Biomedical subjects
Publications and source records attributed to S Minhas.
Erectile dysfunction is a common disease affecting the lives of millions of men worldwide. Sildenafil was the first oral treatment licensed for male erectile dysfunction. However, there are now a number of other options available. In this article the currently available oral treatments are reviewed.
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OBJECTIVE: To evaluate the outcome of patients undergoing the immediate insertion of a penile prosthesis as a treatment for acute low-flow priapism. PATIENTS AND METHODS: Eight patients presenting with low-flow priapism with a mean duration of 91 h (range 32-192) were prospectively evaluated. All had failed conservative management with the instillation of alpha-adrenergic agents, and four had already undergone shunt procedures elsewhere. Immediate management consisted of the insertion of a malleable prosthesis in six patients and an inflatable prosthesis in two. One of the malleable prostheses was subsequently changed to an inflatable device. RESULTS: There were no early complications, with all patients being satisfied with the end result, and seven having sexual intercourse. One patient developed a penile deformity after surgery, cause by fibrosis around one inflatable cylinder. All patients have maintained their penile length. CONCLUSIONS: Prolonged low-flow priapism results in a variable degree of cavernosal fibrosis and a subsequent loss of penile length. The delayed insertion of a penile prosthesis can be difficult, with high complication rates. The immediate insertion of a penile prosthesis in patients with prolonged low-flow priapism is simple and maintains penile length. This should always be offered to the patient at initial presentation, as the complication rate is low and the subsequent outcome excellent.
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Priapism is defined as a prolonged penile erection that fails to subside despite orgasm. It is a medical emergency which should be diagnosed and treated early to preserve erectile function and avoid corporal fibrosis resulting from anoxia of the corporal tissue. Decompression is usually successful with no permanent damage if treatment is provided within 12 hours of onset.
Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse. It is a significant male health problem of global dimensions affecting approximately 150 million men worldwide. A broad range of options are currently available for the management of ED. They include oral agents (phosphodiesterase 5 inhibitors, dopamine agonists and alpha-receptor blocking drugs), intracavernosal injection (papaverine, phentolamine, prostaglandin E1, vasoactive intestinal peptide), transurethral vasoactive agents (prostaglandin E1), vacuum erection devices, vascular surgery and penile prostheses. Here we review the physiology of penile erection and the currently available oral preparations. In addition, novel therapeutic strategies to improve erectile function are discussed.
Penile erection is dependent upon vascular smooth muscle relaxation in erectile tissue and penile arteries, the principal mediator of relaxation being nitric oxide (NO). Evidence from basic scientific studies indicates that oxidative stress mediated through the superoxide radical (superoxide) and other reactive oxygen species (ROS) may be central to impaired cavernosal function in erectile dysfunction (ED). Increased inactivation of NO by superoxide results in impaired penile NO transmission and smooth muscle relaxation. Furthermore, propagation of endothelial dysfunction by ROS may result in chronic impairment of penile vascular function, a process analogous to early atherogenesis. Indeed, ED and atherosclerosis are closely linked through shared risk factors. Given our current understanding of ED pathophysiology, antioxidants may be of benefit in both the short- and long-term. Evidence supporting the paradigm of antioxidant therapy for the prevention or treatment of ED is presented herein.
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.
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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.
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.
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.
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.
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.
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OBJECTIVE: To assess the role of extra-anatomic stents (EAS) as a means of urinary diversion in patients with ureteric obstruction secondary to malignancy. PATIENTS AND METHODS: The technique for inserting EAS in patients with ureteric obstruction was described previously; to date, 13 patients (seven women and six men, mean age 45.3 years, range 22-78) have been treated. All patients had ultrasonographic evidence of hydronephrosis and/or significant biochemical evidence of renal impairment. Patients had advanced malignancy and one patient an abdominal aortic aneurysm. RESULTS: Urinary diversion was successful in all patients; two survived for more than 1 year, with stent changes at 6-monthly intervals. In three patients the stents were replaced by percutaneous nephrostomies because of problems with leakage or infection. The remaining patients died with functioning EAS in situ. CONCLUSIONS: In patients with ureteric obstruction secondary to malignancy or medical conditions excluding them from more invasive surgery, EAS provide a further therapeutic option instead of a permanent nephrostomy, which has associated inherent problems. This technique is not without potential problems and careful selection of patients remains vital in this difficult area.