00059 0325

Herz Urban& Vogel 2003
Non Erectile Dysfunction Application of Sildenafil
Abstract
tion of the compound. In gastrointestinal disorders, sildenafil Sildenafil has proven effective in the therapy of male erectile also exerts several effects which might be of clinical relevance.
dysfunction. However, little is known about other potential In patients with heart failure, endothelial dysfunction is influ- beneficial effects of sildenafil. Meanwhile, first observations enced by the phosphodiesterase-5 (PDE 5) inhibitor and exer- have been made in numerous medical disciplines and disor- cise capacity might be improved. Moreover, in the treatment ders. Small doses of sildenafil may be a useful adjunct to in- of Raynaud’s phenomenon, a disease without highly effective haled iloprost in the management of pulmonary hyperten- medical treatment option yet, first observations with silde- sion. In female sexual dysfunction and infertility, genital blood flow and endometrial thickening are enhanced after applica- Key Words: Sildenafil · Viagra® · Pulmonary hypertension · Female sexual dysfunction · Infertility · Gastroente-
rology · Endothelial dysfunction · Heart failure · Cardioprotection · Raynaud’s phenomenon
Herz 2003;28:325–33
Neue Anwendungsgebiete von Sildenafil
Zusammenfassung
verbesserte Verdickung des Endometriums. Sildenafil übt Sildenafil hat sich in der Therapie der erektilen Dysfunktion auch zahlreiche Effekte am Gastrointestinaltrakt aus, welche des Mannes bewährt. Jedoch ist wenig über mögliche weitere von klinischer Relevanz sein könnten. Bei Patienten mit Herz- günstige Effekte von Sildenafil bekannt. Mittlerweile gibt es insuffizienz wird die endotheliale Dysfunktion günstig durch erste Beobachtungen bei zahlreichen medizinischen Diszipli- den Phosphodiesterase-5-(PDE-5-)Hemmer beeinflusst, und nen und Erkrankungen. Geringe Mengen von Sildenafil könn- die Belastungstoleranz könnte gesteigert werden. Außerdem ten zusätzlich zur Gabe von Iloprost günstigen Einfluss bei der erscheinen erste Beobachtungen in der Anwendung von Sil- Therapie der pulmonalen Hypertonie haben. Bei der sexuellen denafil beim Raynaud-Syndrom, einer Erkrankung ohne hoch- Dysfunktion und Unfruchtbarkeit der Frau zeigten sich nach effektive Behandlungsmethode, viel versprechend.
Gabe der Substanz ein erhöhter genitaler Blutfluss sowie eine Schlüsselwörter: Sildenafil · Viagra® · Pulmonale Hypertonie · Sexuelle Dysfunktion der Frau · Infertilität ·
Gastroenterologie · Endotheliale Dysfunktion · Herzinsuffizienz · Kardioprotektion · Raynaud-Syndrom
Introduction
triphosphate to cGMP. This second messenger then Sildenafil (Viagra®) has proven effective in the thera- provides the signal for relaxation of both vascular py of male erectile dysfunction. The compound is a and trabecular smooth muscle in the corpus caver- highly selective and potent inhibitor of the cyclic nosum, with subsequent increased blood flow into the guanosine monophosphate-(cGMP-)specific phospho- lacunar spaces. As cGMP is hydrolyzed by cyclic nu- diesterase-5 (PDE 5) isoenzyme [1]. Penile erection is cleotide PDE enzymes, sildenafil elevates the cGMP mediated by nitric oxide (NO), which activates guany- signal by inhibiting degradation of the guanosine nu- late cyclase, an enzyme that converts guanosine 1 Medical Clinic and Polyclinic, Internal Medicine III, University Hospi- tals of the Saarland, Homburg, Germany.
Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil After its introduction, the drug has rapidly found monary arterial pressure (PAP) than sildenafil alone (9.4 widespread use and has meanwhile been prescribed suc- ± 1.3 vs. 6.4 ± 1.1 mm Hg, Figure 1a). The reduction in cessfully a million times in the treatment of erectile dys- mean PAP after sildenafil was maximal after the first function. However, little is known about other potential dose of 25 mg (Figure 1b). Interestingly, the combination beneficial effects of sildenafil. No doubt, PDE 5 has of sildenafil plus iloprost lowered mean PAP significantly been detected at high concentrations in the corpus cav- more than iloprost alone (13.8 ± 1.4 vs. 9.4 ± 1.3 mm Hg, ernosum [2] but is also known to exist in several other Figure 1c). No significant changes in heart rate or sys- tissues [3]. Therefore, growing interest was accruing to temic arterial pressure were observed during any treat- examine the effects of sildenafil in various diseases dif- ment. However, pulmonary vascular resistance (PVR) ferent from male erectile dysfunction. Meanwhile, first was markedly diminished after iloprost inhalation, and observations have been made in numerous medical dis- cardiac output increased significantly. Again, sildenafil ciplines and disorders. This review gives some insight in- alone had similar effects on the latter parameters being to the current status of the observations made so far in already maximal after ingestion of the first dose of 25 mg.
the non erectile dysfunction application of sildenafil As for PAP, the combination of inhaled iloprost plus oral and shows potential new therapeutic approaches for sildenafil pronounced and prolonged the effects on PVR and cardiac output. These data suggest that small doses ofsildenafil may be a useful adjunct to inhaled iloprost in Pulmonary Hypertension
the management of pulmonary hypertension.
Primary pulmonary hypertension (PPH) is a progressive The latter study was recently confirmed by disease with a short life expectancy and a median survival Ghofrani et al. [9] in a more heterogeneous group of pa- of 2.8 years from the time of diagnosis [3] that often af- tients with severe pulmonary hypertension due to PPH, fects young people. Continuous infusion of epoprostenol chronic thromboembolic hypertension, CREST syn- (prostacyclin) has been shown to improve exercise capac- drome (calcinosis, Raynaud’s phenomenon, esophageal ity and survival markedly [4]. However, systemic applica- dysmotility, sclerodactyly, teleangiectasias), and aplasia tion is limited by catheter infections, systemic hypoten- of the left pulmonary artery. These data indicate that sion, lack of selectivity for the pulmonary vasculature, oral sildenafil is a potent pulmonary vasodilator that and tachyphylaxis. By contrast, inhalation of aerolized acts synergistically with inhaled iloprost also in sec- iloprost (a long-acting prostacyclin analog) causes prefer- ondary pulmonary hypertension. In an additional study, ential pulmonary vasodilation matched to ventilation this working group could demonstrate that sildenafil is and has been shown to improve exercise capacity and he- also capable of improving gas exchange in patients with modynamics in patients with PPH [5]. However, due to severe lung fibrosis and secondary pulmonary hyper- the short-term effect, repetitive inhalations (six to twelve tension [10]. Moreover, sildenafil has recently been inhalations daily) are required to achieve sustained relief shown to be effective also in the treatment of hypoxia- of pulmonary hypertension and is limited, like systemic induced pulmonary hypertension [11], and first obser- application, by very high costs. One approach to prolong vations in the therapy of HIV-related pulmonary hyper- and to increase the effects of iloprost might be the con- tension are likewise promising [12].
