Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models

Mehmet C. Oz, David J. Pinsky, Shin Koga, Hui Liao, Charles C. Marboe, Daying Han, Richard Kline, Valluvan Jeevanandam, Mathew Williams, Alfredo Morales, Sulli Popilskis, Roman Nowygrod, David M. Stern, Eric A. Rose, Robert E. Michler

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background. Cardiac preservation for transplantation disrupts normal vascular homeostatic mechanisms. Hypoxia and reoxygenation increase endothelial cell permeability, induce procoagulant activity, and alter endothelial cell/leukocyte interactions, with a parallel reduction in endothelial cAMP and nitric oxide levels. Because hypoxia/reoxygenation simulates a significant component of the global ischemia/ reperfusion of cardiac transplantation, we hypothesized that preservation failure may be related to these perturbations. This work focuses on repleting the intercellular/intracellular second messengers nitric oxide/cGMP and cAMP in the donor heart to enhance cardiac preservation for transplantation. Methods and Results. A heterotopic rat heart transplant mode was used to compare lactated Ringer's (LR) and University of Wisconsin (UW) solutions to a novel storage solution (Columbia University solution, CU), which contains a cAMP analogue (dibutyryl cAMP) and nitroglycerin (to enhance nitric oxide-related mechanisms). By 24 to 28 hours of preservation, no LR hearts survived (n=9), 35% of UW hearts survived (n=20), and 88% of CU-preserved hearts survived (n=8; P<.05 versus LR or UW). The viability of preserved hearts was explored by determining whether CU preservation enabled myocytes to maintain resting membrane potentials and preserve their ability to generate an action potential in response to a field stimulus. Of 24 sites explored with a microelectrode in UW-preserved hearts, only 4% were able to generate an action potential, compared with 75% of 36 sites in CU-preserved hearts (P<.001), with corresponding preservation of resting membrane potential in the CU-preserved hearts (-13 mV for UW versus -54 mV for CU, P<.001). Orthotopic baboon cardiac transplantation performed after 24-hour simple hypothermic preservation demonstrated that no UW-preserved heart (n=4) survived the perioperative period; in contrast, four of five hearts stored for 24 hours in CU solution sustained the recipient with minimal inotropic support, and two animals survived long-term. Conclusions. Sustaining higher levels of intercellular/intracellular second messengers cAMP and nitric oxide/cGMP provides a new approach to enhancing cardiac preservation.

Original languageEnglish (US)
Pages (from-to)291-297
Number of pages7
JournalCirculation
Volume88
Issue number5 PART 2
StatePublished - Nov 1993
Externally publishedYes

Fingerprint

Papio
Transplants
Heart Transplantation
Nitric Oxide
Second Messenger Systems
Membrane Potentials
Action Potentials
Perioperative Period
Nitroglycerin
Microelectrodes
Cell Communication
Muscle Cells
Reperfusion
Blood Vessels
Permeability
Leukocytes
Ischemia
Endothelial Cells

Keywords

  • cAMP
  • Nitric oxide
  • Organ preservation
  • Transplantation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Oz, M. C., Pinsky, D. J., Koga, S., Liao, H., Marboe, C. C., Han, D., ... Michler, R. E. (1993). Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models. Circulation, 88(5 PART 2), 291-297.

Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models. / Oz, Mehmet C.; Pinsky, David J.; Koga, Shin; Liao, Hui; Marboe, Charles C.; Han, Daying; Kline, Richard; Jeevanandam, Valluvan; Williams, Mathew; Morales, Alfredo; Popilskis, Sulli; Nowygrod, Roman; Stern, David M.; Rose, Eric A.; Michler, Robert E.

In: Circulation, Vol. 88, No. 5 PART 2, 11.1993, p. 291-297.

