Karl-Erik Andersson

Direct effects of adenosine and adenine nucleotides on isolated human urinary bladder and their influence on electrically induced contractions.

Adenosine triphosphate concentration-dependent contracted strips of isolated human urinary bladder. Three types of responses were recognized. One consisted of an initial, transient, phasic contraction followed by a sustained tonic response, another lacked the tonic part and the 3rd had intermediate-type characteristics. Adenosine diphosphate produced an intermediate type of contraction, while adenosine monophosphate, adenosine and 2-chloroadenosine had no effect. Preparations obtained from hypertrophic bladders were more sensitive to adenosine triphosphate than macroscopically normal preparations. Indomethacin abolished tonic responses and reduced phasic adenosine triphosphate and adenosine diphosphate induced responses by about 30 per cent; addition of PGE2 and PGF2 alpha reestablished the phasic responses. Atropine, physostigmine, hexamethonium and phentolamine had no effect on the adenosine triphosphate induced contractions. These contractions were reduced by 33 to 48 per cent after nifedipine pretreatment and abolished within 10 minutes in a calcium-free medium. The response to transmural nerve stimulation was initially stimulated and then reduced by 30 to 80 per cent by purines in the order of potency ATP greater than APPCP = ADP greater than AMP greater than adenosine = 2-chloroadenosine. Acetylcholine induced contractions were reduced by 10 to 30 per cent. Indomethacin inhibited the response to transmural nerve stimulation by about 30 per cent but did not influence inhibition produced by adenosine triphosphate. Atropine-resistant responses to transmural nerve stimulation were significantly reduced by both adenosine triphosphate and indomethacin; nifedipine abolished the responses. The results suggest that adenosine triphosphate has a calcium-dependent direct contractive effect on isolated human urinary bladder and also that it may release prostaglandins. Muscular hypertrophy seems to increase the sensitivity to adenosine triphosphate. The response to transmural nerve stimulation was influenced by adenosine triphosphate probably both by prejunctional and postjunctional effects.

Latest Evidence on the Use of Phosphodiesterase Type 5 Inhibitors for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia

CONTEXTnSeveral preclinical reports, randomized controlled trials, systematic reviews, and posthoc analyses corroborate the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of men with lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE).nnnOBJECTIVEnUpdate of the latest evidence on the mechanisms of action, evaluate the current meta-analyses, and emphasize the results of pooled data analyses of PDE5-Is in LUTS/BPE.nnnEVIDENCE ACQUISITIONnLiterature analysis of basic researches on PDE5-Is, systematic literature search in PubMed and Scopus until May 2015 on reviews of trials on PDE5-Is, and collection of pooled data available on tadalafil 5mg.nnnEVIDENCE SYNTHESISnLatest evidences on the pathophysiology of LUTS/BPE has provided the rationale for use of PDE5-Is: (1) improvement of LUT oxygenation, (2) smooth muscle relaxation, (3) negative regulation of proliferation and transdifferentiation of LUT stroma, (4) reduction of bladder afferent nerve activity, and (5) down-regulation of prostate inflammation are the proven mechanisms of action of PDE5-Is. Data from eight systematic reviews demonstrated that PDE5-Is allow to improve LUTS (International Prostate Symptom Score mean difference vs placebo: 2.35-4.21) and erectile function (International Index of Erectile Function mean difference vs placebo: 2.25-5.66), with negligible change in flow rate (Qmax mean difference vs placebo: 0.01-1.43). Pooled data analyses revealed that tadalafil 5mg once daily allows the clinically-meaningful improvement of LUTS and nocturnal voiding frequency independent of both erectile dysfunction severity and improvement.nnnCONCLUSIONSnPDE5-Is are safe and effective in improving both LUTS and erectile function in appropriately selected men with LUTS/BPE. Data on the reduction of disease progression, long-term outcomes, and cost-effectiveness analyses are still lacking.nnnPATIENT SUMMARYnWe reviewed recent literature on phosphodiesterase type 5 inhibitors in men with lower urinary tract symptoms associated with prostatic enlargement. We found evidence to confirm that phosphodiesterase type 5 inhibitors are a valid treatment option for men affected by bothersome urinary symptoms with or without erectile dysfunction.