comitant use of PDE 5 inhibitors. The PDE 5 isoenzyme These data provide the basis for larger clinical trials is abundantly expressed in lung tissue [6], and inhibition in patients with pulmonary hypertension. Especially, lit- of cGMP breakdown might be particularly efficacious in tle is still known about a sustained response to oral pulmonary vasodilation, as cGMP formation is increased sildenafil in the long-term treatment of these lung dis- eases. However, smaller studies provide evidence for a Wilkens et al. [8] described the response to a com- substantial improvement in exercise ability and sympto- bined treatment of sildenafil and nebulized iloprost in pa- matic benefit, which has been sustained at 3 and 6 tients suffering from severe PPH with New York Heart Association (NYHA) stage III or IV. The short-term ef-fects of 8.4–10.5 µg of aerosolized iloprost, cumulative Female Sexual Dysfunction and Infertility
doses up to 100 mg sildenafil, and the combination there- Female Sexual Dysfunction
of were compared in five patients. Aerolized iloprost re- Female sexual dysfunction (FSD) is age-related, pro- sulted in a more pronounced decrease in mean pul- gressive, and highly prevalent, affecting 30–50% of Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil Figures 1a to 1c. Time course of mean pulmonary artery pressure (PAP) in five patients with primary pulmonary hypertension (PPH). a) Effects of
iloprost inhalation. b) Effects of sildenafil administration. c) Effects of iloprost and sildenafil. (Modified from Wilkens et al. [8].)
Abbildungen 1a bis 1c. Zeitverlauf des mittleren pulmonalarteriellen Drucks (PAP) bei fünf Patienten mit primärer pulmonaler Hypertonie (PPH).
a) Effekt der Iloprost-Inhalation. b) Effekt der Einnahme von Sildenafil. c) Effekt von Iloprost plus Sildenafil. (Modifiziert nach Wilkens et al. [8].)
American women [14]. Similar to erectile dysfunction in tion of 100 mg sildenafil. Sexual arousal and stimulation men, this disorder in women may develop secondary to result in increased blood flow to the iliohypogastric pu- emotional and psychologic factors. However, there are dendal arterial bed. This leads to increased blood flow a variety of medical and physiologic factors that can to the sexual organs. Berman et al. [17] could demon- lead to sexual arousal disorder (SAD). These include di- strate that sildenafil significantly increases genital blood minished clitoral and vaginal blood flow (e.g., flow at all sites (clitoral, labial, urethral and vaginal) menopause, prior pelvic trauma, surgery), as well as var- measured by duplex Doppler ultrasonography. This is in ious medications [15]. Predictors of male erectile dys- accordance with the findings of D’Amati et al. [18] who function such as arterial hypertension, smoking, high recently could characterize the presence and tissue dis- cholesterol levels, age, and diabetes can also result in tribution of the PDE 5 isoenzyme in the human vagina.
sexual arousal problems in females. It is known that Moreover, following administration of sildenafil, which women with atherosclerosis have markedly reduced in- enhances vascular and nonvascular smooth muscle re- tensity of sexual excitement, arousal, and orgasms, re- laxation, poststimulation intravaginal pressures de- creased significantly and volumes increased [17]. As ag- Based on anatomic and embryologic parallels be- ing and menopause and the concomitant decrease in cir- tween the sexes and recent research demonstrating sim- culating estrogen levels lead to atrophy of vaginal ilarities in the physiology of the arousal response, smooth muscle with secondary vaginal wall fibrosis and Berman et al. [17] suggested that there may be a poten- collagen deposition [19], this newly discovered effect of tial basis for improvement of female sexual dysfunction sildenafil might be of therapeutic relevance. In addition, with sildenafil. A total of 48 women (mean age 45.7 ± pre- and poststimulation genital vibratory thresholds 10.8 years) with complaints of SAD were evaluated.
were significantly lower compared with baseline, sug- Among them were menopausal and postmenopausal gesting that sildenafil may help to improve female geni- women, as well as patients who had undergone hys- tal sensation. Following a 6-week home use of sildenafil, terectomy. Physiologic measurements were recorded subjective components like desire, arousal, lubrication, pre- and postsexual stimulation alone and after applica- pain, and satisfaction improved significantly. However, Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil this study by Berman et al. [17] is limited by the small rates were significantly higher [23]. It is concluded that sample size and lack of placebo, but it might induce although greater numbers of patients and randomized well-controlled clinical trials in the future. But even evaluation are needed to validate this treatment, vagi- though there are similarities between men and women, nal sildenafil may be effective for improving uterine the female sexual response is articulately complex and artery blood flow and endometrial development in IVF distinct from that of men. Although Goldstein et al. [20] patients with prior poor endometrial response.
