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Calcium/calmodulin--protein kinase (CaMK)-dependent nitric oxide (NO) and the downstream intracellular messenger cGMP, which is activated by soluble guanylate cyclase (sGC), are believed to induce long-term changes in efficacy of synapses through the activation of protein kinase G (PKG). The aim of this study was to examine the involvement of the CaMKII-dependent NO/sGC/PKG pathway in a novel form of repetitive stimulation-induced spinal reflex potentiation (SRP). A single-pulse test stimulation (TS; 1/30 Hz) on the afferent nerve evoked a single action potential, while repetitive stimulation (RS; 1 Hz) induced a long-lasting SRP that was abolished by a selective [Ca.sup.2+]/CaMKII inhibitor, autocamtide 2-related inhibitory peptide (AIP). Such an inhibitory effect was reversed by a relative excess of nitric oxide synthase (NOS) substrate, L-arginine. In addition, the RS-induced SRP was abolished by pretreatment with the NOS inhibitor, [N.sup.G]-nitro-L-arginine-methyl ester (L-NAME). The sGC activator, protoporphyrin IX (PPIX), reversed the blocking effect caused by L-NAME. On the other hand, a sGC blocker, 1H-J1, 2, 4]oxadiazolo[4, 3-[alpha]]quinoxalin-l-one (ODQ), abolished the RS-induced SRP. Intrathecal applications of the membrane-permeable cGMP analog, 8-bromoguanosine 3',5'-cyclic monophosphate sodium salt monohydrate (8-Br-cGMP), reversed the blocking effect on the RS-induced SRP elicited by the ODQ. Our findings suggest that a CaMKII-dependent NO/sGC/PKG pathway is involved in the RSinduced SRP, which has pathological relevance to hyperalgesia and allodynia. spinal reflex potentiation; soluble guanylate cyclase; cyclic monophosphate sodium salt monohydrate; spinal cord; windup

This study was conducted to investigate whether dorsolateral pontine tegmentum stimulation modulates spinal reflex potentiation (SRP) and whether serotonergic neurotransmission is involved in such a modulation. Reflex activities of the external urethra sphincter (EUS) electromyogram in response to a test stimulation (TS; 1/30 Hz) or repetitive stimulation (RS; 1 Hz) on the pelvic afferent nerve in 35 anesthetized rats were recorded with/without synchronized train pontine stimulation (PS; 300 Hz, 30 ms) and/or intrathecal administrations of 10 [micro]l of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX; 100 [micro]M), D-2-amino-5-phosphonovalerate (APV; 100 [micro]M), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY 100635; 100 [micro]M), and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 100 [micro]M). The TS evoked a single action potential (1.00 [+ or -] 0.00 spikes/stimulation), while the RS produced a long-lasting SRP (16.12 [+ or -] 1.59 spikes/stimulation) that was abolished by APV (1.57 [+ or -] 0.29 spikes/stimulation) and was attenuated by NBQX (7.42 [+ or -] 0.57 spikes/stimulation). Synchronized train PS with RS (PS+RS) produced facilitation in RS-induced SRP (25.17 [+ or -] 2.21 spikes/stimulation). Intrathecal WAY 100635 abolished the facilitation in SRP as a result of the synchronized PS (14.66 [+ or -] 1.58 spikes/stimulation). On the other hand, intrathecal 8-OH-DPAT elicited facilitation in the RS-induced SRP (25.16 [+ or -] 1.05 spikes/ stimulation) without synchronized PS. Our findings suggest that dorsolateral pontine tegmentum may modulate N-methyl-o-aspartic acid-dependent SRP via descending serotonergic neurotransmission. This descending modulation may have physiological/pharmacological relevance in the neural controls of urethral closure. long term potentiation; SRP; pontine tegmentum; serotonin; WAY 100635; 8-OH-DPAT

The purposes of this study were to investigate whether the pelvic nerve-to-external urethra sphincter (EUS) reflex potentiation can be induced under physiological conditions and to determine whether glutamatergic neurotransmission is involved in the reflex potentiation. Stimulation-evoked reflex activities, during rhythmic bladder contractions caused by a continuous saline infusion, in 21 anesthetized rats were recorded with/without the intrathecal administration of 10 [micro]1 of CNQX (a glutamatergic AMPA receptor antagonist; 100 [micro]M) and APV (a glutamatergic NMDA receptor antagonist; 100 [micro]M). Reflex activities became potentiated following the increment of intravesical pressure (IVP) during the storage phase (2.39 [+ or -] 0.28 spikes/mmHg, n = 21) and the ascending period of the voiding phase (1.46 [+ or -] 0.35 spikes/ mmHg, n = 21) and decreased following the decrement of IVP during the descending period of the voiding phase (1.50 [+ or -] 0.33 spikes/ mmHg, n = 21). Although it is characterized by a low IVP, a postvoiding reflex potentiation in stimulation-evoked activities was elicited at the critical period after a voiding contraction had just finished (23.95 [+ or -] 8.96 spikes/mmHg, n = 21). The slope of the regression line of evoked activities vs. the IVP during the storage phase was significantly (P < 0.01) higher than that of the ascending and descending periods of the voiding phase, but there was no statistical difference between the ascending and the descending periods (P > 0.05). In addition, the slope of the regression line of posttetanic reflex potentiation was significantly higher than that of the storage phase (P < 0.01). All the slopes of the regression lines decreased after intrathecal CNQX administration (from 3.15 [+ or -] 0.44, 2.10 [+ or -] 0.57, 2.13 [+ or -] 0.53, and 21.30 [+ or -] 3.41 to 0.83 [+ or -] 0.31, 0.74 [+ or -] 0.12, 0.76 [+ or -]0.12, and 4.31 [+ or -] 3.71 spikes/mmHg in storage, ascending and descending period of the voiding phase, and postvoiding potentiation, respectively; all P < 0.01, n = 10). The slopes of the regression lines became almost horizontal after intrathecal APV administration (from 3.15 [+ or -] 0.44, 2.10 [+ or -] 0.57, 2.13 [+ or -] 0.53, and 21.30 [+ or -] 3.41 to 0.16 [+ or -] 0.12,0.21 [+ or -] 0.07,0.18 [+ or -]] 0.05, and 0.23 [+ or -] 0.76 spikes/mmHg in storage, ascending and descending period of voiding phase, and postvoiding potentiation, respectively; all P < 0.01, n = 10). Our results suggest that a potentiation in the pelvic nerve-to-EUS reflex can be induced under physiological conditions and the glutamatergic mechanism appears to be involved in this reflex potentiation. postvoiding potentiation; posttetanic potentiation; glutamate

