Vasculogenic erectile dysfunction: beyond the haemodynamic changes.
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Atherosclerosis↗
Biomedical subjects
Kazem M Azadzoi
Publications and source records attributed to Kazem M Azadzoi.
Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants.
PURPOSE: We searched for markers of oxidative stress in cavernous ischemia and examined the effect of long-term antioxidant intake on arteriogenic erectile dysfunction (ED) in the rabbit. MATERIALS AND METHODS: Antioxidant activity of known antioxidant beverages, such as pomegranate juice (PJ), red wine, blueberry juice, cranberry juice, orange juice and green tea, was examined spectrophotometrically. PJ demonstrated the highest free radical scavenging capacity. The effect of long-term PJ intake on intracavernous blood flow and penile erection was then examined in the rabbit model. Erectile tissues were processed to assess oxidative stress and smooth muscle relaxation, immunohistochemical staining of nitric oxide synthase (NOS) and histomorphometry. RESULTS: On spectrophotometric analysis PJ showed the highest capacity to decrease low density lipoprotein oxidation and inhibit cellular oxidative stress in macrophages. The rabbit model of arteriogenic ED demonstrated decreased intracavernous blood flow, erectile dysfunction, loss of smooth muscle relaxation, decreased endothelial NOS and neuronal NOS, increased inducible NOS expression, diffused cavernous fibrosis and increased cavernous levels of the oxidative product isoprostane 8-epi-prostaglandin F2alpha. Long-term PJ intake increased intracavernous blood flow, improved erectile response and smooth muscle relaxation in ED and control groups while having no significant effect on NOS expression. PJ intake prevented erectile tissue fibrosis in the ED group. CONCLUSIONS: Arteriogenic ED accumulates oxidative products in erectile tissue, possibly via an intrinsic mechanism. Oxidative stress may be of great importance in the pathophysiology of arteriogenic ED. Antioxidant therapy may be a useful prophylactic tool for preventing smooth muscle dysfunction and fibrosis in ED.
Animals↗
Alteration of urothelial-mediated tone in the ischemic bladder: role of eicosanoids.
AIMS: Previously we showed that ischemia alters bladder smooth muscle contractility in the rabbit. This study investigates the role of urothelium and eicosanoid-release in ischemic bladder smooth muscle instability. MATERIALS AND METHODS: Male New Zealand white rabbits were divided into treated (n = 12) and age-matched control (n = 10) groups. The treated group underwent balloon endothelial injury of the iliac arteries, and then received 4 weeks of cholesterol diet, followed by 4 weeks of regular diet. The control group received a regular diet for 8 weeks. After 8 weeks, blood flow for both the iliac arteries and the bladder as well as bladder oxygen tension were recorded. In one-half of each ischemic and control bladder, the urothelium was removed. Bladder tissues were processed for organ bath and enzyme-immunoassay (EIA) of prostaglandins (PGs) and leukotrienes (LTs). RESULTS: A significant decrease in iliac arterial blood flow, bladder wall blood flow, and bladder oxygen tension was found in the treated group. Bladder ischemia increased the frequency and amplitude of baseline spontaneous smooth muscle contractility. Ischemic tissues with urothelium (Uro+) demonstrated significant increases in the contractile response to electrical field stimulation (EFS) and carbachol relative to control Uro+ tissues. Urothelial removal increased smooth muscle contraction in the control tissues but had no significant effect in the ischemic/hypoxic tissues. Contraction of control tissues without urothelium (Uro-) was similar to contraction of ischemic Uro+ tissues. Contractions of ischemic Uro+ and control Uro- tissues were unchanged after treatment with the cyclooxygenase (COX) inhibitor indomethacin, while they were significantly reduced by the 5-lipoxygenase (5-LO) inhibitor NDGA. EIA showed no change in PGs release from the ischemic urothelium, but significant increase in PGF(2-alpha) and thromboxane A(2) release from the ischemic suburothelial tissue. Ischemia increased the release of LTB(4), LTC(4), and LTE(4) from both urothelium and suburothelial tissue. CONCLUSIONS: Our studies suggest loss of urothelial-mediated tone and LTs-mediated smooth muscle instability in the chronically ischemic/hypoxic bladder.
Animals↗
Effect of chronic ischemia on bladder structure and function.
Our studies with the animal model show that arterial stenosis and insufficiency--a common problem in the elderly--lead to marked changes in bladder structure and function. Moderate chronic ischemia leads to functional and structural changes quite different from those caused by severe chronic ischemia. The extent of histopathophysiologic changes in the chronically ischemic bladder depends on the degree of arterial stenotic disease and the severity of bladder ischemia. Histopathophysiologic changes in our animal model appear to be similar in many ways to those reported in clinical detrusor instability. This would suggest that vascular risk factors and ensuing arterial obstructive disease and bladder ischemia might play an important role in the development of bladder dysfunction. A better understanding of the involvement of vascular risk factors in voiding dysfunction may lead to more accurate assessment of LUTS, precise patient selection for prostatectomy, and the development of prophylactic strategies and newer treatment.
