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Eicosanoids, impotence and pharmacologically induced erection
Pmtaglandins Lcukotrienesand Essential Fatty Acids (1990) 40,239~242 @ Lm.gnan Group UK Ltd 1990
Eicosanoids, Impotence and Pharmacologically Induced Erection A selected symposium overview of the 1st International Symposium on Pharmacological Erection, Paris, 17 November 1989 Aetiology of impotence and clinical-experimental correlations
man in relation to the incidence of both atheroma and impotence (8). A relationship between the duration of DM and impotence is also evident in both the experimental models and patients (9). These findings suggested (l-3) that the initiation of erection was associated with a cholinergic-induced release of PGIz which then contributed to the increased penile blood flow observed at this stage of sexual activity. The discussion of these findings led to the identification of several additional correlations between the clinical and the experimental situation (presented at the 1st International Symposium on Pharmacological Erection, Paris 1989); these are summarised below:
The first eicosanoid-related presentation of the meeting concerned the use of the rat penis as a model for the study of the role of prostacyclin (PG13 in the pathogenesis of impotence. Dr D. P. Mikhailidis reviewed the work (l-3) carried out at the Royal Free Hospital School of Medicine (London, UK) using this animal model. The rat penis releases PG12 following the in vitro addition of cholinergic, but not adrenergic, agonists. Furthermore, streptozotocin-induced diabetes mellitus (DM) in the rat was associated with a significant reduction (up to 50%) in penile PGIz release. Incubating healthy or DM rat penile tissue with cigarette smoke extracts also resulted in the significant inhibition of local PGIZ release (4). A reduction in PGI, release is not a universal phenomenon in DM since an increase, as well as a lack of change, in the release of this eicosanoid has been documented (5, 6). These animal-based findings gained pathological credibility when it was confirmed that human corpus cavernosum tissue also releases PGI, in response to cholinergic, but not adrenergic, agonists (2). The animal-based findings suggest that PG12 plays a role in mediating erection since they correlate well with the human situation. Thus, cholinergic stimuli are associated with the increase in penile blood flow necessary to induce erection and PGL, which was shown to be released by this stimulus, is a vasodilator. Moreover, adrenergic stimulation, which is known to contribute to detumescence, had no effect on PGI, release. This agonist-PGI? relationship is somewhat organ specific since the aorta in the same animals responds to adrenergic, but not cholinergic, agonists (7). Smoking and DM are major risk factors for both impotence and atheroma (8). Therefore, the major decrease in penile PG12 synthesis caused by DM and cigarette smoke extracts is in accordance with the concept that this eicosanoid plays a role in the pathogenesis of impotence. The cumulative effect of smoking and DM observed in animals has been documented in
Al
Bl
239
G Conti (University of Fribourg, Switzerland) and R Virag (CERI, Paris, France) showed that there was an association between the decrease in the amount (and morphology) of smooth muscle in human corpus cavernosum tissue and the severity of erectile dysfunction. We suggest that this association could be explained by the fact that smooth muscle is known (10) to produce considerable amounts of PGI?. In fact, smooth muscle may produce more PGI, than the endothelium because it is quantitatively much better represented in the corpus cavernosum. The local deficiency of PGIz may then in turn impair vasodilatation. It was also suggested that PGI, may help reduce venous drainage from the penis since it is known to have contractile capacity on corpus cavernosum tissue (11). This view is supported by the observation that the main problem observed in this category of patients was an increase in ‘venous leakage’ from the erect/semi-erect penis. There is convincing evidence indicating that the distension of a PGI?-producing organ is associated with the increased release of this eicosanoid (12-15). Therefore, the same rationale as that outlined in (A) above may also account for the changes in flow observed during therapeutic perfusions aimed at restoring erectile function. These intracavernous perfusions were realized by Virag and Shoukry (Virag, R and Shoukry, K: CERI, Paris, France; unpublished observations) for patients presenting with erectile dysfunction due to arterial insufficiency secondary to either atheroma of the vascular tree supplying the penis or to the complications of diabetes mellitus. Thus, the intracavernous infusion of 20400 ml of physiological saline per min is required to induce erection. In contrast, a flow of lo-40 ml/min is required to maintain erection once it has been achieved by the
240 Prostaglandins Leukotrienes and Essential Fatty Acids
Cl
Dl
mittal perfusion volume. Erection is thus sustained for lo-15 min. Consequently, it was suggested that the distension of the corpora cavenosa results in the local release of PGI, which in turn contributes to the reduction in venous outflow. Clinical results obtained from therapeutic perfusions indicate that they re-establish spontaneous erectile function and restore an active sexual life. There did not appear to be a scientific explanation to account for the improvement (often marked in extent and lasting a few months) in erection following corpus cavernosum perfusion. However, it is possible that an increase in PGI, release (as described in B above) exerts a beneficial effect on the local vasculature. A similar improvement in patients with peripheral vascular disease has been documented (16, 17) following the intravascular infusion of PGI?; these latter effects also last for a few months. Dr A Ledda (University of Chieti, Italy) presented evidence that penile blood flow in impotent men was significantly diminished 10 min after smoking one cigarette. Furthermore, cessation of smoking for a period of four weeks resulted in a significant improvement in flow. These findings are in agreement with the concept that PGI2 plays a role in mediating increases in penile blood flow. These findings also support those of Glina et al (18) which indicate that smoking impairs papaverine-induced erection in man.
