Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin.
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Glycated Hemoglobin↗
Biomedical subjects
R J Morgan
Publications and source records attributed to R J Morgan.
Possible role of endothelin-1 in the rabbit urinary bladder hyperplasia secondary to partial bladder outlet obstruction.
OBJECTIVES: Urinary bladder hypertrophy and hyperplasia are common features of bladder outlet obstruction (BOO). The urinary bladder is known to synthesize endothelin-1 (ET-1), which is a potent vasoconstrictor peptide with mitogenic properties. Using an animal model of partial BOO, we investigated the potential role of ET-1 and its receptor subtypes (ET(A) and ET(B)) in bladder smooth muscle cell (SMC) proliferation. MATERIALS AND METHODS: Partial BOO was produced in adult male New Zealand White rabbits. After 3 weeks, the bladder was removed and SMCs from the dome and bladder neck were grown using standard explant methodology. At passage 2, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or partial BOO serum (BRS) in the presence or absence of ET(A)-antagonist (BQ123) or ET(B)-antagonist (BQ788). SMC proliferation was then measured 24 h later with 5-bromo-2'deoxy-uracil and by cell counting using a haemocytometer at 48 h. Immunostaining for alpha-actin was performed on detrusor and bladder neck cells to confirm the presence of smooth muscle cells. RESULTS: BQ123 and BQ788 did not influence detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of BRS, BQ123 and BQ788 (100 nmol/L) significantly (p = 0.008) inhibited detrusor and bladder neck SMC proliferation. Cell counts were significantly reduced from the detrusor (p = 0.03, p = 0.01 with BQ123 and BQ788, respectively) and bladder neck (p = 0.01 for both BQ123 and BQ78). CONCLUSIONS: These results suggest that ET antagonists may have a role in preventing SMC hyperplasia associated with partial BOO.
Animals↗
Altered cavernosal endothelin-B-receptor binding sites in the rabbit model of partial bladder outlet obstruction.
Erectile dysfunction (ED) is a common problem that significantly affects the quality of life. Benign prostatic hyperplasia (BPH) is the commonest known benign proliferative disorder. Recently there has been growing evidence to suggest that patients with high BPH symptom scores have an increased incidence of ED. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is thought to play an important role as a modulator of erectile physiology and dysfunction. We investigated whether there are any changes in the density and distribution of ET-1 and its receptor subtypes in the corpora cavernosa (CC) of a rabbit model of partial bladder outflow obstruction (BOO). ET-1, endothelin-A- and -B- (ET(A) and ET(B)) receptor binding sites were primarily localized to the smooth muscle cells (SMC) of the CC and the endothelium lining the cavernosal space. ET(B)-receptor binding sites were significantly decreased (p = 0.04) in the 6-week BOO cavernosal tissue. ET-1 may play a role in the pathophysiology of ED associated with BPH. This may be partly a result of enhanced vasoconstrictor actions and SMC proliferation secondary to a reduction in ET(B)-receptors. Further work is needed to evaluate this possibility.
Animals↗
Endothelin-1 and urinary bladder hyperplasia following partial bladder outlet obstruction.
Urinary bladder hypertrophy and hyperplasia is a common feature of bladder outlet obstruction (BOO). The urinary bladder is known to synthesize endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor peptide with mitogenic properties. Using an animal model of partial BOO we investigated the potential role of ET-1 and its receptor subtypes [endothelin-A and -B (ET(A) and ET(B))] in bladder vascular smooth muscle cells (SMC) proliferation. In the presence of 3-week-old BOO serum, ET(A) and ET(B) antagonists significantly (p = 0.008) inhibited detrusor and bladder neck SMC proliferation. Cell counts were significantly reduced from the detrusor (p = 0.03, p = 0.01 with ET(A) and ET(B) antagonists, respectively) and bladder neck (p = 0.01 for both ET(A) and ET(B) antagonists). These results suggest that ET-1 antagonists may prevent SMC hyperplasia associated with partial BOO.
Animals↗
Urological aspects of female sexual dysfunction.
The aetiology of male sexual dysfunction has been extensively investigated over the past few decades. This has led to the development of effective treatment for this common problem. However, to date, female sexual dysfunction has received very little attention, particularly from a urological point of view. In this review, we discuss the anatomy and physiology of the female sexual organs as well as the aetiological factors that are associated with female sexual dysfunction. An improved awareness and understanding of this subject may, in the future, enable us to address female sexual dysfunction more appropriately and develop suitable treatment.
Female↗
Public awareness of cigarette smoking and erectile dysfunction.
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Adult↗
The molecular basis of penile erection.
Over the past two decades our understanding of the physiology and the various mediators involved in the pathway of penile erection has greatly increased. This has enabled us to develop effective pharmacological treatments for ED.
Animals↗
The treatment of hypertension in patients with erectile dysfunction.