Digoxin inhibition of relaxation induced by prostacyclin and vasoactive intestinal polypeptide in small human placental arteries

Small chorionic plate arteries were obtained from human placentae following normal vaginal delivery. Tubal vascular preparations were dissected, mounted in organ baths, and their isometric tension was recorded. Digoxin (10(-6) M) caused a rise in basic tension, reaching a maximum of 17 per cent of contractions induced by potassium (124 mM) depolarization. Pretreatment with digoxin did not significantly influence the concentration-dependent contractile responses to 5-hydroxytryptamine and prostaglandin F2 alpha (PGF2 alpha). In preparations contracted with PGF2 alpha, cumulative addition of prostacyclin (PGI2) and vasoactive intestinal polypeptide (VIP) produced concentration dependent relaxations. Digoxin (10(-8) to 10(-6) M) inhibited and finally abolished these relaxant effects of PGI2 and VIP in a concentration-dependent fashion. Pretreatment by digoxin (10(-8) to 10(-6) M) diminished the relaxant effect of sodium nitroprusside, but the effect was less pronounced than that on PGI2- and VIP-induced relaxation. As PGI2 and VIP may be of importance for the maintenance of a low resistance of the fetal placental vascular bed, the finding that digoxin decreases the vasodilating effects of these agents might imply effects on placental resistance of cardiac glycosides when used in late human pregnancy.

Effects of prostaglandin E2 applied locally on intravesical and intraurethral pressures in women.

In 21 women undergoing simultaneous urethrocystometry because of dysuria, urge, and difficulties to empty the bladder, the effects of prostaglandin E2 (PGE2) applied locally in the bladder and urethra were investigated. In all 9 patients receiving PGE2 intravesically, the bladder pressure increased. Simultaneously, there was a signficant decrease in maximum urethral pressure (p less than 0.05), and in urethral closure pressure (p less than 0.005). Residual urine decreased in the 4 patients, in whom it exceeded 50 ml before administration. All 12 patients receiving PGE2 intraurethrally showed a decrease in maximum urethral pressure). There was a significant increase in bladder pressure (p less than 0.05); urethral closure pressure decreased in all patients. Bladder capacity decreased significantly (p less than 0.01). Residual urine exceeding 50 ml was found in 6 patients; it decreased in 4 after PGE2 administration. It is concluded that PGE2 applied intraurethrally can decrease the intraurethral pressure and increase the bladder pressure without side effects. By these actions, the drug might be useful for facilitating bladder emptying in patients with acute retention of urine.

Urothelial mucosal signaling and the overactive bladder-ICI-RS 2013.

There is abundant evidence that the lower urinary tract (LUT) mucosal layer is involved both in mechanosensory functions that regulate bladder contractile activity and in urethral sensation. Changes to the mucosa can be associated with a number of bladder pathologies. For example, alterations of the urothelium and underlying lamina propria at both the molecular and structural levels have been reported in both patients and animals associated with disorders such as bladder pain syndrome and diabetic cystopathy. In contrast to the urinary bladder, much less is known about the urothelium/lamina propria of the bladder neck/proximal urethra. There are important gender differences in the outflow region both anatomically and with respect to innervation, hormonal sensitivity, and location of the external urethral sphincter. There is reasonable evidence to support the view that the mucosal signaling pathway in the proximal urethra is important for normal voiding, but it has also been speculated that the proximal urethra can initiate bladder overactivity. When dysfunctional, the proximal urethra may be an interesting target, for example, botulinum toxin injections aiming at eliminating both urgency and incontinence due to detrusor overactivity. Neurourol. Urodynam. 33:597–601, 2014.

Nocturia: morbidity and management in adults

Nocturia is an increasingly prevalent and bothersome urinary symptom associated with considerable impact and morbidity in later life. Nocturnal frequency is associated with a number of underlying pathologies, both related and unrelated to the lower urinary tract. Following careful assessment, diagnosis and management, the condition is amenable to amelioration, if not complete cure in the majority of cases. This paper outlines the epidemiology, underlying pathophysiology and diseases associated with nocturia and reviews current treatment strategies.

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia

The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action.

Determinates of muscle precursor cell therapy efficacy in a nonhuman primate model of intrinsic urinary sphincter deficiency