found that sildenafil resolves erectile dysfunction evenin men with psychogenic erectile disorders, Berman et Gastrointestinal Disorders
al. [21] suggested that women experience sexuality in a Achalasia
different context than men. By contrast, they could also NO is the principal neurotransmitter released after de- demonstrate that sildenafil does not resolve sexual glutition by the nonadrenergic noncholinergic (NANC) symptoms in women with unresolved psychologic, emo- inhibitory neurons, and through the production of cGMP, tional, or relational issues related to unresolved child- it releases the lower esophageal sphincter (LES) and reg- ulates peristaltic contractions. Its decrease or absence isconsidered responsible for the typical motor alterations Infertility in Women with Poor Endometrial
of achalasia [24]. Therefore, one might suggest that the Thickening
inhibitory effect of sildenafil on penile smooth muscle Endometrial growth is thought to depend on uterine cells is also displayed on the esophageal musculature of artery flow. As NO relaxes vascular smooth muscle patients with achalasia. In 14 patients affected by achala- through a cGMP-mediated pathway and NO synthase sia with an esophageal diameter of ≤ 5 cm, Bortolotti et isoforms were found in the human uterus, one might al. [25] recorded esophageal motility with a low-compli- suggest that sildenafil may augment the vasodilatory ef- ance manometric system. They could demonstrate that fects of NO by preventing the degradation of cGMP.
50 mg sildenafil, infused in the stomach, decreased LES Sher & Fisch [22] were the first to report about im- tone, residual pressure, and wave amplitude significantly.
proved uterine artery blood flow and endometrial de- However, the inhibitory effect (maximum 15–20 min af- velopment after treatment with vaginal sildenafil in ter infusion) lasted < 1 h and a marked interpatient vari- women undergoing in vitro fertilization (IVF). In four ability was observed. The latter finding could be ex- patients with prior failed assisted reproductive cycles plained by the fact that the pathologic process of achala- due to poor endometrial response, the uterine artery sia has not damaged the intrinsic neurons in the same pulsatility index (PI) was measured. After 1 week of degree in all patients [26]. In cases in which the NANC sildenafil treatment, the PI was decreased indicating in- neurons are nearly completely destroyed, the production creased blood flow and returned to baseline values fol- of NO and cGMP could be extremely reduced or absent lowing treatment with placebo. In addition, the combi- making the block of PDE 5 by sildenafil ineffective [25].
nation of sildenafil and estradiol improved blood flow Consequently, sildenafil is not indicated in the medical and endometrial thickness, and these findings were re- treatment of these forms of achalasia. The administration produced in an ensuing gonadotropin-stimulated cycle.