Diagnosis and treatment of impotence Dr R Hasun (Krankenanstalt Rudolfstiftung der Stagt, Vienna, Austria) presented the results of trials where the intracavernous injection of PGEi was successfully used to diagnose and treat impotence. This group consider that PGEi is a first line drug in this field. This conclusion was reached after the entry of 260 patients into an autoinjection protocol. Some of these patients had as many as 200 injections without any fibrosis or angulation. Dr M Sohn (University Clinics of RWTH Aachen, Aachen, West Germany) also reported satisfactory results with PGEi with a low incidence of systemic side-effects. (tachycardia, blood pressure fluctuations). The clinical experience of Virag and Shoukry (Virag, R and Shoukry, K; unpublished results) indicates that patients with moderate maintaining insufficiency manifest more systemic effects after the intracavernous administration of PGEr. These side-effects include temporary flushes, throbbing headaches, malaise that may end in marked hypotension, cold sweats, pallor and even loss of consciousness and marked venous incompetence necessitating the use of saline infusions and intravenous corticoids. Dr W Halbig (Stadtische Kliniken Neuss, Neuss, West Germany) reported that the majority of patients with negative erection responses to intracavernous papaverine, or papaverine + phentolamine, responded to intracavernous PGEi injection. Dr R Tulli (Clinica de Cirugia Cardiovascular, Sao Paulo, Brazil) presented his experience with PGE, during pe-
nile caversnosometry. Dr A Dittrich (Bundeswehrkrankenhaus, Hamburg, West Germany) presented the results of a study where PGE, solutions were used to distend the corpora cavernosa of impotent patients. This treatment was considered successful since a large number (70%) of patients reported that further autoinjections were not necessary to obtain satisfactory intercourse. These findings are similar to those discussed in (C) above. Dr A H Bennett (Albany Medical Centre, Albany, New York, USA) described his successful use of a combination of papaverine, PGE, and phentolamine for autoinjection. There was a general agreement amongst the delegates for a need to develop such combinations since they were likely to be more potent, safer (in relation to the incidence of priapism) and less costly than single drug preparations. Evidence was also presented (Dr R Virag, CERI, Paris, France) that the transcutaneous application of another eicosanoid, PGE2, was not associated with a therapeutic benefit. Dr C G McMahon (Burns Bay Medical Center, Sydney, Australia) claimed that PGEi may suppress the anxiety effects of erection probably by decreasing the action of endogenous catecholamines. Dr H Claes (A. Z. Sint-Pieter, Leuven, Belgium) discussed the results of a double blind study showing that local (penile shaft) transcutaneous nitroglycerine therapy may help improve penile function in patients suffering from impotence. The drug action may be local and/or systemic since very high concentrations were detected in the antecubital veins of the arm. These observations are of interest to those working with eicosanoids because nitroglycerine is a potent stimulator of vascular PG12 release from the .vascular endothelium (19). Dr R Virag (CERI, Paris, France) concluded that testing intracavernous PGEi at a dose of 6.6 pg in randomly selected patients complaining of impotence resulted in a complete erection lasting for 1 h and resolving spontaneously in 25% of cases. Only 4% of these patients had a prolonged erection. Hence this dose is safe as regards the risk of prolonged erection, but using it alone for initial evaluation may result in the underestimation of the patient’s true erectile response. There was considerable discussion as to whether PGEl was superior to papaverine, or papaverine + phentolamine, in terms of potency and safety. The results with PGE, presented at the meeting or cited in the literature (19-25) are very encouraging. There was, however, general agreement that more experience with this prostaglandin was necessary before a final judgement could be made. In this context, the animal experiments (26) which showed penile fibrosis occurring following the administration of papaverine but not after PGEi were dis-
Eicosanoids, Impotence and Pharmacologically
Induced Erection
cussed. The conclusions from this latter study were,
however, limited by the high doses of papaverine injected, the increased frequency of administration and the possibility of species differences.