Hypertension is another predictor of erectile dysfunction (ED). This is further evidence supporting a link between the pathogenesis of atherosclerotic disease and ED. In one study (TOMHS) involving hypertensive patients, the incidence of ED was 14.4%. The drugs used to treat hypertension may cause ED. However, there is little trial-based evidence to indicate which drugs are more likely to cause this side effect. In general, thiazide diuretics and beta-blockers seem to cause ED more often. In contrast, the alpha-blocker, doxazosin, has not been associated with an increased incidence of ED as a side effect. Doxazosin also improves urinary flow in patients with benign prostatic hyperplasia (BPH). This condition is common in elderly men as is hypertension and ED. Therefore, doxazosin may present a special advantage among this group of patients. This alpha-blocker would also be a good choice in patients with impaired glucose tolerance/diabetes because it improves insulin sensitivity. Moreover, ED and hypertension are more prevalent among diabetics. On a more speculative note, doxazosin may potentiate the therapeutic impact of specific treatments for ED.
Antihypertensive Agents↗
Sildenafil: a urologist's view.
Erectile dysfunction (ED) is a common problem with a multifactorial aetiology. The treatment of ED has been revolutionised by the introduction of intracavernosal injections some two decades ago. However, the recent development of the orally-administered drug sildenafil (Viagra) has had a major impact on the treatment of ED. We discuss the trials with sildenafil with special reference to cardiovascular risk factors associated with ED.
Adult↗
Normal and pathological erectile function: the potential clinical role of endothelin-1 antagonists.
Erectile dysfunction (ED) is a common problem, particularly in older men. The production of penile erection involves an interplay between autonomic nerves and locally released vasoactive mediators. Endothelin-1 (ET-1) is a peptide released from endothelium in the corpus cavernosum, which causes smooth muscle contraction. Recent studies have investigated the physiological significance of ET-1 in the control of erectile function and it may play a role in detumescence. There is also much evidence to link ET-1 to risk factors for ED. ET-1 antagonists may prove beneficial in the treatment of ED and also in prevention of long term deterioration of erectile function. These antagonists may also find a role when used in combination with agents, which are established for the treatment of ED.
Animals↗
Chemoprevention: an important treatment option for prostate cancer.
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Aged↗
Interactions between nitric oxide and endothelin-1 in vessels from hypercholesterolaemic rabbits.
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Animals↗
Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease?
There is convincing evidence that the prevalence of erectile dysfunction is increased among men with ischaemic heart disease. This association may be attributed to the fact that both erectile dysfunction and ischaemic heart disease share similar risk factors (e.g. hypertension, dyslipidaemia, diabetes and smoking). Nitric oxide (NO) activity is adversely affected, in penile and vascular tissue, by these risk factors. It is therefore not surprising that a defect in NO activity is thought to play a role in the pathogenesis of both erectile dysfunction and ischaemic heart disease. We consider this evidence and propose that defective NO activity provides a unifying explanation for the association between these two conditions. Further research in this area may improve our understanding of the pathogenesis of cardiovascular diseases as a whole.
Cardiovascular Diseases↗
Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and cyclophosphamide in previously untreated patients with advanced ovarian cancer-long-term follow-up.
Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.
Adult↗
Up-regulation of endothelin (ET(A) and ET(B)) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction.
Bladder outlet obstruction (BOO) is associated with altered bladder structure and function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties. There are two ET receptors: ET(A) and ET(B). Nitric oxide synthase (NOS) is the enzyme responsible for the synthesis of nitric oxide (NO) which is involved in smooth muscle relaxation. We investigated whether there are any changes in the density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit model of BOO. Partial BOO was induced in adult male New Zealand White rabbits. Sham operated age-matched rabbits acted as controls. After six weeks the urinary bladders were excised and detrusor and bladder neck sections incubated with radioligands for ET-1, ET(A) and ET(B) receptors and with [3H]-1-NOARG (a ligand for NOS). NADPH histochemistry was also performed. BOO bladder weights were significantly increased (P = 0.002). ET-1 binding and ETA receptor binding sites were significantly increased in the BOO detrusor smooth muscle (P = 0.04, P = 0.03 respectively) and urothelium (P = 0.002, P = 0.02 respectively). ET(B) receptor binding sites were also significantly increased in the BOO detrusor smooth muscle (P = 0.04). However, there was no change in the BOO bladder neck. NOS was significantly decreased in the detrusor smooth muscle (P = 0.003) and urothelium (P = 0.0002). In the bladder neck NOS was also significantly reduced in the urothelium (P = 0.003). NADPH staining was decreased in the detrusor and bladder neck. The up-regulation of ET receptors along with the down-regulation of NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET-1 has a mitogenic role, especially via its ETA receptors, the increase in ETA receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET antagonists may therefore have a role in the treatment of patients with BOO.