of nitrate derivates and nifedipine should be expected to Lately, three of the four patients conceived [22]. In a be more effective, because nitrate derivates supply ex- subsequent study, Sher & Fisch [23] evaluated the ef- ogenous NO and nifedipine acts directly on the smooth fects of vaginally administered sildenafil on endometri- muscle fibers, blocking the transmembrane influx of cal- al thickness and IVF outcome in a larger cohort of in- cium necessary for the contraction [25]. However, other fertile women with poor endometrial development. In spastic esophageal motor disorders, such as nutcracker this study, 105 infertile women aged < 40 years, with nor- esophagus, hypertensive LES and diffuse spasm, could mal ovarian reserve and at least two consecutive prior benefit from the use of an esophageal PDE inhibitor, be- IVF failures attributed to inadequate endometrial de- cause the NANC inhibitory neurons are present in these velopment underwent IVF using a long GnRH-a proto- diseases, although they are functionally impaired. Cau- col with the addition of sildenafil vaginal suppositories tion should be given in patients with gastroesophageal re- (25 mg, four times per day) for 3–10 days. Of these pa- flux disease, as sildenafil could further decrease the an- tients, 70% attained an endometrial thickness of ≥ 9 tireflux function of the LES, leading to a worsening of mm. In this group, implantation and ongoing pregnancy Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil Gastroduodenal Motility
occurs in infantile hypertrophic pyloric stenosis [33]. As As well as being responsible for the LES relaxation, the the stomachs of spontaneously diabetic rats have de- NO-cGMP pathway is also involved in the gastric reflex creased NO-mediated relaxation of gastric muscle strips relaxation and participates in the regulation of the in- and attenuated expression of nNOS protein and mRNA terdigestive and digestive gastrointestinal motility [27, [34], these studies suggest that nNOS expression may be 28]. Consequently, Bortolotti et al. [29] hypothesized disrupted in diabetes. Using diabetic mice, Watkins et that sildenafil also might inhibit gastroduodenal motili- al. [35] could demonstrate that these animals develop ty. In 16 healthy subjects, antroduodenal motility was delayed gastric emptying and a loss of NO-mediated recorded by means of a low-compliance manometric NANC relaxation in the pylorus that resembles the phe- system. After infusion of 50 mg sildenafil in the gut, notype of mice with genomic deletion of nNOS. Insulin antral and duodenal wave frequency and amplitude treatment reversed these effects and restored pyloric were significantly lower during the first 60 min after ad- nNOS protein and mRNA. Interestingly, sildenafil was ministration. This inhibition of gastroduodenal motility also capable of reversing delayed gastric emptying. The could be responsible for the dyspeptic complaints of pa- authors conclude that diabetic gastropathy in mice re- tients taking this drug. While this rapidly reversible ef- sults from a reversible loss of nNOS expression within fect should not represent a relevant clinical problem in myenteric neurons that can be reversed with sildenafil.
healthy subjects, it might be of importance in patients Although comprehensive clinical studies in man are with delayed gastric emptying or gastroparesis. Con- lacking, there is evidence that sildenafil might also re- versely, in patients with dumping-type syndromes or ac- duce symptoms in diabetic gastropathy in humans [36].
celerated gastric emptying, a beneficial effect of silde-nafil might be expected [29]. Further studies in patients Cardiovascular System
with functional dyspepsia would be advisable. The clini- Endothelial Dysfunction
cal utility of sildenafil is currently limited in these gas- The vascular endothelium plays an important role in the trointestinal disorders, until a long-acting slow releasing regulation of peripheral vasomotor tone in conduit and form of sildenafil might be introduced.
resistance blood vessels [37]. In patients with heart fail-ure, impaired endothelium-dependent, flow-mediated Diabetic Gastropathy
vasodilation can be found, which is partly attributable Another promising approach to the treatment of gas- to hyporesponsiveness of cGMP-mediated vasorelax- trointestinal disorders might involve the use in diabetic ation effector mechanisms in vascular smooth muscle gastropathy. Gastrointestinal dysfunction may occur in [38]. Katz et al. [38] suggested that acute inhibition of as many as 75% of diabetic patients [30, 31] and include cGMP degradation with sildenafil will increase flow- diabetic gastropathy, a syndrome of delayed gastric mediated vasodilation in the forearm circulation of pa- emptying, leading to nausea, vomiting, abdominal pain, tients with chronic congestive heart failure (CHF).
