gms | German Medical Science

Introduction: Bladder enlargement is a consistent feature of animal models of type 1 and of some of type 2 diabetes and the most frequently reported parameter of diabetic cystopathy in animal models [1]. The role of sphingosine kinases is altered in euglycemic models of bladder dysfunction [2]; a mediator generated by sphingosine kinase, sphingosine-1-phosphate (S1P) can cause detrusor smooth muscle contraction [3]. Therefore, we have explored changes in the role of sphingosine kinase in bladder contraction and of S1P-induced contraction in the rat streptozotocin model.

Methods: Male Wistar rats (277±15 g) were assigned to receive an i.p. injection of 50 mg/kg streptozotocin to induce diabetes or vehicle (control). Two weeks later, rats were killed, bladders were weighed, and bladder strip contractility was tested in organ bath experiments. Carbachol concentration-response curves were performed in the absence and presence of the sphingosine kinase 1 and 2 inhibitors, SLP7111228 and SLM6031434, respectively. S1P concentration-response curves were generated in the absence and presence of the S1P2 receptor antagonist, JTE-013. Experiments were designed to reach at least n = 8 for the organ bath. Data are shown as means ± SD. In line with the exploratory character of the study, no hypothesis-testing statistical analysis was performed as per recent guidelines on reproducibility.

Results: Streptozotocin injection led to the expected diabetic phenotype (blood glucose 506±65 vs. 120±21 mg/dl) and increase of bladder weight (241±37 vs. 126±15 mg). As observed in euglycemic models, the potency of carbachol was reduced in the presence of the sphingosine kinase inhibitors (SLP7111228 control -0.24 log units, diabetes -0.35 log units; SLM6031434 control -0.29 log units, diabetes -0.31 log units). Neither inhibitor affected the maximum contraction induced by carbachol in either group. S1P-induced contraction was weak (10-20% of KCl effects) but doubled in diabetic rats; in both groups, it was strongly inhibited by the S1P2 receptor antagonist JTE-013 (Figure 1 [Fig. 1]).

Conclusion: We conclude that the role of the bladder sphingosine kinase/S1P receptor system is altered in the streptozotocin rat mode of type 1 diabetes; however, effects were of weak to moderate strength only.