Effect of pre-treatment with catecholamines on cold preservation and ischemia/reperfusion-injury in rats

Abstract

Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4 degrees Celsius in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 microg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 microg/kg/min) and DB (5 microg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-beta 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 microg/kg/min) and DB (5 microg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation.

Evaluation of a Novel Cold Storage Solution (HBS) in a Rat Kidney Transplant Model

“…After we reviewed the literature and analyzed our previous experience with different strains of rats and various preservation solutions, it was evident that the Dark Agouti rats used mostly in Australia showed excellent results after 24 h of kidney preservation [7][8][9][10]. The use of kidneys from Lewis rats in the literature showed results similar to the ones from our group, except for the experiments reported from the University of California-San Francisco, which recognized a considerable variance with others since they observed 100% 7-day survival after 24 h of UWS kidney preservation [11]. In a different study, kidneys transplantated into Lewis rats in our laboratories were not able to tolerate 24 h of cold preservation with either the UWS, HTK, or HBS solutions.…”

N-acyl dopamine derivates as lead compound for implementation in transplantation medicine

“…However, it remains to be elucidated which of these effects are responsible for the clinical findings on donor dopamine treatment as described by Schnuelle et al [15]. Among the beneficial mechanisms, the finding that catecholamines in general can protect endothelial cells against cold inflicted injury [22] is highly intriguing and opens the possibility for novel therapeutic modalities to prevent or limit organ damage during static cold storage [15,16,[23][24][25]. The mechanism by which catecholamines protect against organ damage during hypothermic preservation is not completely understood, albeit that involvement of the H 2 S pathway [26], the HO-1 pathway [27] and redox activity [22] has been postulated.…”

“…Clearly, as FDA approval for the use of NADD in human does not exist, similar studies with the use of NADD are not possible. Although NADD may also have the propensity to protect allografts when used as additive to the organ preservation solution, there is no supportive evidence using whole organs, albeit that it has been reported for experimental models that addition of dopamine to the preservation solutions is protective to liver [23] and renal allografts [25]. Also the type of NADD for implementation in transplantation medicine requires careful considerations since some of the beneficial effects of NADD are meditated by the fatty acid tail and therefore not present in all NADD.…”

The use of β-adrenergic drugs improves hepatic oxygen metabolism in cirrhotic patients undergoing liver resection

“…Recently, it has become evident that catecholamines display antioxidative properties. They over express antioxidant proteins that may inhibit lipid peroxidation of membranes; in this class of agents, dobutamine is the most powerful inhibitor scavenging the ROS [26]. Additionally, experimental studies have shown that dopamine and dobutamine may act on b-1 adrenergic receptors of the pericentral hepatocytes leading to an up-regulation of heme oxygenase enzyme via the protein kinase A [27].…”