BackgroundCell therapy for intrinsic urinary sphincter deficiency (ISD) in women has been moderately effective, and improvements are needed. To improve treatment efficacy, it is important to better understand determinates of cell efficacy in the different patient cohorts. We have reported that in nonhuman primates the chronicity of ISD may affect cell efficacy, but additional factors (age, psychosocial stress, hormone status, body weight) can be associated with many disease/treatment outcomes in women – and these factors are the focus of this study.MethodsAdult female cynomolgus monkeys were divided into groups: (1) younger (nu2009=u200910, 5–8 years of age) versus older (nu2009=u200910, 13–18 years of age); (2) age-matched/socially subordinate (nu2009=u200915) versus socially dominant (nu2009=u200915); and (3) age-matched lower body weight (nu2009=u20096) versus higher body weight (nu2009=u20096). Autologous skeletal muscle precursor cells (skMPCs, 5 million) were injected into the urinary sphincter 6xa0weeks after a surgically induced ISD procedure. Resting and pudendal nerve-stimulated maximal urethral pressures (MUP) were measured before, and 3 and 6xa0months post-skMPC treatment and urinary sphincter muscle/collagen content within the sphincter complex was measured by quantitative histology 6xa0months posttreatment.ResultsEfficacy of skMPCs on MUP and sphincter muscle/collagen ratios are affected by age (average 40% reduction in efficacy, pu2009<u20090.05 vs. younger NHPs), social stress (average 30% reduction in efficacy, pu2009<u20090.05 vs. socially dominant) and body weight/fasting glucose concentrations (average 35% reduction in efficacy, pu2009<u20090.05 vs. lower body weight).ConclusionMultiple factors (age, stress-induced dysmenorrhea, and body weight) affect the efficacy of cell therapy to restore structure and function in the urinary sphincter complex in NHPs with ISD. Consideration of, and alternatives for, these patient cohorts should be considered.

Can incontinence be cured? A systematic review of cure rates

BackgroundIncontinence constitutes a major health problem affecting millions of people worldwide. The present study aims to assess cure rates from treating urinary (UI) or fecal incontinence (FI) and the number of people who may remain dependent on containment strategies.MethodsMedline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PEDro were searched from January 2005 to June 2015. Supplementary searches included conference abstracts and trials registers (2013–2015). Included studies had patientsu2009≥u200918xa0years with UI or FI, reported treatment cure or success rates, hadu2009≥u200950 patients treated with any intervention recognized in international guideline algorithms, a follow-upu2009≥u20093xa0months, and were published from 2005 onwards. Title and abstract screening, full paper screening, data extraction and risk-of-bias assessment were performed independently by two reviewers. Disagreements were resolved through discussion or referral to a third reviewer where necessary. A narrative summary of included studies is presented.ResultsMost evidence was found for UI: Surgical interventions for stress UI showed a median cure rate of 82.3% (interquartile range (IQR), 72–89.5%); people with urgency UI were mostly treated using medications (median cure rate for antimuscarinicsu2009=u200949%; IQR, 35.6–58%). Pelvic floor muscle training and bulking agents showed lower cure rates for UI. Sacral neuromodulation for FI had a median cure rate of 38.6% (IQR, 35.6–40.6%).ConclusionsMany individuals were not cured and hence may continue to rely on containment. No studies were found assessing success of containment strategies. There was a lack of data in the disabled and in those with neurological diseases, in the elderly and those with cognitive impairment. Surgical interventions were effective for stress UI. Other interventions for UI and FI showed lower cure rates. Many individuals are likely to be reliant on containment strategies.PROSPERO RegistrationPROSPERO registration number: CRD42015023763.

Long-Term Caloric Restriction in Rats may Prevent Age Related Impairment of In Vitro Bladder Function

PURPOSEnBladder function is often impaired with aging. In other organs caloric restriction has had a prophylactic effect on the biological changes associated with aging. We tested the hypothesis that long-term caloric restriction can prevent age related impaired bladder function in the rat.nnnMATERIALS AND METHODSnFisher 344 male rats were divided into 3 groups, including 16 young rats at age 6 months with free access to normal food, 15 old rats at age 25 to 28 months with free access to normal food and 16 old rats at age 25 to 28 months fed with normal food 3 days per week since age 6 weeks (caloric restriction). We performed frequency volume measurements, in vitro organ bath functional studies using full-thickness longitudinal detrusor strips, evaluation of muscarinic and purinergic receptor mRNA expression, and histological examination with Masson trichrome staining of bladder tissue.nnnRESULTSnFrequency volume changes did not significantly differ among the 3 groups. The old group fed normal food showed weaker contractile responses to carbachol and electrical field stimulation (especially in the cholinergic component), lower M3 receptor mRNA expression and higher collagen deposition compared to the young group. These age related bladder changes were milder in the old group with caloric restriction than in the old group fed normal food.nnnCONCLUSIONSnThis study suggests that in the rat long-term caloric restriction has a preventive effect against age related functional and morphological bladder changes. These changes include impaired detrusor contractility that may be related to decreased expression of M3 receptors and to bladder wall fibrosis.