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Biomedical subjects

I Eardley

Publications and source records attributed to I Eardley.

At least 19 recordsLinked to original sources
PubMed2002

Potassium channel KV alpha1 subunit expression and function in human detrusor muscle.

PURPOSE: We determined whether voltage gated K+ (KV) channels are expressed and functional in human detrusor smooth muscle MATERIALS AND METHODS: Information on KV channels was obtained using electrophysiological patch clamp, immunofluorescence, Western blot and isometric tension recording techniques RESULTS: Patch clamp recordings from detrusor cells revealed a Ca2+ independent K+ current that was activated by depolarization in a voltage range near the resting potential of detrusor smooth muscle. The current was inhibited by 3,4-diaminopyridine, a blocker of KV channels. Antibodies targeted to KValpha1 subunits revealed KV1.3 and KV1.6 expression in whole bladder tissue samples and specifically in detrusor smooth muscle cells. New specific blockers of KValpha1 channel currents (correolide and recombinant agitoxin-2) had a myogenic effect, characterized by increased amplitude of spontaneous contractions without an effect on the frequency of contractions or on resting baseline tension. CONCLUSIONS: KValpha1 subunits are expressed and functionally important in human detrusor muscle.

Animals↗
PubMed2002

Tadalafil (Cialis) for men with erectile dysfunction.

Tadalafil is an inhibitor of phosphodiesterase type 5, and is currently undergoing regulatory review in the US and in Europe. Its chemical structure is significantly different from sildenafil, and in vitro studies confirm significant potency for PDE5 inhibition, with little activity against most of the other isoforms of the enzyme including PDE6, which is the isoform of the enzyme found within the retina. The half-life of tadalafil is 17.5 hours and clinical studies suggest significant activity 24 hours post-dosing. As with sildenafil, efficacy depends upon a normal sexual stimulus, and the drug can taken be as required. Tadalafil is effective in the treatment of men with erectile dysfunction, and it appears to have a relatively mild side-effect profile, with no visual side-effects noted.

Carbolines↗
PubMed2002

A systematic approach to erectile dysfunction in the cardiovascular patient: a Consensus Statement--update 2002.

Sexual activity is no more stressful to the heart when compared with a number of other natural daily activities, e.g. walking one mile on the level in 20 minutes. The cardiac risk of sexual activity in patients diagnosed with cardiovascular disease is minimal in properly assessed and advised patients. Erectile dysfunction (ED) is extremely common, affecting over half of men aged 40-70 years, and increases in frequency with age. ED and cardiovascular disease share many of the same risk factors and commonly coexist. ED in the otherwise asymptomatic man may be a marker for underlying coronary artery disease. ED in the diagnosed cardiovascular patient should be identified by routine questioning in general practice. Modern therapies can restore a sexual relationship in the majority of patients with ED and can lead to a substantial improvement in quality of life. The majority of patients assessed to be at low or intermediate cardiac risk, as defined later in this paper, can be effectively managed in primary care. Primary care treatment for ED in patients defined as high risk can be initiated following a specialist opinion and/or confirmation that the patient's cardiovascular condition is stabilised. There is no evidence that currently licensed treatments for ED add to the overall cardiovascular risk in patients with or without diagnosed cardiovascular disease. If one form of therapy is not effective, follow-up will identify the need for alternative approaches. The pro-active management of ED in the cardiovascular patient provides an ideal and effective opportunity to address other cardiovascular risk factors and improve treatment outcomes.

Activities of Daily Living↗
PubMed2001

Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes.

OBJECTIVE: To examine nitric-oxide (NO)-mediated relaxation in cavernosal smooth muscle in a rat model of diabetes, as previous experiments showed that HbA1c (an isoform of glycosylated haemoglobin and a marker of long-term diabetic control) impaired NO-mediated relaxation of normal corpus cavernosal tissue through the generation of superoxide anions. MATERIALS AND METHODS: Eight weeks after the induction of diabetes, male Wistar rats were killed and cavernosal tissue obtained. Strips were contracted with 1 micromol/L noradrenaline before applying acetylcholine or electrical field stimulation (EFS) or sodium nitroprusside (SNP). Relaxation responses were repeated in the presence of L-arginine (100 micromol/L), indomethacin (10 micromol/L) or superoxide dismutase (SOD, 120 IU/mL). Young and age-matched control animals were examined in the same way. RESULTS: Eight weeks of uncontrolled diabetes caused a significant impairment in mean relaxation responses to acetylcholine (P < 0.05) and to EFS (P < 0.05), but not to SNP, compared with young and age-matched controls, respectively. L-arginine, indomethacin and SOD had no significant effect on this impairment. Ageing caused a lesser but significant impairment in EFS-mediated cavernosal smooth muscle relaxation (P < 0.05). CONCLUSION: Diabetes impairs endothelial and neuronal NO-mediated cavernosal smooth muscle relaxation in rats in vitro. This effect is not mediated by an alteration in the intracellular action of NO, the availability of NO, superoxide anion inactivation of NO or the generation of constrictor prostanoids. It is possible that cholesterol or advanced glycation end products are responsible for the effect of diabetes on penile smooth function.