Animals↗
Alterations in the formation of cyclic nucleotides and prostaglandins in the lower urinary tract of the diabetic rabbit.
Dysfunction of the urinary bladder is a recognised complication of diabetes mellitus (DM) which has been attributed, in part, to a direct effect on bladder smooth muscle tissue. The objective of this study was to investigate the effect of alloxan-induced DM on endogenous modulators of smooth muscle tone such as cyclic AMP (cAMP), cyclic GMP (cGMP) and prostaglandins. Male New Zealand white rabbits were rendered diabetic (hyperosmolar, non-ketotic) with an i.v. injection of alloxan. After 6 months, the urinary bladders and urethrae were excised, cut into segments, incubated with stimulators and the formation of prostaglandins (PG), cAMP and cGMP measured using radioimmunoassays. PGE2 and PGI2 formation was impaired in response to arachidonic acid stimulation, whereas it was increased in response to acetylcholine in DM detrusor, bladder neck and urethra compared to controls. Cyclic AMP and cGMP formation in response to forskolin and sodium nitroprusside, respectively, was significantly reduced in the DM tissues of the lower urinary tract compared to the control. Alterations in the formation of prostaglandins, cAMP and cGMP by the smooth muscle of DM lower urinary tract suggests that these biochemical mediators may have a pathophysiological role in the urinary bladder dysfunction associated with DM.
Animals↗
Time-dependent up-regulation of neuronal 5-hydroxytryptamine binding sites in the detrusor of a rabbit model of partial bladder outlet obstruction.
Serotonin (5-hydroxytryptamine; 5-HT), a vasoactive bioamine with potent contractile activity, is thought to act indirectly in the urinary bladder by the stimulation of its presynaptic receptors. This results in the release of acetylcholine (ACh), which then acts on muscarinic receptors to produce bladder contractility. Bladder outlet obstruction (BOO) can lead to detrusor instability associated with denervation supersensitivity to ACh. Using a rabbit model of partial BOO, we investigated whether there were any associated changes in the neuronal 5-HT binding sites. Partial BOO was induced in adult male New Zealand White rabbits. Sham-operated age-matched rabbits acted as controls. After 1, 3 and 6 weeks the urinary bladders were excised. Detrusor sections were incubated with [(3)H]-5-HT. Autoradiographs were generated and analysed densitometrically. The presence of nerves was detected using immunohistochemistry with NF200. Autoradiography demonstrated a time-dependent, significant (P < 0.0001) up-regulation of [(3)H]-5-HT binding sites in the detrusor smooth muscle after the induction of BOO. Immunohistochemistry confirmed that the [(3)H]-5-HT binding sites were neuronal. In the rabbit model of partial BOO there was a significant time-dependent up-regulation of neuronal [(3)H]-5-HT binding sites in the detrusor. This change may influence 5-HT-mediated ACh release, resulting in increased bladder contractility. This, in turn, may play a role in detrusor instability associated with denervation post-junctional supersensitivity. These results provide a possible rationale for further investigation into the use of 5-HT antagonists in the treatment of detrusor instability associated with BOO.
Animals↗
Down-regulation of endothelin-B receptor sites in cavernosal tissue of a rabbit model of partial bladder outlet obstruction: potential clinical relevance.
Erectile dysfunction (ED) is a common problem that significantly affects quality of life and psychological well-being. Benign prostatic hyperplasia (BPH) is the commonest known benign proliferative disorder. Recently there has been growing evidence to suggest that patients with high BPH symptom scores have an increased incidence of ED. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is thought to play an important role as a modulator of erectile physiology and dysfunction. We investigated whether there were any changes in the penile histology and in the density and distribution of ET-1 and its receptor subtypes in the corpora cavernosa of a rabbit model of partial bladder outflow obstruction (BOO). BOO was induced in 12 adult New Zealand White rabbits; 12 sham-operated rabbits acted as controls. Penises were excised after 3 and 6 weeks (n=6 each for control and BOO). Low- and high-resolution autoradiography was performed using radioligands for ET-1, ET(A) and ET(B) receptors and the results were analysed densitometrically. Ultrastructural evaluation of the corpus cavernosum (CC) was also performed. ET-1, ET(A) and ET(B) receptor-binding sites were primarily localised to the smooth-muscle cells (SMC) of the CC and to the endothelium lining the cavernosal space. ET(B) receptor-binding sites were significantly decreased (P=0.04) in the 6-week BOO cavernosal tissue. These receptor changes were accompanied by ultrastructural changes in the CC. ET-1 may play a role in the pathophysiology of ED associated with BPH. This may partly be due to enhanced vasoconstrictor actions and SMC proliferation secondary to a reduction in ET(B) receptors. Further work is needed to evaluate this possibility.
Actins↗