GENERAL COMMENTS It was surprising that there were no reports on the effect of PG12 administration since this eicosanoid is available in its natural form and as stable analogs. These preparations have been extensively investigated for the treatment of various forms of vascular disease (16, 17). It is hoped that such investigations will be initiated as a result of the lively discussions that followed several presentations. It will be important to consider, however, that although PG12 is a more potent vasodilator than PGEl it is also a contractor of corpus cavernosum muscle, unlike PGE, which is a relaxor (11). Another surprise was that there was no awareness of any published work showing that the human penis can actually synthesise PGE, . This state of affairs is even more surprising when one considers that all the successful clinical trials are actually based on the intracavernous administration of PGE,! We hope that readers who are aware of such evidence will write to the Editors of this journal so that the relevant study can be mentioned in the correspondence section. There was no work presented concerning eicosanoids other than PGE,, PGE? and PG12. It is to consider that other important, however, eicosanoids, and their specific receptors, have been identified in the penis. All these eicosanoids often have opposing actions and they probably interact as part of normal penile function. A similar interplay between eicosanoids has been proposed for the urinary bladder (27). It was also mentioned that eicosanoids may influence neurotransmitter (e.g. noradrenaline) action (28, 29). Researchers in this field should also consider that eicosanoids may play a role in the normal production-function of sperm (30) and contribute to the mechanism of ejaculation (31). A brief review of the role of eicosanoids in erectile function has been published elsewhere (32). D P Mikhailidis J Y Jeremy Dept. of Chemical Pathology & Human Metabolism Royal Free Hospital & School of Medicine (University of London) Pond Street London NW3 20G, UK K Shoukry R Virag Centre d’Etudes et de Recherche de I’lmpuissance 18 Rue Boissiere 75116 Paris, France (Correspondence of JYJ)
1. leremy J Y, Mikhailidis D P, Dandona P.
Giuscarinic stimulation of prostacyclin synthesis by he rat penis. Eur J PhaAacol 1986; li3: 67-71 leremv J Y. Morean R J. Mikhailidis D P. Dandina P: Prosracyclin synthesis by the corpora :avernosa of the human penis: evidence for nuscarinic control and pathological implications. Prostagl Leukotr Med 1986; 23: 211-16. leremy J Y, Thompson C S, Mikhailidis D P, Dandona P. Experimental diabetes mellitus inhibits lrostacyclin synthesis by the rat penis: pathological mplications. Diabetologia 1985; 28: 365-68. 4. leremy J Y, Mikhailidis D P, Dandona P. The :ffect of cigarette smoke and diabetes mellitus on muscarinic stimulation of prostacyclin synthesis by the rat penis. Diab Res 1986; 3: 467-69. 5. Colwell J A. Winocour P D, Lopez-Virella M. Halushka P V. New concepts about the pathogenesis of atherosclerosis in diabetes mellitus. Am J Med 1983; 75 (suppl. 5B): 67-80. 6 Jeremy J Y, Mikhailidis D P. Thompson C S. Dandona P. The effect of streptozotocin-induced diabetes on PGI, synthesis by the rat bladder. J Ural 1986; 135: 1290-92. Jeremy J V, Mikhailidis D P, Dandona P. Adrenergic stimulation of vascular prostacyclin (PGI,) secretion. Eur J Pharmacol 1985: 114: 33-40. 8. Virag R. Bouilly P. Frydman D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; i: 181-84. 