Acetylcholine↗
PubMed2001

Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes.

OBJECTIVE: To determine if advanced glycation end-products (AGEs) are responsible for the lower neuronal and endothelial-derived nitric oxide (NO)-mediated relaxation of corpus cavernosum in tissue in diabetic rats than in control rats. MATERIALS AND METHODS: Diabetes was induced in male Wistar rats by an intraperitoneal injection with streptozotocin (60 mg/kg). One group of diabetic rats was given free access to water and standard diet. A second group was given standard diet and aminoguanidine with their water (50 mg/100 mL) from the initiation of diabetes. Two groups of rats that were not diabetic acted as age-matched controls. After 8 weeks animals were killed by cervical dislocation, corpus cavernosal tissue strips harvested and mounted in an organ bath to measure isometric tension. After 90 min of equilibration at optimal resting tension and contraction with 1 micromol/L noradrenaline, the response to either acetylcholine or electrical field stimulation (EFS) after adding guanethidine (5 micromol/L) and atropine (1 micromol/L) was determined for each group. RESULTS: There was no difference between the baseline characteristics of all the experimental groups. After 8 weeks the mean body mass and glycosylated haemoglobin (HbA1c) were significantly greater in the diabetic than in control animals. Aminoguanidine had no effect on the recorded body mass or HbA1c. The in vitro relaxation response to the application of acetylcholine or EFS of tissue strips from age-matched control animals fed a standard diet and those supplemented with aminoguanidine were the same. The administration of aminoguanidine to diabetic animals for 8 weeks reversed the expected impaired relaxation response to acetylcholine; the response to EFS was similar. CONCLUSION: AGEs are more prevalent in erectile tissue from diabetic than in control animals. Aminoguanidine reversed the impairment in neuronal and endothelial NO-mediated penile smooth muscle relaxation seen in diabetes. As aminoguanidine prevents AGE formation, erectile dysfunction in diabetes is probably caused partly by the generation of AGEs.

Animals↗
PubMed2001

The interaction of nitric oxide and prostaglandins in the control of corporal smooth muscle tone: evidence for production of a cyclooxygenase-derived endothelium-contracting factor.

OBJECTIVE: To investigate the interaction of endothelium-derived nitric oxide (NO) and prostaglandins (PGs) in regulating corporal smooth muscle tone in vitro. Materials and methods Strips of rabbit corpus cavernosum were mounted in organ chambers for the measurement of isometric tension. Strips were submaximally contracted with noradrenaline and concentration-response curves (CRCs) to acetylcholine (ACh) were constructed before and after treatment with 5 micromol/L atropine, 20 micromol of the cyclooxygenase inhibitor indomethacin and 10 micromol of the PGH2/thromboxane A2 receptor antagonist SQ29548. The NO synthase (NOS) inhibitors L-NG-monomethyl arginine (L-NMMA) and L-NG-nitroarginine (L-NOARG) were added to strips at tonic tension in the presence and absence of indomethacin, and after this CRCs to ACh were constructed. RESULTS: The addition of ACh to strips produced a concentration-dependent relaxation which was inhibited by atropine. Indomethacin, but not SQ29548, significantly increased relaxation to ACh. Relaxation to ACh was impaired by L-NMMA, but adding ACh to strips treated with L-NOARG resulted in contractile responses, whilst both effects were reversed by indomethacin. L-NMMA and L-NOARG led to increases in tonic tone which were unaffected by indomethacin. CONCLUSIONS: In rabbit corpus cavernosum there is a tonic release of NO which does not appear to be inhibited by a vasoconstrictor prostanoid. Endothelium-dependent relaxation to ACh results in the dual production of NO and a cyclooxygenase-derived endothelium contracting factor which acts in opposition to NO; this factor is unlikely to act on PGH2/TXA2 receptors.

Acetylcholine↗
PubMed2001

Efficacy and safety of sildenafil citrate in the treatment of men with mild to moderate erectile dysfunction.