Animals↗
Increased leukotriene and prostaglandin release, and overactivity in the chronically ischemic bladder.
PURPOSE: Chronic ischemia has been shown to alter bladder contractility. We studied the roles of cyclooxygenase (COX) and lipoxygenase products in ischemia induced bladder overactivity in the rabbit. MATERIALS AND METHODS: A total of 28 male New Zealand White rabbits were divided into 2 groups. In group 1 atherosclerotic occlusion of the iliac arteries was induced by balloon endothelial injury, followed by a short period of a high cholesterol diet. Group 2 received a regular diet alone. After 12 weeks blood flow measurements and cystometry were performed. Bladder tissues were processed for enzyme immunoassay of leukotrienes and prostaglandins (PGs), Western blotting of COX and lipoxygenase, isometric tension measurement and histology. RESULTS: Atherosclerotic occlusion of the iliac arteries significantly decreased bladder blood flow. Moderate ischemia caused bladder overactivity, while severe ischemia inhibited bladder contractions. Ischemia increased leukotriene B4, E4 and C4 release by 141%, 132% and 254%, and increased PG F2alpha and thromboxane A2 release by 95% and 93%, respectively, although it did not alter PG E2 release. Western blotting showed increased 5-lipoxygenase, COX-1 and COX-2 protein levels in ischemic bladder tissues. Moderate ischemia increased bladder smooth muscle contraction in response to carbachol and electrical field stimulation. Tissue treatment with the COX inhibitor indomethacin significantly increased control tissue contraction but had no effect on ischemic tissues. Treatment with the 5-lipoxygenase inhibitor REV5901 abolished this effect of indomethacin in control tissues. Treatment with REV5901 significantly decreased the contraction of ischemic tissues but had no significant effect on control tissues. The effect of indomethacin plus REV5901 was similar to the effect of REV5901 alone. Histology showed urothelial thickening and mild fibrosis in the moderately ischemic bladder. CONCLUSIONS: Chronic ischemia increased bladder 5-lipoxygenase, and COX-1 and COX-2 protein expression, and altered leukotriene and PG production. Treatment with COX and lipoxygenase inhibitors produced completely different effects in the ischemic bladder compared with the control bladder. Functional changes in the ischemic bladder were concurrent with structural changes in the urothelium. PGs modulate smooth muscle contractility in the healthy bladder. However, under ischemic conditions leukotrienes dominate bladder tone and appear to have a leading role in increased smooth muscle contraction and bladder overactivity.
Animals↗
Chronic ischemia increases prostatic smooth muscle contraction in the rabbit.
PURPOSE: We studied the effect of chronic ischemia on prostatic smooth muscle contraction in the rabbit. MATERIALS AND METHODS: New Zealand male rabbits weighing 3 to 3.5 kg were assigned to 2 groups. Group 1 (10 rabbits) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet for 4 weeks and then a regular diet for 8 weeks. Control group 2 (10 rabbits) received a regular diet. After 12 weeks the animals were anesthetized. Iliac artery and prostate blood flow was recorded. Prostate tissues were prepared for isometric tension measurement, enzyme immunoassay to determine cyclic guanosine monophosphate (cGMP) release and histological examination. RESULTS: In group 1 atherosclerosis as well as a significant decrease in iliac artery and prostate blood flow were observed. Ischemia significantly increased prostatic tissue contraction, decreased cGMP release and led to capsular and stromal thickening, and epithelial atrophy. The alpha1-adrenoceptor blocker doxazosin and the phosphodiesterase-5 inhibitor sildenafil citrate significantly decreased the contraction of control and ischemic tissues. Doxazosin was more effective in decreasing contractions when it was combined with sildenafil or the nitric oxide (NO) precursor L-arginine. In contrast, doxazosin was less effective when it was combined with the NO synthase inhibitor N omega-nitro-L-arginine or with the guanylate cyclase inhibitor methylene blue. Doxazosin significantly increased cGMP release in control tissues but not in ischemic tissues. Sildenafil significantly increased cGMP release in control and ischemic tissues. CONCLUSIONS: Ischemia increased prostatic smooth muscle contraction and led to marked structural damage. Stimulators of NO synthesis and cGMP production enhanced the efficacy of doxazosin in decreasing prostatic tissue contraction. Sildenafil decreased contractility and increased cGMP release. Increased smooth muscle tone and structural changes in the ischemic prostate may suggest a role for prostate ischemia in resistance to urinary flow independent of prostate size.
Adrenergic alpha-Antagonists↗
Vasculogenic erectile dysfunction: newer therapeutic strategies.