9. Kaiser F E. Korenman S G. Impotence in diabetes mellitus. Am J Med 1988; 85 (suppl. 5A): 147-52. IO. Moncada S. Herman A. Higgs E A. Vane J R. Differential formation of prostacyclin (PGX or PGI:) by layers of the arterial wall. An explanation for the antithrombotic properties of vascular endothelium. Thromb Res 1977; I I: 323-35. II. Hedlund H. Andersson K-E. Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J Ural l9k5; 134: 1245-50. I2 Ritter J M. Barrow S E. Blair I A. Dollerv C T. Release of prostacyclin in vivo and its role in man. Lancet 1983; i: 317-19. 13 Jeremy J Y. Mikhailidis D P. Dandona P. The rat urinary bladder synthesises prostacyclin as well as other prostanoids. Prostagl Leukotr Med 1984; 16: 235-42. I4 Tsang V. Jeremy J Y. Mikhailidis D P. Walesby R K. Wright J C. Dandona P. Release of prostacy& from the human aorta. Cardiovasc Res 1988; 22: 489-93. I5 Ritter J M, Hamilton G. Barrow S E et al. Prostacyclin in the circulation of patients with with vascular disorders undergoing surgery. Clin Sci lY86; 71: 743-47. I6 Belch J J F, Newman P, Drury J K et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud’s syndrome. Lancet 1983; i: 313-15. 17. Belch J J F. McKay A, McArdle B et al. Epoprostenol (prostacvclin) and severe arterial disease. A double-blinh trial. Lancet 1983; i: 315-17 18. Glina S. Reichelt A C. Leao P P. DOS Reis J M S M. Impact of cigarette smoking on papaverine-induced erection. J Urol 1988: 140: 523-24. IO. Levin R I. Jaffe E A, Weksler B B, Tackgoldman K. Nitroglycerin stimulates synthesis of prostacyclin by cultured human endothelial cells. J Clin Invest 1981; 67: 762-6. 20 Waldhauser M, Schramek P. Efficiency and side-effects of prostaglandin E, in the treatment of erectile dysfunction. J Urol 1988; 140: 525-27.
241
242 Prostaglandins
Leukotrienes and Essential Fatty Acids
21. Lee L M, Stevenson R W D, Szasz G. Prostaglandin E, versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J Urol 1989; 141: 549-50. 22. Sarsody M F, Hudnall C H, Erickson D R, Hardin T C, Novicki D E. A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E, in the treatment of impotence. J Urol 1989; 141: 551-53. 23. Stack1 W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E, in impotent men. J Ural 1988; 140: 66-68. 24. Virag R, Adaikan PG. Effects of prostaglandin E, on penile erection and erectile failure. J Urol 1987; 137: 1010. 25. Hwang T I-S, Yang C-R, Wang S-J, Chang C-L. Tzai T-S, Chang C-H, Wu H-C. Impotence evaluated by the use of prostaglandin E,. J Urol 1989; 141: 1357-59. 26. Aboseif S R, Breza J, Bosch R J L, et al. Local and systemic effects of chronic intracavernous injection
27.
28.
29.
30.
31.
32.
ot papaverine, prostaglandin E, and saline in primates. J Urol 1989; 142: 403-08. Mikhailidis D P, Jeremy J Y, Dandona P. Urinary bladder prostanoids: their synthesis, function and possible role in the pathogenesis and treatment of disease. J Urol 1987; 137: 577-82. Trachte C J. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves. J Pharmacol Exoer Ther 1986: 237: 473-77. Serio R, Daniel E E. gicosanoids and peripheral neurotransmission. Prostagl Leukotr Essntl Fatty Acids: Reviews 1989; 38: 237-46. Yamamoto M, Hashimoto J, Takaba H, Miyake. Response of the isolated human semineferous tub;le to prostaglandins Flalpha,Fzalphil,E, and E,. J Urol 1987: 137: 345-48. Gottlieb d, Bygdeman M. Prostanoids in sperm function. Prostagl Leukotr Essntl Fatty Acids: Reviews 1988; 34: 205-14. Jeremv J Y. Mikhailidis D P. Prostanoids and impotence. Br J Sexual Med 1989; 16: 411-13.