and early satiety. The mechanisms leading to diabetic Therefore, flow-mediated vasodilation after release of gastropathy are not fully elucidated yet, but may in- 1, 3, and 5 min of transient arterial occlusion was meas- volve perturbation in the relaxation of the pyloric ured in the brachial artery with high-resolution two-di- sphincter that leads to impaired gastric emptying. Cur- mensional ultrasound imaging in 48 patients with chron- rently, the major drugs used in treating diabetic gas- ic heart failure before and 1 h after randomized, double- tropathy include domperidone, metoclopramide, cis- blind assignment to a single oral dose of sildenafil 12.5, apride, and erythromycin. These drugs act by increasing 25, or 50 mg or matching placebo. In response to oral ad- stomach contractions. However, their limited clinical ministration of a single dose of study drug, the change in utility may reflect the finding that abnormalities in dia- flow-mediated vasodilation after release of 1, 3, and 5 betic gastropathy are primarily in the NANC relaxation min of arterial occlusion was significantly greater in pa- rather than the contractile component of gastropyloric tients receiving 25 and 50 mg sildenafil than that of pa- function. What holds true for the LES and the stomach, tients receiving placebo (Figure 2). Interpretation of NO has been found to have also an important function these findings is limited by the relatively small number as a neurotransmitter in the pylorus [32]. It has been of patients and the short duration of therapy. Hence, shown that loss of pyloric neuronal nitric oxide synthase further studies are warranted to characterize the safety (nNOS) is associated with gastric outflow obstruction as and efficacy of long-term PDE 5 inhibition in the treat- Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil arteries (+6.9 ± 1.3%; p < 0.0001). Coronary epicardialand microvascular responses with acetylcholine and cold-pressor testing improved, with a greater enhancement inpatients with CAD and endothelial dysfunction. Interest-ingly, both resting and adenosine diphosphate-stimulatedplatelet IIb/IIIa receptor activation was inhibited bysildenafil (p < 0.05). Brachial arteries dilated in responseto sildenafil in controls. Peak flow-mediated dilation wassimilar, but the duration of hyperemia was prolonged af-ter sildenafil administration (p < 0.001). Compared withplacebo, ISDN improved myocardial ischemia during ex- Figure 2. Change in flow-mediated dilation (FMD, %) from pretreat-
ercise (p < 0.05), whereas the effect of sildenafil was in- ment values after release of 1, 3, and 5 min of arterial occlusion in pa- termediate between the two. Further studies are required tients treated with placebo (closed squares), sildenafil 12.5 mg (open to determine the clinical impact of these observations.
squares), sildenafil 25 mg (open circles), and sildenafil 50 mg (open tri-angles). (Modified from Katz et al. [38].) Abbildung 2. Veränderung der flussvermittelten Dilatation (FMD, %)
Heart Failure
im Vergleich zur Kontrolle 1, 3 und 5 min nach arterieller Okklusion bei Erectile dysfunction affects 60–70% of patients with Patienten nach Einnahme von Plazebo (geschlossene Quadrate), Sil- CHF [41]. To retain sexual activity, some patients may denafil 12,5 mg (offene Quadrate), Sildenafil 25 mg (offene Kreise) undSildenafil 50 mg (offene Dreiecke). (Modifiziert nach Katz et al. [38].) become noncompliant with CHF treatment that theyfeel causes or worsens their erectile dysfunction. How-ever, evidence-based guidelines about sildenafil use in ment of endothelial dysfunction in chronic heart failure.
patients with CHF are lacking. Recently, Bocchi et al.
In a recent study, the findings by Katz et al. [38] [42] investigated the effects of sildenafil treatment on were confirmed in patients with type 2 diabetes. In par- exercise, neurohormonal activation, and clinical status ticular, Desouza et al. [39] could demonstrate in 14 pa- in 24 male patients with heart failure (NYHA class tients that acute and prolonged sildenafil treatment has II–IV). The study consisted of a first phase with a fixed a favorable effect on brachial artery flow-mediated dila- dose of 50 mg sildenafil and a second phase using a flex- tion that persists for at least 24 h after the last dose.
