The physiology of the mammalian urinary outflow tract.
Urinary outflow from the mammalian bladder occurs through the urethra. This outflow tract is a complicated structure composed of striated and smooth muscle and vascular urothelium. It is controlled by somatic and autonomic nerves and has several functions: it generates sustained tone to prevent urinary leakage during bladder filling; it generates transient reflex increases in pressure to prevent opening of the lumen when abdominal pressure rises; it undergoes relaxation preceding micturition and can generate urethral opening and shortening during micturition. A urethral pressure profile shows a peak pressure of > or = 100 cmH2O. The outermost coat is striated muscle, the striated or external sphincter. The fibres are predominantly circularly oriented. The extent varies in different species and between sexes. In the human female it extends the length of the urethra, and is composed mainly of slow twitch fibres. In the male, the sphincter extends from the membranous urethra over the base of the prostate and has nearly equal numbers of slow and fast twitch fibres. In both sexes, the posterior border may be deficient in striated muscle, and filled by circularly oriented smooth muscle. Activity in the slow twitch fibres through somatic nerves may be continuous during bladder filling. Outer circular and inner longitudinal smooth muscle is present Strips from either layer will generate sustained tone particularly if dissected from the high pressure zone. This tone is myogenic, and may be achieved in the absence of action potentials, but relies on influx of calcium through L-type calcium channels. Both layers receive sympathetic and parasympathetic excitatory innervation and nitrergic inhibitory innervation. Normal urethral pressure requires blood flow to the urothelium (lamina propria). Striated and smooth muscles are both thought to contribute to the resting urethral pressure in the human. The precise role of the smooth muscles during micturition is as yet unresolved. (+info)
KMD-3213, a uroselective and long-acting alpha(1a)-adrenoceptor antagonist, tested in a novel rat model.
KMD-3213, an alpha(1a)-adrenoceptor (AR) antagonist, is under development for the treatment of urinary outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we developed a rat model to investigate simply the effects of alpha(1)-AR antagonists on the intraurethral pressure (IUP) response to phenylephrine. Using this model, inhibitory effects of both i.v. and intraduodenally administered KMD-3213 on the IUP response were evaluated and compared to those of other reference compounds, including prazosin and tamsulosin. In addition, the hypotensive effects of these compounds were estimated to evaluate uroselectivity. Intravenously administered alpha(1)-AR antagonists tested, including KMD-3213, potently inhibited the IUP response in a dose-dependent manner. Although the higher doses of those compounds almost completely inhibited the IUP response, yohimbine failed to inhibit the response. When the in vivo potencies of those compounds on IUP response were correlated with their affinities for the human or animal recombinant alpha(1)-AR subtypes, alpha(1a)-AR gave the best correlation. In this model, KMD-3213 had greater uroselectivity than any other compounds examined, by both i.v. and intraduodenal routes. Moreover, 12, 18, and 24 h after the oral administration of KMD-3213, a dose-dependent inhibition of the IUP response was found, whereas the effect of tamsulosin disappeared at 18 h after the oral administration. These data indicate that KMD-3213 is a highly uroselective alpha(1)-AR antagonist with a longer duration of action. In addition, this model is useful for not only estimation of uroselectivity but also some part of the administration, distribution, metabolism, and excretion of many compounds to discover uroselective compounds. (+info)
Basolateral LAT-2 has a major role in the transepithelial flux of L-cystine in the renal proximal tubule cell line OK.