Eicosanoids, Impotence and Pharmacologically Induced Erection A selected symposium overview of the 1st International Symposium on Pharmacological Erection, Paris, 17 November 1989 Aetiology of impotence and clinical-experimental correlations
man in relation to the incidence of both atheroma and impotence (8). A relationship between the duration of DM and impotence is also evident in both the experimental models and patients (9). These findings suggested (l-3) that the initiation of erection was associated with a cholinergic-induced release of PGIz which then contributed to the increased penile blood flow observed at this stage of sexual activity. The discussion of these findings led to the identification of several additional correlations between the clinical and the experimental situation (presented at the 1st International Symposium on Pharmacological Erection, Paris 1989); these are summarised below:
The first eicosanoid-related presentation of the meeting concerned the use of the rat penis as a model for the study of the role of prostacyclin (PG13 in the pathogenesis of impotence. Dr D. P. Mikhailidis reviewed the work (l-3) carried out at the Royal Free Hospital School of Medicine (London, UK) using this animal model. The rat penis releases PG12 following the in vitro addition of cholinergic, but not adrenergic, agonists. Furthermore, streptozotocin-induced diabetes mellitus (DM) in the rat was associated with a significant reduction (up to 50%) in penile PGIz release. Incubating healthy or DM rat penile tissue with cigarette smoke extracts also resulted in the significant inhibition of local PGIZ release (4). A reduction in PGI, release is not a universal phenomenon in DM since an increase, as well as a lack of change, in the release of this eicosanoid has been documented (5, 6). These animal-based findings gained pathological credibility when it was confirmed that human corpus cavernosum tissue also releases PGI, in response to cholinergic, but not adrenergic, agonists (2). The animal-based findings suggest that PG12 plays a role in mediating erection since they correlate well with the human situation. Thus, cholinergic stimuli are associated with the increase in penile blood flow necessary to induce erection and PGL, which was shown to be released by this stimulus, is a vasodilator. Moreover, adrenergic stimulation, which is known to contribute to detumescence, had no effect on PGI, release. This agonist-PGI? relationship is somewhat organ specific since the aorta in the same animals responds to adrenergic, but not cholinergic, agonists (7). Smoking and DM are major risk factors for both impotence and atheroma (8). Therefore, the major decrease in penile PG12 synthesis caused by DM and cigarette smoke extracts is in accordance with the concept that this eicosanoid plays a role in the pathogenesis of impotence. The cumulative effect of smoking and DM observed in animals has been documented in
Al
Bl
239
G Conti (University of Fribourg, Switzerland) and R Virag (CERI, Paris, France) showed that there was an association between the decrease in the amount (and morphology) of smooth muscle in human corpus cavernosum tissue and the severity of erectile dysfunction. We suggest that this association could be explained by the fact that smooth muscle is known (10) to produce considerable amounts of PGI?. In fact, smooth muscle may produce more PGI, than the endothelium because it is quantitatively much better represented in the corpus cavernosum. The local deficiency of PGIz may then in turn impair vasodilatation. It was also suggested that PGI, may help reduce venous drainage from the penis since it is known to have contractile capacity on corpus cavernosum tissue (11). This view is supported by the observation that the main problem observed in this category of patients was an increase in ‘venous leakage’ from the erect/semi-erect penis. There is convincing evidence indicating that the distension of a PGI?-producing organ is associated with the increased release of this eicosanoid (12-15). Therefore, the same rationale as that outlined in (A) above may also account for the changes in flow observed during therapeutic perfusions aimed at restoring erectile function. These intracavernous perfusions were realized by Virag and Shoukry (Virag, R and Shoukry, K: CERI, Paris, France; unpublished observations) for patients presenting with erectile dysfunction due to arterial insufficiency secondary to either atheroma of the vascular tree supplying the penis or to the complications of diabetes mellitus. Thus, the intracavernous infusion of 20400 ml of physiological saline per min is required to induce erection. In contrast, a flow of lo-40 ml/min is required to maintain erection once it has been achieved by the
240 Prostaglandins Leukotrienes and Essential Fatty Acids
Cl
Dl
mittal perfusion volume. Erection is thus sustained for lo-15 min. Consequently, it was suggested that the distension of the corpora cavenosa results in the local release of PGI, which in turn contributes to the reduction in venous outflow. Clinical results obtained from therapeutic perfusions indicate that they re-establish spontaneous erectile function and restore an active sexual life. There did not appear to be a scientific explanation to account for the improvement (often marked in extent and lasting a few months) in erection following corpus cavernosum perfusion. However, it is possible that an increase in PGI, release (as described in B above) exerts a beneficial effect on the local vasculature. A similar improvement in patients with peripheral vascular disease has been documented (16, 17) following the intravascular infusion of PGI?; these latter effects also last for a few months. Dr A Ledda (University of Chieti, Italy) presented evidence that penile blood flow in impotent men was significantly diminished 10 min after smoking one cigarette. Furthermore, cessation of smoking for a period of four weeks resulted in a significant improvement in flow. These findings are in agreement with the concept that PGI2 plays a role in mediating increases in penile blood flow. These findings also support those of Glina et al (18) which indicate that smoking impairs papaverine-induced erection in man.