Research output: Contribution to journalArticle

Oz, MC, Pinsky, DJ, Koga, S, Liao, H, Marboe, CC, Han, D, Kline, R, Jeevanandam, V, Williams, M, Morales, A, Popilskis, S, Nowygrod, R, Stern, DM, Rose, EA & Michler, RE 1993, 'Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models', Circulation, vol. 88, no. 5 PART 2, pp. 291-297.
Oz MC, Pinsky DJ, Koga S, Liao H, Marboe CC, Han D et al. Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models. Circulation. 1993 Nov;88(5 PART 2):291-297.
Oz, Mehmet C. ; Pinsky, David J. ; Koga, Shin ; Liao, Hui ; Marboe, Charles C. ; Han, Daying ; Kline, Richard ; Jeevanandam, Valluvan ; Williams, Mathew ; Morales, Alfredo ; Popilskis, Sulli ; Nowygrod, Roman ; Stern, David M. ; Rose, Eric A. ; Michler, Robert E. / Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models. In: Circulation. 1993 ; Vol. 88, No. 5 PART 2. pp. 291-297.
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abstract = "Background. Cardiac preservation for transplantation disrupts normal vascular homeostatic mechanisms. Hypoxia and reoxygenation increase endothelial cell permeability, induce procoagulant activity, and alter endothelial cell/leukocyte interactions, with a parallel reduction in endothelial cAMP and nitric oxide levels. Because hypoxia/reoxygenation simulates a significant component of the global ischemia/ reperfusion of cardiac transplantation, we hypothesized that preservation failure may be related to these perturbations. This work focuses on repleting the intercellular/intracellular second messengers nitric oxide/cGMP and cAMP in the donor heart to enhance cardiac preservation for transplantation. Methods and Results. A heterotopic rat heart transplant mode was used to compare lactated Ringer's (LR) and University of Wisconsin (UW) solutions to a novel storage solution (Columbia University solution, CU), which contains a cAMP analogue (dibutyryl cAMP) and nitroglycerin (to enhance nitric oxide-related mechanisms). By 24 to 28 hours of preservation, no LR hearts survived (n=9), 35{\%} of UW hearts survived (n=20), and 88{\%} of CU-preserved hearts survived (n=8; P<.05 versus LR or UW). The viability of preserved hearts was explored by determining whether CU preservation enabled myocytes to maintain resting membrane potentials and preserve their ability to generate an action potential in response to a field stimulus. Of 24 sites explored with a microelectrode in UW-preserved hearts, only 4{\%} were able to generate an action potential, compared with 75{\%} of 36 sites in CU-preserved hearts (P<.001), with corresponding preservation of resting membrane potential in the CU-preserved hearts (-13 mV for UW versus -54 mV for CU, P<.001). Orthotopic baboon cardiac transplantation performed after 24-hour simple hypothermic preservation demonstrated that no UW-preserved heart (n=4) survived the perioperative period; in contrast, four of five hearts stored for 24 hours in CU solution sustained the recipient with minimal inotropic support, and two animals survived long-term. Conclusions. Sustaining higher levels of intercellular/intracellular second messengers cAMP and nitric oxide/cGMP provides a new approach to enhancing cardiac preservation.",
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T1 - Novel preservation solution permits 24-hour preservation in rat and baboon cardiac transplant models

AU - Oz, Mehmet C.

AU - Pinsky, David J.

AU - Koga, Shin

AU - Liao, Hui

AU - Marboe, Charles C.

AU - Han, Daying

AU - Kline, Richard

AU - Jeevanandam, Valluvan

AU - Williams, Mathew

AU - Morales, Alfredo

AU - Popilskis, Sulli

AU - Nowygrod, Roman

AU - Stern, David M.

AU - Rose, Eric A.

AU - Michler, Robert E.