During renal reabsorption, the amino acid transporters b(o,+) and y(+)L have a major role in the apical uptake of cystine and dibasic amino acids and in the basolateral efflux of dibasic amino acids, respectively. In contrast, the transporters responsible for the basolateral efflux of the apically transported cystine are unknown. This study shows the expression of system L and y(+)L transport activities in the basolateral domain of the proximal tubule-derived cell line OK and the cloning of the corresponding LAT-2 and y(+)LAT-1 cDNAs. Stable transfection with a LAT-2 antisense sequence demonstrated the specific role of LAT-2 in the basolateral system L amino acid exchange activity in OK cells. This partial reduction of LAT-2 expression decreased apical-to-basolateral trans-epithelial flux of cystine and resulted in a twofold to threefold increase in the intracellular content of cysteine. In contrast, the content of serine, threonine, and alanine showed a tendency to decrease, whereas other LAT-2 substrates were not affected. This demonstrates that LAT-2 plays a major specific role in the net basolateral efflux of cysteine and points to LAT-2 as a candidate gene to modulate cystine reabsorption. (+info)
Surgical treatment of renal artery dissection in 25 patients: indications and results.
OBJECTIVE: Results of surgical revascularization in 25 patients with renal artery dissection (RAD) over 14 years, with mean follow-up of 55.3 months (range, 10-111 months), were analyzed. Indications for surgery were renovascular hypertension and preservation or improvement of kidney function. PATIENTS AND METHODS: Two patients (both 20 years of age) underwent emergency surgery after severe trauma; 23 patients (mean age, 41 years) underwent elective surgery in a chronic stage of disease. Preoperative, postoperative, and follow-up examinations included duplex ultrasound scanning, determination of serum creatinine and urea concentrations, and evaluation of blood pressure control. All long-term patients underwent digital subtraction angiography preoperatively and postoperatively. All histologic specimens of resected renal arteries were re-evaluated by two independent pathologists. RESULTS: Histologic re-evaluation confirmed the traumatic origin in 2 patients who underwent emergency surgery and 1 who underwent elective surgery. Renal artery dissection developed spontaneously, with no histologic signs of trauma or fibromuscular dysplasia, in 22 patients. In 17 revascularized kidneys (61%) a kidney infarction had already developed preoperatively, and the kidneys were diminished in size or function. Results of revascularization and improvement of hypertension depended on preoperative extent of renal infarction. Hypertension resolved or improved in 86% of patients without preoperative kidney damage, but in only 38% with preoperatively damaged kidneys. Kidney function was preserved in 23 of 28 revascularized kidneys (82%). During follow-up, late renal artery occlusion developed in 3 kidneys. CONCLUSIONS: Renal artery dissection can be effectively treated with surgical revascularization. Primary nephrectomy should be considered only in patients with a large ischemic kidney infarction, with significant deterioration of kidney function, to effectively cure or improve severe renovascular hypertension. (+info)
Lower urinary-interleukin-1 receptor-antagonist excretion in IgA nephropathy than in Henoch-Schonlein nephritis.
BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schonlein nephritis (HSN) share many clinical, histological and immunological features. It has been postulated that these two conditions have a common pathogenesis and that HSN might be a systemic form of IgAN. Activity of interleukin-1beta (IL-1beta) in urine has been found to be higher in IgAN and HSN patients than in healthy controls. Interaction between IL-1beta and interleukin-1 receptor antagonist (IL-1ra) plays a significant role in the regulation of inflammatory responses. We studied levels of urinary excretion of IL-1beta and IL-1ra in patients with IgAN and HSN. METHODS: Amounts of IL-1beta and IL-1ra excreted in 24-h urine samples collected from 241 IgAN, 26 HSN patients and from 33 healthy controls were determined. Results were expressed as cytokine/creatinine (ng/mmol) ratios. RESULTS: Urinary IL-1beta excretion by the IgAN and HSN patients was no greater than urinary IL-1beta excretion by healthy controls. Urinary IL-1ra excretion by the IgAN patients was lower than urinary IL-1ra excretion by healthy controls (P < 0.05) and by the HSN patients (P < 0.01). In both patients and controls women had significantly higher IL-1ra, IL-1beta excretion levels and IL-1ra/IL-1beta ratios. The differences in urinary excretions of IL-1ra by the healthy controls and by the IgAN and HSN patients were significant in both sexes. Excretion of IL-1beta or IL-1ra did not correlate with excretion of urinary protein, duration of the disease or any histopathological variable. However, histopathological changes in renal biopsy specimens from patients with IL-1ra/IL-1beta ratios above normal were significantly milder than in renal biopsy specimens from patients with low or normal IL-1ra/IL-1beta ratios. CONCLUSION: Urinary IL-1ra levels in IgAN patients were lower than urinary IL-1ra levels in healthy controls or HSN patients, a finding which may indicate that the two diseases have a different pathogenesis. Whether the male predominance in IgAN and HSN and the worse outcomes in males that have been reported previously in IgAN and HSN are connected with the lower excretion of IL-1ra and consequently lower IL-1ra/IL-1beta ratios in male patients than in female patients needs more thorough investigation. (+info)
Nitric oxide and relaxation of pig lower urinary tract.