The current study investigates whether the spinal pelvic nerve-to-external urethra sphincter (EUS) reflex potentiation can be induced by a mechanical stimulation and whether the glutamatergic mechanism is involved in yielding such a reflex potentiation. The external urethra sphincter electromyogram (EUSE) activity, evoked by a single or by repetitive pelvic nerve stimulation, in 30 anesthetized rats was recorded with/without bladder saline distension. Without saline distension (0 cm[H.sub.2]O), a single pulse nerve stimulation evoked a single action potential in the reflex activity, whereas repetitive pelvic stimulation and saline distension (6-20 cm[H.sub.2]O) both elicited a long-lasting reflex potentiation (20.05 [+ or -] 3.21 and 75.01 [+ or -] 9.87 spikes/ stimulation, respectively). The saline distension-induced pelvic nerve-to-EUS reflex potentiation was abolished by D-2-amino-5-phosphonovalerate [APV; a glutamatergic N-methyl-D-aspartic acid (NMDA) receptor antagonist; 100 [micro]M, 10 [micro]l, 1.72 [+ or -] 0.31 spikes/ stimulation] and attenuated by 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline [NBQX; a glutamatergic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptor antagonist; 100 [micro]M, 10 [micro]l, 26.16 [+ or -] 7.27 spikes/stimulation], but was not affected by bicuculline (a GABAergic antagonist; 100 [micro]M, 10 [micro]l, 53.62 [+ or -] 15.54 spikes/stimulation). Intrathecal administration of glutamate (31.12 [+ or -] 8.25 spikes/stimulation, 100 [micro]M, 10 [micro]l) and NMDA (26.25 [+ or -] 4.12 spikes/stimulation, 100 [micro]M, 10 [micro]l) both induced a long-lasting pelvic nerve-to-EUS reflex potentiation without saline distension, which was similar to the findings observed from saline distension only. The duration of the contraction wave of the urethra was elongated by the saline distension-induced pelvic nerve-to-EUS reflex potentiation, whereas the peak pressure of the contraction wave was not affected. Our findings suggest that saline distension in the bladder elicits a pelvic nerve-to-EUS reflex potentiation and the glutamatergic mechanism contributes to the presence of such a reflex potentiation. pelvic nerve; urethra; LTP; AMPA doi: 10.1152/ajprenal.00443.2006

Objective: Previous studies have shown that anterior vaginal wall prolapse (AVWP) results in reduction of pressure in the proximal urethra. However, the effect of severity of AVWP on urethral pressure is controversial. This study aimed to evaluate parameters of the urethral pressure profile in different stages of AVWP. Materials and methods: From 2016 to 2017, 286 consecutive patients with urogynecologic complaints who were referred to our urodynamic unit were enrolled in this study to analyze their urethral pressure profiles. Stages of AVWP were regrouped into three groups ranging from mild to severe stages (groups 1‐3). Maximal urethral pressure, urethral closure pressure, functional urethral length, length of continence zone, as well as area of continence zone were compared among these three groups. Results: Distribution of age, parity, and menopausal women were significantly different among these three groups. Maximal urethral pressure (pressures for groups 1, 2, and 3 were 74.6∼75.9cmH2O, 69.7∼73.4cmH2O, and 58.3∼60.5cmH2O, respectively; all P<.05) and stress urethral closure pressure (pressures for groups 1, 2, and 3 were 69.3cmH2O, 62.3cmH2O, and 52.2cmH2O, respectively; all P<.05) gradually and significantly decreased, consistent with the severity of AVWP. However, the attenuated maximal urethral pressure and stress urethral closure pressure in accordance with severity did not show any significant difference after controlling for age, body mass index, parity, menopause, and stress urinary incontinence symptoms. Conclusion: Our results showed that AVWP significantly attenuated urethral pressure. However, patient age, menopausal status, and number of parities seem to be more influential in compromising urethral function than just AVWP alone. [ABSTRACT FROM AUTHOR]