Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway

David J. Pinsky, Mehmet C. Oz, Shin Koga, Ziad Taha, M. Johan Broekman, Aaron J. Marcus, Hui Liao, Yoshifumi Naka, Jerold Brett, Paul J. Cannon, Roman Nowygrod, Tadeusz Malinski, David Stern

Research output: Contribution to journalArticle

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Abstract

Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1±0.4 μM for freshly explanted hearts to 0.7±0.2 and 0.2±0.08 μM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist N(G)-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP- dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.

Original languageEnglish (US)
Pages (from-to)2291-2297
Number of pages7
JournalJournal of Clinical Investigation
Volume93
Issue number5
DOIs
StatePublished - Jan 1 1994

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Nitric Oxide
Transplants
Nitroglycerin
Blood Vessels
Arginine
Organ Transplantation
Graft Survival
Reperfusion
Leukostasis
Endothelial Cells
Nitric Oxide Donors
Nitroprusside
Bradykinin
Platelet Aggregation
Nitric Oxide Synthase
Thrombin
Superoxides
Free Radicals
Reactive Oxygen Species
Serotonin

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway. / Pinsky, David J.; Oz, Mehmet C.; Koga, Shin; Taha, Ziad; Broekman, M. Johan; Marcus, Aaron J.; Liao, Hui; Naka, Yoshifumi; Brett, Jerold; Cannon, Paul J.; Nowygrod, Roman; Malinski, Tadeusz; Stern, David.

In: Journal of Clinical Investigation, Vol. 93, No. 5, 01.01.1994, p. 2291-2297.

Research output: Contribution to journalArticle

Pinsky, DJ, Oz, MC, Koga, S, Taha, Z, Broekman, MJ, Marcus, AJ, Liao, H, Naka, Y, Brett, J, Cannon, PJ, Nowygrod, R, Malinski, T & Stern, D 1994, 'Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway', Journal of Clinical Investigation, vol. 93, no. 5, pp. 2291-2297. https://doi.org/10.1172/JCI117230
Pinsky, David J. ; Oz, Mehmet C. ; Koga, Shin ; Taha, Ziad ; Broekman, M. Johan ; Marcus, Aaron J. ; Liao, Hui ; Naka, Yoshifumi ; Brett, Jerold ; Cannon, Paul J. ; Nowygrod, Roman ; Malinski, Tadeusz ; Stern, David. / Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway. In: Journal of Clinical Investigation. 1994 ; Vol. 93, No. 5. pp. 2291-2297.
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abstract = "Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1±0.4 μM for freshly explanted hearts to 0.7±0.2 and 0.2±0.08 μM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92{\%} of hearts supplemented with NTG surviving 12 h of preservation versus only 17{\%} in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist N(G)-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP- dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.",
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T1 - Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway

AU - Pinsky, David J.

AU - Oz, Mehmet C.

AU - Koga, Shin

AU - Taha, Ziad

AU - Broekman, M. Johan

AU - Marcus, Aaron J.

AU - Liao, Hui

AU - Naka, Yoshifumi

AU - Brett, Jerold

AU - Cannon, Paul J.

AU - Nowygrod, Roman

AU - Malinski, Tadeusz

AU - Stern, David

PY - 1994/1/1

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N2 - Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1±0.4 μM for freshly explanted hearts to 0.7±0.2 and 0.2±0.08 μM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist N(G)-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP- dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.

AB - Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1±0.4 μM for freshly explanted hearts to 0.7±0.2 and 0.2±0.08 μM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5'monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist N(G)-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP- dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.

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