Diagnosis and treatment of impotence Dr R Hasun (Krankenanstalt Rudolfstiftung der Stagt, Vienna, Austria) presented the results of trials where the intracavernous injection of PGEi was successfully used to diagnose and treat impotence. This group consider that PGEi is a first line drug in this field. This conclusion was reached after the entry of 260 patients into an autoinjection protocol. Some of these patients had as many as 200 injections without any fibrosis or angulation. Dr M Sohn (University Clinics of RWTH Aachen, Aachen, West Germany) also reported satisfactory results with PGEi with a low incidence of systemic side-effects. (tachycardia, blood pressure fluctuations). The clinical experience of Virag and Shoukry (Virag, R and Shoukry, K; unpublished results) indicates that patients with moderate maintaining insufficiency manifest more systemic effects after the intracavernous administration of PGEr. These side-effects include temporary flushes, throbbing headaches, malaise that may end in marked hypotension, cold sweats, pallor and even loss of consciousness and marked venous incompetence necessitating the use of saline infusions and intravenous corticoids. Dr W Halbig (Stadtische Kliniken Neuss, Neuss, West Germany) reported that the majority of patients with negative erection responses to intracavernous papaverine, or papaverine + phentolamine, responded to intracavernous PGEi injection. Dr R Tulli (Clinica de Cirugia Cardiovascular, Sao Paulo, Brazil) presented his experience with PGE, during pe-
nile caversnosometry. Dr A Dittrich (Bundeswehrkrankenhaus, Hamburg, West Germany) presented the results of a study where PGE, solutions were used to distend the corpora cavernosa of impotent patients. This treatment was considered successful since a large number (70%) of patients reported that further autoinjections were not necessary to obtain satisfactory intercourse. These findings are similar to those discussed in (C) above. Dr A H Bennett (Albany Medical Centre, Albany, New York, USA) described his successful use of a combination of papaverine, PGE, and phentolamine for autoinjection. There was a general agreement amongst the delegates for a need to develop such combinations since they were likely to be more potent, safer (in relation to the incidence of priapism) and less costly than single drug preparations. Evidence was also presented (Dr R Virag, CERI, Paris, France) that the transcutaneous application of another eicosanoid, PGE2, was not associated with a therapeutic benefit. Dr C G McMahon (Burns Bay Medical Center, Sydney, Australia) claimed that PGEi may suppress the anxiety effects of erection probably by decreasing the action of endogenous catecholamines. Dr H Claes (A. Z. Sint-Pieter, Leuven, Belgium) discussed the results of a double blind study showing that local (penile shaft) transcutaneous nitroglycerine therapy may help improve penile function in patients suffering from impotence. The drug action may be local and/or systemic since very high concentrations were detected in the antecubital veins of the arm. These observations are of interest to those working with eicosanoids because nitroglycerine is a potent stimulator of vascular PG12 release from the .vascular endothelium (19). Dr R Virag (CERI, Paris, France) concluded that testing intracavernous PGEi at a dose of 6.6 pg in randomly selected patients complaining of impotence resulted in a complete erection lasting for 1 h and resolving spontaneously in 25% of cases. Only 4% of these patients had a prolonged erection. Hence this dose is safe as regards the risk of prolonged erection, but using it alone for initial evaluation may result in the underestimation of the patient’s true erectile response. There was considerable discussion as to whether PGEl was superior to papaverine, or papaverine + phentolamine, in terms of potency and safety. The results with PGE, presented at the meeting or cited in the literature (19-25) are very encouraging. There was, however, general agreement that more experience with this prostaglandin was necessary before a final judgement could be made. In this context, the animal experiments (26) which showed penile fibrosis occurring following the administration of papaverine but not after PGEi were dis-
Eicosanoids, Impotence and Pharmacologically
Induced Erection
cussed. The conclusions from this latter study were,
however, limited by the high doses of papaverine injected, the increased frequency of administration and the possibility of species differences.