1. We studied the non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation induced by electrical stimulation in pig isolated lower urinary tract smooth muscle, and the possible involvement of the L-arginine (L-ARG)/nitric oxide (NO) pathway in this response. 2. Trigonal strips, precontracted by noradrenaline (NA), carbachol or endothelin-1 (ET-1), relaxed frequency-dependently in response to electrical stimulation. Maximum relaxation was obtained at 6-8 Hz, and amounted to 56 +/- 2%, 77 +/- 3% and 62 +/- 6% of the agonist-induced tension in preparations contracted by NA, carbachol, or ET-1, respectively. Exposure to NG-nitro-L-arginine (L-NOARG; 10(-7)-10(-5) M) concentration-dependently reduced the relaxant response in preparations contracted by NA. L-NOARG (10(-6) M) reduced the maximal response to 51 +/- 8% of control. L-NOARG (10(-5) M) abolished all relaxation, and unmasked a contractile component; D-NOARG had no effect. Also in trigonal preparations, where the tension had been raised by carbachol or ET-1, L-NOARG (10(-5) M) markedly reduced relaxations evoked by electrical stimulation. 3. In trigonal preparations contracted by NA, maximal relaxation was increased after pretreatment with L-ARG (10(-3) M), and the inhibitory effect of L-NOARG (10(-6) M) was prevented. Incubation of the trigonal strips with methylene blue had no effect on relaxations elicited at frequencies less than 6 Hz, but a small inhibition was observed at higher frequencies. 4. Administration of NO (present in acidified solution of NaNO2) induced concentration-dependent relaxations in trigonal preparations contracted by NA, carbachol, or ET-1.L-NOARG (10-5 M) and L-ARG (10-3M) had no effect on these relaxations. However, methylene blue (10-S M) significantly shifted the concentration-response curve for NO to the right. NANC-relaxation and NO-induced relaxation of trigonal preparations were both inhibited by oxyhaemoglobin (10-5 M) and pyrogallol (10-4 M).5. In urethral preparations precontracted by NA, electrical stimulation caused frequency-dependent relaxations. A maximum relaxation of 73 +/- 4% was obtained at 10 Hz. Also in the urethra, NANCrelaxation was blocked by L-NOARG (10-5 M), and a contractile response generally appeared.6. Detrusor strips treated with alpha-beta methylene ATP (10-i M) and atropine (10-6 M), and then contracted by ET-1, showed relaxations (19 +/- 3% of the induced tension) in response to electrical field stimulation (2-20 Hz) only when the tension was high. No response at all, or small contractions, were found in response to electrical stimulation in K+ (35 mM)-contracted detrusor strips. Detrusor preparations contracted by carbachol were concentration-dependently relaxed by exogenously administered NO, SIN-1 (NO-donor), and isoprenaline, whereas vasoactive intestinal polypeptide had minor effects. NO and SIN-1 induced maximal relaxations of 63 +/- 3% and 70 +/- 4%, respectively, of the tension induced by carbachol. Isoprenaline produced an almost complete relaxation (96 +/- 4%).7. The results suggest that NANC-nerve mediated relaxation, involving the L-ARG/NO pathway, can be demonstrated consistently in the pig trigonal and urethral, but not in detrusor smooth muscle. The importance of this pathway for lower urinary tract physiology and pathophysiology remains to be established. (+info)
Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro.