PURPOSE: Despite recent advances in therapy, reversal of vasculogenic erectile dysfunction (ED) is rarely possible. A review of vasculogenic ED may further our understanding of the underlying pathophysiology and help develop more effective curative therapy. MATERIALS AND METHODS: We reviewed the mechanisms of vasculogenic erectile dysfunction and discuss the therapies currently available or being developed for possible future use. RESULTS: Penile erection is a complex neurovascular phenomenon that may be affected by hypercholesterolemia, atherosclerotic vascular occlusive disease, veno-occlusive dysfunction and cavernosal fibrosis. Animal models of diffuse pelvic atherosclerosis can be maintained by feeding oral cholesterol and injuring the arterial endothelium. Impaired inflow may be addressed by penile revascularization but this strategy is applicable only in select cases. Neovascularization using vascular growth factors has recently been demonstrated to be feasible in animal models. Permanent reversal of impaired cavernosal relaxation requires control of hypercholesterolemia and lifestyle changes, such as smoking cessation. Cavernosal fibrosis may be reversible via some of the same approaches used in treating Peyronie's disease but to date little clinical success has been reported. Venous ligation appears to have a limited role in treating veno-occlusive dysfunction only in highly selected men with minimal cavernosal smooth muscle dysfunction. Hypoxemia, sleep apnea and respiratory failure may also affect erectile dysfunction. However, little attention has been paid to oxygen as therapy for ED. CONCLUSIONS: Current therapy, while effective in circumventing vasculogenic ED, is relatively ineffective in permanently reversing the condition. Further research aimed at long-term treatment strategies in vasculogenic ED is needed.
Animals↗
Regulation of blood flow and microcirculation resistance in rabbit bladder.
PURPOSE: Human and animal studies have shown that filling, contraction and emptying produce cyclical changes in bladder blood flow. The mechanism of these hemodynamic changes remains unclear. We studied the regulation of bladder blood flow in the rabbit model. MATERIALS AND METHODS: A total of 18 male New Zealand White rabbits were anesthetized. Arterial pressure, intravesical pressure, and dome and base blood flow were measured simultaneously in the empty bladder, at 25 and 50 ml. intravesical volume, and after draining. These measurements were recorded before and then after intravenous administration of atropine, phentolamine, propranolol, L-arginine or N-nitro-L-arginine. Changes in dome and base microcirculation resistance, and blood flow after treatment were compared with those recorded before treatment. RESULTS: In the empty bladder dome microcirculation resistance was greater than at the base and base blood flow was greater than at the dome. Filling increased dome microcirculation resistance, decreased dome blood flow and increased base blood flow without changing base microcirculation resistance. Emptying produced much greater reactive hyperemia at the dome than at the base. Atropine did not alter microcirculation resistance or blood flow. Phentolamine had no effect on dome or base microcirculation resistance, blood flow in the empty bladder or at 25 ml. intravesical volume but it decreased dome microcirculation resistance at 50 ml. intravesical volume. Propranolol caused dome contraction, increased dome microcirculation resistance and decreased dome blood flow in the empty bladder, and at 25 and 50 ml. intravesical volume. Propranolol increased base blood flow without changing base microcirculation resistance. N-nitro-L-arginine increased dome microcirculation resistance in the empty bladder and at 25 ml. intravesical volume but decreased dome blood flow in the empty bladder alone. N-nitro-L-arginine increased base microcirculation resistance and decreased base blood flow in the empty bladder and at 25 ml. intravesical volume but not at 50 ml. intravesical volume. L-arginine decreased dome and base microcirculation resistance, and increased blood flow in the empty bladder, and at 25 and 50 ml. intravesical volume. Reactive hyperemia decreased after N-nitro-L-arginine and increased after L-arginine. CONCLUSIONS: Our studies show large variations in bladder dome and base microcirculation resistance and blood flow. Bladder blood flow appears to be largely regulated locally by nitric oxide mediated changes in bladder microcirculation resistance. beta-adrenergic receptors may regulate bladder blood flow indirectly by modulating dome tension and shifting blood flow between the dome and base. Mechanical changes in bladder wall and vasculature shape may also contribute to changes in microcirculation resistance.
Animals↗
Blood flow, pressure and compliance in the male human bladder.
