Acyloxyacyl hydrolase regulates voiding activity.

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington's nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington's nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH-Crf axis is a therapeutic target for treating voiding dysfunction.

Significance of nitric oxide and its modulation mechanisms by endogenous nitric oxide synthase inhibitors and arginase in the micturition disorders and erectile dysfunction.

Evidence indicates that nitric oxide (NO) deficiency contributes to micturition disorders, especially in the afferent pathway and erectile dysfunction (ED). Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine: ADMA) in plasma and tissues. Elevated tissues of ADMA and N(G)-monomethyl-L-arginine (L-NMMA) have been reported to be associated with impaired NO-mediated urethral, trigonal and cavernosal relaxations by pelvic ischemia. Also, plasma ADMA may help to identify underlying cardiovascular disease in men with ED. Decreased l-arginine availability to NO synthase is due to the shunting of L-arginine into other pathways such as arginase. Interaction between NO synthase and arginase has been reported to be involved in NO-mediated urethral and prostatic relaxations. Also, increased arginase activity in cavernosal tissues likely contributes to the ED that accompanies diabetes mellitus and aging. Therefore, arginase inhibition has been reported to enhance the NO-dependent physiological process for erectile function.

Role of spinal nitric oxide synthase-dependent processes in the initiation of the micturition hyperreflexia associated with cyclophosphamide-induced cystitis.

The aim of this study was to examine the participation of nitrergic neurotransmission in the initiation of micturition hyperreflexia associated to cyclophosphamide (CP)-induced cystitis in rats. Micturition threshold volume was significantly reduced 4 h after CP administration (100 mg/kg, i.p.); this reduction was attenuated by intra-arterially injected N(G)-nitro-l-arginine-methyl ester (l-NAME), a non selective nitric oxide synthase (NOS) inhibitor, but not by intravesical infusion of S-methyl-l-thiocitrulline (l-SMTC), another structurally different NOS inhibitor. Interestingly, l-NAME failed to affect micturition threshold volume in normal rats. The magnitude of isolated detrusor strips contractions elicited by either carbachol or nerve activation was significantly reduced in CP-treated rats but was unaffected by the addition of N(G)-nitro-l-arginine (l-NOARG), a nonselective NOS inhibitor. In contrast, intrathecal l-NAME and l-SMTC but not N(G)-nitro-d-arginine-methyl ester (d-NAME) administration augmented the micturition threshold volume in CP-treated rats in an l-arginine preventable manner. As with the systemic injection, intrathecal l-NAME also did not affect the micturition threshold volume in normal rats. Four hours after CP injection, the number of neuronal NOS immunoreactive or nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) positive neurons in spinal lumbosacral segments (L6-S2) was not altered whereas the number of c-Fos immunoreactive neurons increased significantly in the dorsal gray commissural nucleus (DGC), the parasympathetic sacral nucleus (PSN) and lamina X of these segments. Ca(2+)-dependent, but not Ca(2+)-independent NOS activity increased significantly in spinal L6-S2 segments but not in thoracic segments of CP-treated rats. These data indicate that the micturition hyperreflexia observed in the initial hours of CP-induced cystitis is associated with an increase in Ca(2+)-dependent NOS activity in spinal L6-S2 segments suggesting an increased production of nitric oxide (NO). The increased production of NO in these spinal segments appears to be necessary for the initiation of the micturition hyperreflexia.

Urinary lactic dehydrogenase isoenzyme analysis in children with spinal lesions.

In 48 children with spinal lesions and micturition problems urinary lactic dehydrogenase (LDH) isoenzymes were analyzed. They had higher total LDH activities (716.8 +/- 1,050.2 nkat/I), isoenzymes V percents (22.2 +/- 13.0%) and isoenzyme V activities (203.4 +/- 308.4 nkat/I) than those of healthy children (150.0 +/- 83.4 nkat/I, 1.9 +/- 1.0%, 5.0 +/- 3.3 nkat/I). Many subjects had an isoenzyme V-dominant LDH isoenzyme pattern. Among 48 subjects the patients with pyuria, bacteriuria or abnormal pyelograms had markedly high total LDH activities, isoenzyme V percents and isoenzyme V activities. The rise in LDH isoenzyme V levels may reflect the renal damage in the patients with neurogenic bladders.

Acute and chronic retention of urine: relevance of raised serum prostatic acid phosphatase levels. A prospective study.

A prospective study of serum prostatic acid phosphatase (PAP) levels in benign prostatic disease is reported. In 12 patients with acute retention the initial PAP level when compared with the level twenty-four hours after catheterization showed a significant fall (p less than 0.02). The initial PAP level was raised above the upper limit of normal in 7 patients (in 3 markedly so, of whom 2 had subsequent histologic evidence of prostatic infarction). In 10 patients with chronic retention there was a significant rise in the PAP level twenty-four hours after catheterization, but in only 1 case did this exceed the normal range. We discuss the significance of a raised PAP level in patients with acute retention and suggest that it may indicate a group of patients in whom the etiology of acute retention is spontaneous prostatic infarction and subsequently may require different management.