GENERAL COMMENTS It was surprising that there were no reports on the effect of PG12 administration since this eicosanoid is available in its natural form and as stable analogs. These preparations have been extensively investigated for the treatment of various forms of vascular disease (16, 17). It is hoped that such investigations will be initiated as a result of the lively discussions that followed several presentations. It will be important to consider, however, that although PG12 is a more potent vasodilator than PGEl it is also a contractor of corpus cavernosum muscle, unlike PGE, which is a relaxor (11). Another surprise was that there was no awareness of any published work showing that the human penis can actually synthesise PGE, . This state of affairs is even more surprising when one considers that all the successful clinical trials are actually based on the intracavernous administration of PGE,! We hope that readers who are aware of such evidence will write to the Editors of this journal so that the relevant study can be mentioned in the correspondence section. There was no work presented concerning eicosanoids other than PGE,, PGE? and PG12. It is to consider that other important, however, eicosanoids, and their specific receptors, have been identified in the penis. All these eicosanoids often have opposing actions and they probably interact as part of normal penile function. A similar interplay between eicosanoids has been proposed for the urinary bladder (27). It was also mentioned that eicosanoids may influence neurotransmitter (e.g. noradrenaline) action (28, 29). Researchers in this field should also consider that eicosanoids may play a role in the normal production-function of sperm (30) and contribute to the mechanism of ejaculation (31). A brief review of the role of eicosanoids in erectile function has been published elsewhere (32). D P Mikhailidis J Y Jeremy Dept. of Chemical Pathology & Human Metabolism Royal Free Hospital & School of Medicine (University of London) Pond Street London NW3 20G, UK K Shoukry R Virag Centre d’Etudes et de Recherche de I’lmpuissance 18 Rue Boissiere 75116 Paris, France (Correspondence of JYJ)
1. leremy J Y, Mikhailidis D P, Dandona P.
Giuscarinic stimulation of prostacyclin synthesis by he rat penis. Eur J PhaAacol 1986; li3: 67-71 leremv J Y. Morean R J. Mikhailidis D P. Dandina P: Prosracyclin synthesis by the corpora :avernosa of the human penis: evidence for nuscarinic control and pathological implications. Prostagl Leukotr Med 1986; 23: 211-16. leremy J Y, Thompson C S, Mikhailidis D P, Dandona P. Experimental diabetes mellitus inhibits lrostacyclin synthesis by the rat penis: pathological mplications. Diabetologia 1985; 28: 365-68. 4. leremy J Y, Mikhailidis D P, Dandona P. The :ffect of cigarette smoke and diabetes mellitus on muscarinic stimulation of prostacyclin synthesis by the rat penis. Diab Res 1986; 3: 467-69. 5. Colwell J A. Winocour P D, Lopez-Virella M. Halushka P V. New concepts about the pathogenesis of atherosclerosis in diabetes mellitus. Am J Med 1983; 75 (suppl. 5B): 67-80. 6 Jeremy J Y, Mikhailidis D P. Thompson C S. Dandona P. The effect of streptozotocin-induced diabetes on PGI, synthesis by the rat bladder. J Ural 1986; 135: 1290-92. Jeremy J V, Mikhailidis D P, Dandona P. Adrenergic stimulation of vascular prostacyclin (PGI,) secretion. Eur J Pharmacol 1985: 114: 33-40. 8. Virag R. Bouilly P. Frydman D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985; i: 181-84. 