BACKGROUND: Erectile dysfunction is a common, multi-factorial disorder. AIMS: To evaluate the efficacy, tolerability and frequency of use of sildenafil citrate in men with mild to moderate erectile dysfunction of no established organic cause. METHOD: This double-blind, randomised, placebo-controlled, flexible-dose, two-way crossover study was conducted at four centres in the UK in 44 men with mild to moderate erectile dysfunction of no clinically obvious organic cause. The study included two 28-day treatment periods, during which time sildenafil or placebo (25-75 mg, based on efficacy) was taken as required. RESULTS: Compared with placebo, sildenafil was associated with increases in frequency of use, erections adequate for sexual intercourse and level of sexual satisfaction (P:<0.0001). More patients receiving sildenafil stated they would use the treatment again compared with those receiving placebo (P:<0.0001). There were no discontinuations due to sildenafil treatment. CONCLUSIONS: Sildenafil is effective and well tolerated in men with mild to moderate erectile dysfunction of no clinically identifiable organic cause.

Adolescent↗
PubMed2001

The role of nitric oxide in penile erection.

The functional state of the penis, flaccid or erect is governed by smooth muscle tone. Sympathetic contractile factors maintain flaccidity whilst parasympathetic factors induce smooth muscle relaxation and erection. It is generally accepted that nitric oxide (NO) is the principal agent responsible for relaxation of penile smooth muscle. NO is derived from two principal sources: directly from non-adrenergic non-cholinergic parasympathetic nerves and indirectly from the endothelium lining cavernosal sinusoids and blood vessels in response to cholinergic stimulation. The generation of NO from L-arginine is catalysed by nitric oxide synthase (NOS). There has been controversy over the relative prevalence of endothelial or neuronal NOS within the penis of different animal species. This review examines the role of NO in the penis in detail. Established and new treatments for erectile dysfunction whose effects are mediated via manipulation of the NO pathway are also described.

Animals↗
PubMed2001

The pathophysiological role of prostaglandins in penile erection.

Penile erection is a complex haemodynamic event and relaxation of the vascular smooth muscle of the penis is fundamental to this process. This is primarily mediated by nitric oxide (NO) produced from non-adrenergic non-cholinergic (NANC) nerves and the endothelium surrounding the corporal sinusoids. However, corporal tissue has been shown to produce a number of other vasoactive factors, including prostaglandins (PGs), which appear to not only have diverse physiological effects, but are also able to modulate the effects of other neurotransmitters, including NO.

Collagen↗
PubMed2000

Endothelial and neuronal-derived nitric oxide mediated relaxation of corpus cavernosal smooth muscle in a rat, in vitro, model of erectile function.

We set out to establish a simple, reproducible, rat in vitro model of erectile function and to use this to demonstrate the functional importance of both neuronal- and endothelial-derived nitric oxide within this animal. Two corpora cavernosal smooth muscle strips were harvested from sexually mature male Wistar rats and mounted in an organ bath for measurement of isometric tension. Following contraction with noradrenaline the strips were relaxed by the addition of either acetylcholine or sodium nitroprusside. Electrical field stimulation was performed in the presence of atropine and guanethidine. Relaxation responses were repeated in the presence of methylene blue, L-arginine, L-NNA and haemoglobin +/- L-arginine. Methylene blue abolishes the relaxation to acetylcholine and EFS; L-NNA and haemoglobin cause a significant impairment in the relaxation response. L-arginine reverses the effect of haemoglobin. In conclusion, the inhibitory, relaxant stimulus of rat corpora cavernosa is due to both neuronal nitric oxide and endothelial-derived nitric oxide released in response to cholinergic stimulation.

Animals↗
PubMed2000

Single dose methodology to assess the influence of an alpha1-adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia.

AIMS: To establish methodology which rapidly and reliably assesses the effect of an alpha1-adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH. METHODS: Twenty-five patients with BPH enrolled in a double-blind, placebo-controlled, two-period crossover study. Patients were either withdrawn from their current alpha1-adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s-1 off therapy (or < 10 ml s-1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s-1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two-period crossover. Uroflowmetry was performed predose and once postdose (4.5-5.5 h postdose) on day 1, and once postdose (4.5-5.5 h postdose) on day 8 of each treatment period. RESULTS: After a single dose of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s-1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s-1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference). CONCLUSIONS: Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for 'responsiveness' to an alpha1-adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis.