PURPOSE: The regulation of human bladder blood flow during filling is poorly understood. We characterized changes in bladder blood flow with filling and examined the relationship of bladder compliance and blood flow. MATERIALS AND METHODS: A total of 17 awake male patients underwent saline cystometry followed by cystoscopy while under local anesthesia, during which a laser Doppler flow probe was placed into the posterior bladder wall detrusor. Systemic blood pressure, bladder blood flow and intravesical pressure were measured with the bladder empty and filled to 25%, 50%, 75% and 100% of awake maximum cystometric capacity as well as immediately after bladder drainage. RESULTS: Mean bladder blood flow was lowest in the empty bladder and increased with bladder filling. A mean peak flow plus or minus standard error of 7.6 +/- 1.1 ml. per minute per 100 gm. tissue was observed at volumes greater than 75% but less than 100% of maximum cystometric capacity. At 100% maximum cystometric capacity mean intravesical pressure increased by 73% from 25.2 to 43.5 cm. water and bladder blood flow decreased by 36%. Rapid bladder drainage was associated with a rebound in mean bladder blood flow to approximately 1.6 times baseline. Bladder compliance calculated for the whole filling curve positively correlated with bladder blood flow (p = 0.025), that is low compliance was associated with low blood flow. CONCLUSIONS: Human bladder blood flow tends to increase with increasing volume and pressure, and depends largely on local regulation. At capacity bladder blood flow is significantly decreased. Immediately after bladder drainage there is a rebound in blood flow, allowing reperfusion to occur. Decreased bladder blood flow and decreased bladder wall compliance correlated strongly, suggesting that ischemia may lead to structural changes in the bladder wall.
Adult↗
Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue.
Arterial occlusive disease is one of the leading causes of organic erectile dysfunction (ED). Recent studies have shown that the incidence of cardiovascular disease closely correlates with the prevalence of ED. Also, ED is thought to be an early signal of impending cardiovascular problems. We previously found that the atherosclerosis of iliohypogastric arteries in the rabbit causes ED, down-regulates cavernosal neuronal nitric oxide synthase (nNOS) gene expression, and impairs NO synthesis. The goal of this study was to determine the effect of atherosclerosis-induced ischemia on cavernosal nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) expression and NO-mediated smooth muscle relaxation in the rabbit. Our study showed that iliac artery blood flow, intracavernosal blood flow, and intracavernosal oxygen tension were unchanged 4 weeks after the induction of arterial atherosclerosis, whereas they were significantly diminished at weeks 8 and 16. Erectile responses to nerve stimulation and cavernosal smooth muscle relaxation were unchanged at week 4 and were significantly diminished at weeks 8 and 16 after the induction of atherosclerosis. Western blotting showed that cavernosal nNOS and eNOS protein levels were unaffected at week 4 but were significantly decreased at weeks 8 and 16 after the induction of atherosclerosis. iNOS protein, however, markedly increased during the course of the induced arterial disease. Immunohistochemical staining showed no change in cavernosal eNOS or nNOS expression at week 4. A dramatic decrease in both was evident at 8 and 16 weeks. iNOS expression progressively increased between 4 and 16 weeks of atherosclerosis. Down-regulation of nNOS and eNOS, along with up-regulation of iNOS, may explain ischemic cavernosal smooth muscle relaxation impairment in the rabbit. Ischemically altered NOS expression may be of great pathophysiologic importance in atherosclerosis-induced ED. These data may provide further insight into the mechanism of arteriogenic ED.
Animals↗
Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction.
Endothelins have been postulated to be important regulators of penile erectile function. The endothelin-A receptor antagonist BMS-193884 was evaluated as a treatment for mild-to-moderate erectile dysfunction in an animal model and in human volunteer subjects. In laboratory studies, organ bath preparations of rabbit and human penile cavernosal tissue strips were incubated with BMS-193884 and exposed to increasing concentrations of endothelins. In rabbit tissue, 1 microM BMS-193884 significantly inhibited contraction to ET-1, ET-2, and ET-3 by 34.5%, 42.9%, and 100%, respectively. In human tissue, 1 microM BMS-193884 inhibited contraction to ET-2 by 44.4%. In rabbit tissue strips contracted with 20 nM of ET-1 or ET-2, BMS-1 93884 caused dose-dependent relaxation with EC50 values of 107.2 +/- 32.3 nM and 1.7 +/- 0.5 nM, respectively. In anesthetized male rabbits, intravenous administration of BMS-193884 (systemic plasma concentration approximately 50 and 100 nM) increased the duration of pelvic nerve-stimulated penile erection. To further assess the safety and efficacy of BMS-193884, 53 men diagnosed with mild-to-moderate erectile dysfunction were administered oral placebo or 100 mg BMS-193884 in a double-blind fashion. Evaluations were based on 1) erectile function testing during 2 in-office visits and 2) diary and questionnaire data of 4 intercourse attempts over 2-4 weeks of home use. Although the drug was well tolerated, BMS-193884 did not significantly improve erectile function during office visits or home use when compared to placebo. Thus, BMS-193884 facilitated cavernosal smooth muscle relaxation ex vivo and prolonged penile tumescence in vivo. In contrast, a pilot clinical study failed to show enhancement of erectile response in men with mild-to-moderate erectile dysfunction. The disparity between the laboratory and clinical studies suggests that there may be differences between species with regard to the role of endothelin in erectile function.
Administration, Oral↗