ible dose of sildenafil during 1 month. In patients with Since endothelial dysfunction is associated with vas- CHF, sildenafil significantly reduced blood pressure, cular inflammation, platelet activation, and rapid pro- resting heart rate and attenuated the heart rate incre- gression of atherosclerosis and its adverse events, strate- ment (6-min treadmill-walking test and maximal exer- gies that enhance NO bioavailability may have a positive cise test, Figure 3) which was attributed to the modula- impact on outcomes in patients with coronary artery dis- tion of the effects of the NO-cGMP pathway on the ease (CAD). Therefore, Halcox et al. [40] hypothesized pacemaker activity of sinoatrial node cells [43]. More- that PDE 5 inhibition with sildenafil may abrogate coro- nary and peripheral vascular endothelial dysfunction in cise and increased the maximal exercise capacity. Treat- patients with CAD, inhibit platelet activation, and ame- ment was associated with more adverse symptoms, liorate myocardial ischemia during stress. In their conse- however, none of which resulted in discontinuation quent study, the effect of oral sildenafil on resting coro- from the study. Sildenafil was effective in improving nary vascular tone, endothelium-dependent and -inde- erectile dysfunction and did not alter the neurohor- pendent function and platelet activation was measured in monal sympathetic activation (measured by plasma 24 patients. An additional 24 patients with CAD and is- norepinephrine levels). The authors suggested that the chemia during exercise, and twelve control subjects re- reduction of heart rate could decrease the myocardial ceived either 100 mg of sildenafil, 10 mg of isosorbide oxygen consumption during exercise and sexual activi- dinitrate (ISDN), or placebo during exercise on 3 sepa- ty. Therefore, sildenafil could become an important rate days in a randomized, double-blind manner. Flow- tool to resolve the challenge of concomitant improve- mediated dilation of the brachial artery was measured, ment in relevant aspects of quality of life without and CAD patients underwent treadmill exercise testing changes in multiregimen drugs necessary to improve [40]. Sildenafil (100 mg) vasodilated epicardial coronary Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil The fingers are most commonly af-fected, and symptoms may be mild,but can also cause severe ischemiaresulting in digital gangrene. Ray-naud’s phenomenon may occur inconjunction with other diseases,such as CREST syndrome, SLE(systemic lupus erythematosus), orsystemic sclerosis. Treatment isaimed at prevention of attacks and includes also stress reduction Figures 3a and 3b. a) Sildenafil (solid line) attenuated the heart rate increment during the 6-
min treadmill-walking test (p = 0.003) versus placebo (dashed line). b) Heart rate was lower during the recovery period after the 6-min treadmill-walking test with sildenafil (p = 0.007;solid line) versus placebo (dashed line). Last minute indicates 6th minute of the treadmill- walking test. (Modified from Bocchi et al. [42].) Abbildungen 3a und 3b. a) Sildenafil (durchgezogene Linie) verminderte den Herzfrequenzan-
stieg während der 6-min-Ergometrie (p = 0,003) im Vergleich zu Plazebo (gestrichelte Linie). b) Die Herzfrequenz nach der 6-min-Ergometrie war unter Sildenafil (durchgezogene Linie) ge-ringer (p = 0,007) als unter Plazebo (gestrichelte Linie). „Last minute“ bedeutet die 6. Minute der Ergometrie. (Modifiziert nach Bocchi et al. [42].) treated with calcium channel block-ers. Treatment modalities, including Cardioprotection
central and peripheral sympathetic blockade and oral, It has been shown that sildenafil causes mild to moderate topical or systemic vasodilators (including prosta- decreases in systolic and diastolic arterial blood pressure cyclin), have not been reliably and consistently effec- due to inhibition of PDE 5 in smooth muscles in the vas- cular bed [44]. Consequently, Ockaili et al. [45] hypothe- Recently, Lichtenstein [47] reported for the first sized that such a mild vasodilatory effect of sildenafil in the time about successful treatment in ten patients with vasculature could potentially release agents such as Raynaud’s phenomenon, using 50 mg sildenafil once adenosine, bradykinin, or NO, which may trigger a pre- daily. As most patients had previously failed treatment conditioning-like effect in the heart. In their subsequent with calcium channel blockers and other modalities, the study, rabbits were treated with sildenafil (0.7 mg/kg i.v.) results ranged from an excellent response to complete either 30 min or 24 h before 30 min of ischemia and 3 h of relief of symptoms. Included in the study were patients with idiopathic disease, SLE, CREST syndrome, and droxydecanoate (5-HD, 5 mg/kg i.v.) was given 10 min be- systemic sclerosis. Ulcers on the fingers and toes healed fore ischemia-reperfusion. The infarct size (measured by following treatment with sildenafil, and symptoms re- tetrazolium staining) decreased from 33.8 ± 1.7% in con- lapsed after treatment was withdrawn. Furthermore, no trol rabbits to 10.8 ± 0.9% during the acute phase and 19.9 adverse events occurred, however, this absence of side ± 2.0% during the delayed phase. 5-HD abolished protec- effects is likely attributable to the small number of pa- tion with an increase in infarct size to 35.6 ± 0.4% and 36.8 tients treated. It was suggested that sildenafil works for ± 1.6% during the acute and delayed phase, respectively.
