Effects of a calcineurin inhibitor, tacrolimus, on glutamate-dependent potentiation in pelvic-urethral reflex in anesthetized rats

Abstract

Effects of tacrolimus, a protein phosphatase 2B inhibitor, on the reflex plasticity between the pelvic afferent nerve fibers and the urethra were examined in urethane-anesthetized rats. Repetitive stimulation (1Hz) induced a potentiation (0.9±0.2 and 10.5±1.6 spikes in control and repetitive stimulation groups, respectively, P<0.01, N=10) in the activities of the pelvic-urethral reflex. Intrathecal tacrolimus (0.1mM, 10μl, bolus) blocked repetitive stimulation-induced potentiation in pelvic-urethral reflex activities (3.2±0.9 spikes in tacrolimus group versus 10.5±1.6 spikes in repetitive stimulation group, P<0.01, N=10). Glutamate (intrathecal, 0.1mM, 10μl, bolus) and N-methyl- d-aspartic acid (intrathecal, 0.1mM, 10μl, bolus) both reversed the blocking effects exerted by tacrolimus on repetitive stimulation-induced pelvic-urethral reflex potentiation (15.0±1.4 spikes in glutamate group and 11.4±1.4 spikes in N-methyl- d-aspartic acid group versus 3.2±0.9 spikes in tacrolimus-treated repetitive stimulation group, P<0.01, N=7). In addition, the reversal effect elicited by these two agonists of glutamate receptors showed no statistical difference ( P=NS, N=7). All these results demonstrated that tacrolimus could block glutamatergic N-methyl- d-aspartic acid receptor-mediated potentiation in pelvic-urethral reflex activities. This finding may be pathologically relevant in patients who take tacrolimus as immunosuppressant therapy. Whether tacrolimus will induce urine incontinence in such patients or not needs further investigation.