1. The present study was performed to investigate how blockade of the L-arginine/nitric oxide (NO) pathway influences the function of the lower urinary tract in vivo, as studied by cystometry in conscious rats and in vitro, in isolated muscle preparations from the rat detrusor and urethra. 2. L-NG-nitro arginine methyl ester (L-NAME), 10 and 20 mg kg-1, administered intra-arterially, decreased micturition volume and bladder capacity, and increased spontaneous bladder contractions. D-NAME (20 mg kg-1) had no effect. No changes in the urodynamic parameters were recorded if L-NAME (20 mg kg-1) was administered in combination with L-arginine (200 mg kg-1). 3. Cystometries performed after intra-arterial administration of sodium nitroprusside (SNP) (3 mg kg-1) and 3-morpholino-sydnonimin hydrochloride (SIN-1, 2 mg kg-1) showed a decrease in bladder capacity, micturition volume and threshold pressure. SIN-1, but not SNP, induced spontaneous bladder contractions. 4. Isolated precontracted urethral preparations responded to electrical stimulation with a frequency-dependent tetrodotoxin-sensitive relaxation. L-NAME (10(-4) M), but not D-NAME, reduced the maximal relaxation to 31 +/- 8% (n = 8) of the response prior to drug administration. The inhibition induced by L-NAME was completely reversed by L-arginine (10(-3) M). SNP (10(-8)-10(-4) M), SIN-1 (10(-6)-3 x 10(-4) M) and NO (10(-5)-10(-3) M; present in acidified solution of NaNO2), caused relaxation (93-100%) of urethral preparations. L-NAME did not affect these relaxations.5. Detrusor strips contracted by carbachol or K' showed contractions in response to electrical stimulation, even when pretreated with a,p-methylene ATP and/or atropine. Small relaxations (14-41%) of detrusor strips were evoked by SNP (10-6-10-4M), SIN-1 (10-5-3 x 10-4M) and NO (10-5-10-3M). Electrically (20 Hz) induced contractions of the detrusor muscle were unaffected by addition of L-NAME (10-6_10-4 M) or L-arginine (10-3 M).6. The present results suggest that the L-arginine/NO pathway is of functional importance for the bladder outlet region, but that its role in the detrusor is questionable. They also suggest that the site of action of L-NAME for inducing bladder hyperactivity in the rat is the outlet region rather than the detrusor muscle. (+info)
Regulation of cyclic nucleotides in the urinary tract.
Cyclic nucleotide levels are controlled through their synthesis from nucleotide triphosphates by cyclases and their degradation to 5'-monophosphates by phosphodiesterases (PDEs). Components controlling cyclic AMP-induced relaxation in the urinary tract include receptors, inhibitory and stimulatory G-proteins, isoforms of adenylyl cyclase and PDEs. The responsiveness of PDEs to a variety of physiological challenges is related to the presence of multiple families of isoenzymes with specific localization within tissues and within cells. At least 11 families of PDEs encode more than 50 PDE proteins produced in mammalian cells. In the urinary tract, characterization of PDE isoforms has lagged behind other systems and much of the literature was published prior to identification of PDE7, 8, 9, 10, 11. Specific PDE inhibitors regulate smooth muscle function in the bladder, urethra, prostate and ureter. The pharmacological potential of these inhibitors may include treatment of urge incontinence and the low compliance bladder, and treatment of prostate cancer. G-proteins also regulate cyclic AMP production. Changes in specific G- protein isoforms with aging, most prominently Gialpha2, cause decreased relaxation response in the aging bladder. As we have seen here with aging and certainly in other disease processes, levels of the components of adenylyl cyclase/phosphodiesterase/protein kinase can change and thus affect the relaxation response. By exploitation of differences in PDE expression in disease, such as the overexpression of PDEs in cancer, treatment options may present themselves. (+info)