lee et al.

    Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice

    Nat Med

    (2002)
  • I. Petrache et al.

    Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts

    Am J Physiol Lung Cell Mol Physiol

    (2000)
  • R. Foresti et al.

    Generation of bile pigments by heme oxygenase: a refined cellular stratagem in response to stressful insults

    Biochem Soc Symp

    (2004)
  • L.E. Otterbein et al.

    Carbon monoxide provides protection against hyperoxic lung injury

    Am J Physiol

    (1999)
  • R.M. Tyrrell et al.

    The proximal promoter region of the human heme oxygenase gene contains elements involved in stimulation of transcriptional activity by a variety of agents including oxidants

    Carcinogenesis

    (1993)
  • L.E. Otterbein et al.

    Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway

    Nature Med

    (2000)
  • B. Brune et al.

    Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase

    Mol Pharmacol

    (1987)
  • L.E. Otterbein et al.

    Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury

    Nature Med

    (2003)
  • S. Brouard et al.

    Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis

    J Exp Med

    (2000)
  • R. Motterlini et al.

    Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities

    Circ Res

    (2002)
  • Cited by (48)

    • Emerging role of carbon monoxide in intestinal transplantation

      2021, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      The challenges associated with the use of CO gas protocol was partially overcome following the development of CO-RMs. Although there is currently no studies on the use of CO-RMs in intestinal transplantation, there are studies showing salutary effects of various CO-RMs in experimental transplantation of kidney, heart, lung, liver and pancreatic islets [68–72]. These studies should be expanded to cover the use of CO-RMs in intestinal transplantation.

    • Application of carbon monoxide in kidney and heart transplantation: A novel pharmacological strategy for a broader use of suboptimal renal and cardiac grafts

      2021, Pharmacological Research
      Citation Excerpt :

      Besides, the concentration of iCORM (50 μM) used by the authors is lower than what is used in other studies, which suggests its potency. The report by Musameh and colleagues [92] corroborates that of a previous study involving cardiac transplant rejection model in mice, where intraperitoneal administration of donor mice with 10 μM of CORM-3 at 24 h before organ procurement, and in recipient mice 24 h prior to reperfusion followed by 1 h after transplantation and daily administration from post-operative day 1–8 displayed a substantial cardioprotection against the damaging effects of cold IRI, and improved graft quality and prolonged graft survival compared to control group that received 10 μM of iCORM [94]. Further evidence supporting the protection by CO against myocardial IRI was strengthened in a model of IRI using isolated rat hearts.

    • Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

      2016, Translational Research
      Citation Excerpt :

      Finally, applications for CORMs in transplantation models have also been described. For example, in a cardiac transplantation model, inclusion of CORM-3 in the preservation fluid was shown to improve cardiac function after transplantation.319 These examples of salutary effects of CORMs are suggestive of possible therapeutic applications of CORMs in human disease, although more research regarding safety and efficacy of these compounds for human application is needed.

    View all citing articles on Scopus

    Supported by grants from the Foundation for Al-Quds University Medical School and Karim Rida Said Foundation.

    View full text