9. Kaiser F E. Korenman S G. Impotence in diabetes mellitus. Am J Med 1988; 85 (suppl. 5A): 147-52. IO. Moncada S. Herman A. Higgs E A. Vane J R. Differential formation of prostacyclin (PGX or PGI:) by layers of the arterial wall. An explanation for the antithrombotic properties of vascular endothelium. Thromb Res 1977; I I: 323-35. II. Hedlund H. Andersson K-E. Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J Ural l9k5; 134: 1245-50. I2 Ritter J M. Barrow S E. Blair I A. Dollerv C T. Release of prostacyclin in vivo and its role in man. Lancet 1983; i: 317-19. 13 Jeremy J Y. Mikhailidis D P. Dandona P. The rat urinary bladder synthesises prostacyclin as well as other prostanoids. Prostagl Leukotr Med 1984; 16: 235-42. I4 Tsang V. Jeremy J Y. Mikhailidis D P. Walesby R K. Wright J C. Dandona P. Release of prostacy& from the human aorta. Cardiovasc Res 1988; 22: 489-93. I5 Ritter J M, Hamilton G. Barrow S E et al. Prostacyclin in the circulation of patients with with vascular disorders undergoing surgery. Clin Sci lY86; 71: 743-47. I6 Belch J J F, Newman P, Drury J K et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud’s syndrome. Lancet 1983; i: 313-15. 17. Belch J J F. McKay A, McArdle B et al. Epoprostenol (prostacvclin) and severe arterial disease. A double-blinh trial. Lancet 1983; i: 315-17 18. Glina S. Reichelt A C. Leao P P. DOS Reis J M S M. Impact of cigarette smoking on papaverine-induced erection. J Urol 1988: 140: 523-24. IO. Levin R I. Jaffe E A, Weksler B B, Tackgoldman K. Nitroglycerin stimulates synthesis of prostacyclin by cultured human endothelial cells. J Clin Invest 1981; 67: 762-6. 20 Waldhauser M, Schramek P. Efficiency and side-effects of prostaglandin E, in the treatment of erectile dysfunction. J Urol 1988; 140: 525-27.
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21. Lee L M, Stevenson R W D, Szasz G. Prostaglandin E, versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J Urol 1989; 141: 549-50. 22. Sarsody M F, Hudnall C H, Erickson D R, Hardin T C, Novicki D E. A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E, in the treatment of impotence. J Urol 1989; 141: 551-53. 23. Stack1 W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E, in impotent men. J Ural 1988; 140: 66-68. 24. Virag R, Adaikan PG. Effects of prostaglandin E, on penile erection and erectile failure. J Urol 1987; 137: 1010. 25. Hwang T I-S, Yang C-R, Wang S-J, Chang C-L. Tzai T-S, Chang C-H, Wu H-C. Impotence evaluated by the use of prostaglandin E,. J Urol 1989; 141: 1357-59. 26. Aboseif S R, Breza J, Bosch R J L, et al. Local and systemic effects of chronic intracavernous injection
27.
28.
29.
30.
31.
32.
ot papaverine, prostaglandin E, and saline in primates. J Urol 1989; 142: 403-08. Mikhailidis D P, Jeremy J Y, Dandona P. Urinary bladder prostanoids: their synthesis, function and possible role in the pathogenesis and treatment of disease. J Urol 1987; 137: 577-82. Trachte C J. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves. J Pharmacol Exoer Ther 1986: 237: 473-77. Serio R, Daniel E E. gicosanoids and peripheral neurotransmission. Prostagl Leukotr Essntl Fatty Acids: Reviews 1989; 38: 237-46. Yamamoto M, Hashimoto J, Takaba H, Miyake. Response of the isolated human semineferous tub;le to prostaglandins Flalpha,Fzalphil,E, and E,. J Urol 1987: 137: 345-48. Gottlieb d, Bygdeman M. Prostanoids in sperm function. Prostagl Leukotr Essntl Fatty Acids: Reviews 1988; 34: 205-14. Jeremv J Y. Mikhailidis D P. Prostanoids and impotence. Br J Sexual Med 1989; 16: 411-13.