PY - 1993/11

Y1 - 1993/11

N2 - Background. Cardiac preservation for transplantation disrupts normal vascular homeostatic mechanisms. Hypoxia and reoxygenation increase endothelial cell permeability, induce procoagulant activity, and alter endothelial cell/leukocyte interactions, with a parallel reduction in endothelial cAMP and nitric oxide levels. Because hypoxia/reoxygenation simulates a significant component of the global ischemia/ reperfusion of cardiac transplantation, we hypothesized that preservation failure may be related to these perturbations. This work focuses on repleting the intercellular/intracellular second messengers nitric oxide/cGMP and cAMP in the donor heart to enhance cardiac preservation for transplantation. Methods and Results. A heterotopic rat heart transplant mode was used to compare lactated Ringer's (LR) and University of Wisconsin (UW) solutions to a novel storage solution (Columbia University solution, CU), which contains a cAMP analogue (dibutyryl cAMP) and nitroglycerin (to enhance nitric oxide-related mechanisms). By 24 to 28 hours of preservation, no LR hearts survived (n=9), 35% of UW hearts survived (n=20), and 88% of CU-preserved hearts survived (n=8; P<.05 versus LR or UW). The viability of preserved hearts was explored by determining whether CU preservation enabled myocytes to maintain resting membrane potentials and preserve their ability to generate an action potential in response to a field stimulus. Of 24 sites explored with a microelectrode in UW-preserved hearts, only 4% were able to generate an action potential, compared with 75% of 36 sites in CU-preserved hearts (P<.001), with corresponding preservation of resting membrane potential in the CU-preserved hearts (-13 mV for UW versus -54 mV for CU, P<.001). Orthotopic baboon cardiac transplantation performed after 24-hour simple hypothermic preservation demonstrated that no UW-preserved heart (n=4) survived the perioperative period; in contrast, four of five hearts stored for 24 hours in CU solution sustained the recipient with minimal inotropic support, and two animals survived long-term. Conclusions. Sustaining higher levels of intercellular/intracellular second messengers cAMP and nitric oxide/cGMP provides a new approach to enhancing cardiac preservation.

AB - Background. Cardiac preservation for transplantation disrupts normal vascular homeostatic mechanisms. Hypoxia and reoxygenation increase endothelial cell permeability, induce procoagulant activity, and alter endothelial cell/leukocyte interactions, with a parallel reduction in endothelial cAMP and nitric oxide levels. Because hypoxia/reoxygenation simulates a significant component of the global ischemia/ reperfusion of cardiac transplantation, we hypothesized that preservation failure may be related to these perturbations. This work focuses on repleting the intercellular/intracellular second messengers nitric oxide/cGMP and cAMP in the donor heart to enhance cardiac preservation for transplantation. Methods and Results. A heterotopic rat heart transplant mode was used to compare lactated Ringer's (LR) and University of Wisconsin (UW) solutions to a novel storage solution (Columbia University solution, CU), which contains a cAMP analogue (dibutyryl cAMP) and nitroglycerin (to enhance nitric oxide-related mechanisms). By 24 to 28 hours of preservation, no LR hearts survived (n=9), 35% of UW hearts survived (n=20), and 88% of CU-preserved hearts survived (n=8; P<.05 versus LR or UW). The viability of preserved hearts was explored by determining whether CU preservation enabled myocytes to maintain resting membrane potentials and preserve their ability to generate an action potential in response to a field stimulus. Of 24 sites explored with a microelectrode in UW-preserved hearts, only 4% were able to generate an action potential, compared with 75% of 36 sites in CU-preserved hearts (P<.001), with corresponding preservation of resting membrane potential in the CU-preserved hearts (-13 mV for UW versus -54 mV for CU, P<.001). Orthotopic baboon cardiac transplantation performed after 24-hour simple hypothermic preservation demonstrated that no UW-preserved heart (n=4) survived the perioperative period; in contrast, four of five hearts stored for 24 hours in CU solution sustained the recipient with minimal inotropic support, and two animals survived long-term. Conclusions. Sustaining higher levels of intercellular/intracellular second messengers cAMP and nitric oxide/cGMP provides a new approach to enhancing cardiac preservation.

KW - cAMP

KW - Nitric oxide

KW - Organ preservation

KW - Transplantation

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