Glutamatergic Mechanisms Involved in Bladder Overactivity and Pudendal Neuromodulation in Cats

Abstract

The involvement of ionotropic glutamate receptors in bladder overactivity and pudendal neuromodulation was determined in α-chloralose anesthetized cats by intravenously administering MK801 (a NMDA receptor antagonist) or CP465022 (an AMPA receptor antagonist). Infusion of 0.5% acetic acid (AA) into the bladder produced bladder overactivity. In the first group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 55.3±10.0% of saline control by AA irritation. Pudendal nerve stimulation (PNS) significantly (P < 0.05) increased bladder capacity to 106.8 ± 15.0% and 106.7 ± 13.3% of saline control at 2T and 4T intensity, respectively. T is threshold intensity for inducing anal twitching. MK801 at 0.3 mg/kg prevented the increase in capacity by 2T or 4T PNS. In the second group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 49.0 ± 7.5% of saline control by AA irritation. It was then significantly (P < 0.05) increased to 80.8±13.5% and 79.0±14.0% of saline control by 2T and 4T PNS, respectively. CP465022 at 0.03-1 mg/kg prevented the increase in capacity by 2T PNS and at 0.3-1 mg/kg prevented the increase in capacity by 4T PNS. In both groups, MK801 at 0.3 mg/kg and CP465022 at 1 mg/kg significantly (P < 0.05) increased the prestimulation bladder capacity (about 80% and 20%, respectively) and reduced the amplitude of bladder contractions (about 30 and 20 cmH₂O, respectively). These results indicate that NMDA and AMPA glutamate receptors are important for PNS to inhibit bladder overactivity and that tonic activation of these receptors also contributes to the bladder overactivity induced by AA irritation.

Fig. 1.

Repeated CMG recordings at different cumulative doses of MK801 during acetic acid infusion with or without pudendal nerve stimulation (PNS). T, threshold PNS intensity to induce external anal sphincter twitch. Black bars under the bladder pressure traces indicate the durations of PNS (5 Hz, 0.2 ms, T = 0.4 V). Infusion rate = 4 ml/min.

Fig. 2.

Summarized results showing bladder capacity at different cumulative doses of MK801. Bladder capacity during acetic acid infusion was normalized to the capacity measured during saline infusion before any drug treatment or pudendal nerve stimulation (PNS). *Significantly (P < 0.05) different from prestimulation data at each drug dosage [2-way analysis of variance (ANOVA)]. #Significantly (P < 0.05) different from the untreated condition in the same data group (1-way ANOVA). n = 5 cats. PNS (5 Hz, 0.2 ms, T = 0.16-0.6 V).

Fig. 3.

Summarized results showing the amplitude of bladder contractions measured during prestimulation CMGs at different cumulative doses of MK801. #Significantly (P < 0.05) different from untreated condition (1-way ANOVA). n = 5 cats.

Fig. 4.

Repeated CMG recordings at different cumulative doses of CP465022 during acetic acid infusion with or without pudendal nerve stimulation (PNS). T, threshold PNS intensity to induce external anal sphincter twitch. Black bars under the bladder pressure traces indicate the durations of PNS (5 Hz, 0.2 ms, T = 0.3 V). Infusion rate = 1.5 ml/min.

Fig. 5.

Summarized results showing bladder capacity at different cumulative doses of CP465022. Bladder capacity was normalized to the capacity measured during saline infusion before any drug treatment or pudendal nerve stimulation (PNS). *Significantly (P < 0.05) different from prestimulation data at each drug dosage (2-way ANOVA). #Significantly (P < 0.05) different from the untreated condition in the same data group (1-way ANOVA). n = 5 cats. PNS (5 Hz, 0.2 ms, T = 0.15–1.6 V).

Fig. 6.

Summarized results showing the amplitude of bladder contractions measured during prestimulation CMGs at different cumulative doses of CP465022. #Significantly (P < 0.05) different from untreated condition (1-way ANOVA). n = 5 cats.