Abstract
BackgroundAlthough donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects.Methodology/Principal FindingsTo this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects.Conclusions/SignificanceIn conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.
Highlights
A prospective randomized multicenter trial has demonstrated a beneficial effect of donor treatment with low-dose dopamine on immediate kidney graft function [1]
Conclusions/Significance: In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity
Kidney transplant recipients who received a graft from a dopamine treated donor had a significantly decreased need for dialysis after kidney transplantation compared to the untreated control group
Summary
A prospective randomized multicenter trial has demonstrated a beneficial effect of donor treatment with low-dose dopamine on immediate kidney graft function [1]. There is a significant relation between the time of dopamine treatment and efficacy on preventing delayed graft function [1]. This might be explained by the fact that dopamine is rapidly degraded in the circulation by monamine oxidase, sufficient tissue dopamine levels can only be obtained by increasing the treatment dose or time of dopamine treatment. The former cannot be used in brain dead donors as this would increase the incidence of tachycardia and hypertension. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects
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