Raynaud’s phenomenon as it does for erectile dysfunc- For the first time, it was demonstrated that sildenafil in- tion: as a potent peripheral vasodilator.
duces acute and delayed protective effects against is- Further studies are warranted to characterize the chemia-reperfusion injury, which are mediated by opening safety and efficacy of PDE 5 inhibition in the treatment of Raynaud’s phenomenon and associated diseases.
needed to understand the exact molecular mechanism ofthe sildenafil-induced cardioprotective effect.
Conclusions
Sildenafil has rapidly become an accepted and ac- Raynaud’s Phenomenon
knowledged drug, and PDE 5 inhibition to date is not Raynaud’s phenomenon is characterized by tempera- replaceable in the therapy of male erectile dysfunc- ture-sensitive vasospasms of the fingers, toes, and ears.
tion. However, growing evidence arises about other Herz 28 · 2003 · Nr. 4 Urban & Vogel Cremers B, Böhm M. Non Erectile Dysfunction Application of Sildenafil Table 1. Disease, liable tissue, and effect of sildenafil.
Tabelle 1. Erkrankung, betroffenes Gewebe und Wirkung von Sildenafil.
Effect of sildenafil
Pulmonary vasodilatation, PAPȇ, PVRȇ, cardiac outputȆ, gas exchangeȆ Clitoral, labial, urethral and vaginal blood flow Ȇ, improvement of sexual arousaldisorder Uterine artery blood flowȆ, endometrial thickness Ȇ, pregnancy rate Ȇ Lower esophageal sphincter tone ȇ, residual pressure ȇ, wave amplitude ȇ Interdigestive and digestive Inhibition of gastroduodenal motility, delayed gastric emptyinggastrointestinal tissue Pyloric sphincter relaxation, enhanced gastric emptying Resting heart rate ȇ, heart rate increment ȇ, exercise capacity Ȇ Protective effects against ischemia-reperfusion injury, which are mediated by opening of mitochondrial KATP channels potential beneficial effects of sildenafil. The eNOS- Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre NO-cGMP pathway contributes to most of the ob- KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Pri-mary pulmonary hypertension. A national prospective study.
served effects, but sildenafil is not entirely dependent on this pathway. Meanwhile, most experience was Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, made in the treatment of pulmonary hypertension, and Groves BM, Tapson VF, Bourge RC, Brundage BH, et al. A compar-ison of continuous intravenous epoprostenol (prostacyclin) with first investigations suggest that the drug is a promising conventional therapy for primary pulmonary hypertension. The candidate for long-term treatment of other diseases as Primary Pulmonary Hypertension Study Group. N Engl J Med well (Table 1). With these findings, sildenafil can be Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiek- tried as a therapeutic agent in these disorders. Howev- erkoetter E, Niedermeyer J, Hamm M, Fabel H. Long-term treat- er, controlled randomized trials have to be performed ment of primary pulmonary hypertension with aerosolized ilo- to confirm these findings, and further studies are war- prost, a prostacyclin analogue. N Engl J Med 2000;342:1866–70.
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