OBJECTIVES: To determine, in a double-blind placebo-controlled crossover study, whether L-arginine improves the symptoms of interstitial cystitis (IC), a chronic condition in which nitric oxide (NO) may be important, as previous open pilot studies suggested that L-arginine reduced the pain and frequency associated with IC. PATIENTS AND METHODS: Patients fulfilling the standard diagnostic criteria for IC were randomized to receive L-arginine (2.4 g/day) or placebo for one month. After a 2-week 'washout' period they received the other medication. Patients were assessed at each stage using a validated symptom index, a voiding diary, urine analysis and records of adverse events. Patients were asked about overall efficacy at the close of the study. The results were compared using a t-test, with significance indicated at P<0.05. RESULTS: Sixteen (16) patients (mean age 51.3 years) were enrolled; the mean duration of IC was 5.4 years, the IC symptom index score 29.1, their nocturnal frequency 3.5 (voided volume 182 mL) and daytime frequency 12.7 (124 mL). Patients on placebo showed no differences in any recorded variable over the baseline values. L-arginine caused a statistically significant reduction in the overall symptom score of 2.2 over baseline, but there was no difference in voided volume, frequency or nocturia. As there was no significant difference for any variable between L-arginine and placebo, this reduction in score should be regarded with caution. Three patients withdrew because of side-effects (severe headaches, night sweats and flushing). CONCLUSION: Oral L-arginine produces a statistically significant improvement in the IC symptom index in patients with IC, but the effect is small. This effect may not be clinically significant as there were no improvements in the other variables assessed and no significant difference between the response to L-arginine and placebo. From these results the use of L-arginine cannot be recommended for treating IC.

Adult↗
PubMed2000

Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin.

OBJECTIVE: To examine the effect of HbA1c, an isoform of glycosylated haemoglobin (GHb, a product of non-enzymatic reactions between elevated blood glucose and haemoglobin), on nitric oxide-mediated corpus cavernosal smooth muscle relaxation, and to categorize the mechanisms involved. MATERIALS AND METHODS: Corpus cavernosal tissue from Wistar rats (300-350 g body weight) was prepared for the measurement of isometric tension. After equilibration in Krebs solution gassed with 95% O2/5% CO2 at 37 degrees C for 90 min, optimal resting tension was applied. Tissue was precontracted with 1 micromol/L noradrenaline (NAd) and either relaxed with incremental doses of acetylcholine (ACh) or sodium nitroprusside (SNP). After washout, strips were again precontracted with NAd and then incubated with pyrogallol (100 micromol/L), 100 microL of haemoglobin or 100 microL of GHb in the presence of either L-arginine (100 micromol/L), indomethacin (10 micromol/L), allopurinol (100 micromol/L), deferoxamine (100 micromol/L), catalase (600 IU/mL), or superoxide dismutase (SOD) (120 IU/mL) before ACh- or SNP-induced relaxation responses were repeated. RESULTS: Haemoglobin and GHb significantly impaired the relaxation of rat corpus cavernosum to ACh in a dose-dependent manner. L-arginine reversed the impairment caused by Hb, but not GHb. A donor of superoxide anions, pyrogallol, mimicked this impairment to ACh when added to control strips. Catalase, deferoxamine, indomethacin and allopurinol had no significant effect on the impaired relaxation response to ACh, whilst L-arginine partially reversed it. SOD completely reversed the GHb-induced impaired relaxation; GHb did not alter the relaxation response to SNP. CONCLUSION: GHb significantly impairs endothelial NO-mediated corpus cavernosal relaxation in the rat, in vitro. This effect is caused partly by the generation of superoxide anions and the extracellular inactivation of NO.

Acetylcholine↗
PubMed2000

The role of prostaglandins in penile erection.

The balance of penile smooth muscle tone is finely controlled, with contractile factors acting in opposition to relaxant factors. The principal agents in this process are undoubtedly noradrenaline and nitric oxide. Prostaglandins probably have a crucial role in the 'fine tuning' of corporal smooth muscle tone. Their effects on control mechanisms in the healthy penis are more likely to be modulatory rather than direct.

Endothelium↗
PubMed2000

The effect of cyclic GMP on rabbit corporal smooth muscle tone and its modulation by cyclo-oxygenase products.

Corporal smooth muscle (CSM) tone is maintained by a finite balance between relaxant and contractile neurotransmitters. The aim of these experiments was to ascertain the degree to which cyclic GMP is involved in these interactions. We also sought to elucidate the pharmacological mechanism of action of MB in rabbit corpus cavernosum (RCC), an important tool in nitric oxide research. Using an organ chamber technique, strips of RCC were treated with the guanylate cyclase inhibitors Methylene Blue (MB) and LY83583; 100 microM MB led to increases in resting tension which were antagonized by indomethacin, nifedipine, phentolamine, but not superoxide dismutase (SOD). Contractile responses to noradrenaline (NA) were increased and relaxation to ACh was impaired by both MB and LY83583 and reversed with indomethacin, but not SOD. Pyrogallol had no effect on agonist-induced responses. The pharmacological action of MB in RCC does not depend on the generation of superoxide anions. Endothelium-dependent relaxation in RCC results in activation of soluble guanylate cyclase and release of a stable endothelium derived contracting factor(s), which is likely to be a constrictor prostanoid(s). Tonic production of cGMP in RCC inhibits the presynaptic release and contractile effects of NA and can be modulated by cyclo-oxygenase inhibition, demonstrating the important interaction and functional antagonism between cGMP and prostaglandins in the control of CSM tone.

Acetylcholine↗