07syedtabraizalif.pdf

Pak J Physiol 2006; 2(2)
EFFECT OF SILDENAFIL CITRATE (VIAGRA) ON PENILE
VASCULATURE AND CARDIODYNAMICS IN DIABETIC MALES WITH
AND WITHOUT NEUROPATHY
Syed Tabrez Ali*, Nabeeh I. Rakkah
Department of Physiology, Faculty of Medicine and Medical Sciences, Umm-Al-Qura University, Makkah,
Saudi Arabia
Background: Erectile and cardiovascular dysfunctions in diabetes are important signs resulting
probably due to pelvic autonomic neuropathy with damage to the parasympathetic nervierignetes.
Direct evidence for a neuropathic etiology comes from studies that show structural changes in
autonomic nerve fibers supplying the corpora cavernosa. The present study deals with the diabetic
neuopathies prevailing in men and the possible role of sildenafil citrate (Viagra) treatment for
these neurogenic cardio-sexual disturbances. Methods: Penile mid shaft circumference and length,
penile pulse amplitude, both systolic and diastolic blood pressure s, and heart rate were measured
in response to erotic stimulation by film and fantasy and the effect of the treatment of sildenafil
citrate (50 mg oral dose) was noted in 50 insulin dependent diabetes mellitus (IDDM) and in 50
non insulin dependent diabetes mellitus (NIDDM) patients with and without an objective evidence
of neuropathy, having an age span in between 20 and 65 years and a duration of diabetes
distributed over 1-25 years with their age matched non diabetic controls. Results: Sildenafil
treatment showed a significant increase (P<0.0005) in penile mid shaft circumference and length,
and penile pulse amplitude, where as both systolic and diastolic blood pressure s and heart rate
exhibited a significant decrease (P<0.025 and P<0.005 respectively) in both IDDM and NIDDM
diabetic neuropathic patients. However this difference was found to be non-significant in both
types of diabetic patients without neuropathy and when compared with their respective control
subjects . Conclusion: Oral administration of sildenafil citrate is an effective first line therapy for
erectile dysfunctions in diabetic impotent men with neuropathic etiology (irrespective of their type
of diabetes) with out much altering the cardiodynamic profile. These results further explain how to
manage sexual disorders as part of diabetic care, and suggest rules for sildenafil prescription in
diabetic neuropathic patients.
Key Words: Diabetes; Neuropathy; Erectile/cardiovascular response; Sildenafil citrate.
INTRODUCTION
with involvement of the sympathetic fibers that sub Erectile dysfunction (ED) has been linked serve the seminal vesicles, vas deferens, and bladder increasingly to cardiovascular risk factors and comorbidities. Considering the potential associated with sexual activity, guidelines were neurogenic bladder, and delayed bulbocavernous developed (Princeton I) for assessment and reflex response latency are indirect evidence for a management of patients with varying degrees of neuropathic etiology of the patient's complaints5. cardiac risk. These guidelines are most recently Failure of ejaculation secondary to emission updated (Princeton II) based on new data concerning disturbances due to sympathetic denervation of the the link between ED and cardiovascular disease and vas deferens is another manifestation of autonomic the availability of additional phosphodiesterase type neuropathy, usually seen in more advanced stages 6-7. 5 inhibitors vardenafil, tadalafil1. Despite the need for It is now established that sexual dysfunction is a careful risk assessment in all cases, sexual activity common complication of diabetic autonomic remains safe for the large majority of patients. neuropathy both in men and in women8-9-10-11. Despite However, all patients presenting with complaints of the general agreement of previous investigators that ED should be carefully assessed for the presence of the prevalence of impotence in diabetic men cardiovascular risk factors like obesity, hypertension, approximates 50 per cent, there is controvers y hyperlipidemia, diabetes and its associated surrounding the etiology of this problem. Direct evidence for a neuropathic etiology of neurological dysfunction of diabetic autonomic diabetic erectile dysfunction comes from studies that show structural changes in autonomic nerve fibers blood pressure homeostasis in a number of ways. The disturbances that occur in diabetes are associated efferent limb of the baroreceptor reflex is composed Pak J Physiol 2006; 2(2)
of sympathetic vasoconstrictor fibers to the MATERIALS AND METHODS
splanchnic, skin, and striated muscle vessels and sympathetic cardiac fibers. Interruption of these For experimental purposes and for the studies of fibers interferes with three compensatory diabetic neuropathy, after getting the permission from mechanisms: vasoconstriction, i.e., a drop in systolic the local ethical committee, 50 insulin dependent blood pressure of 30 mmHg or greater. The lack or (IDDM) and 50 non insulin dependent (NIDDM) inadequacy of the expected increase in heart rate diabetic male patients with and without evidence of differentiates the orthostatic hypertension of neuropathy and 50 age matched non diabetic male autonomic neuropathy from those seen under controls were selected. Every male aged between 20 hypovolaemic conditions such as dehydration or to 65 years with duration of the onset of the disease The presence of diabetic complications were diastolic supine blood pressure have been described assessed by a review of the medical record. in diabetic impotent patients with idiopathic Neuropathy was present if the records indicated autonomic dysfunction following food ingestion16-17. absence of ankle jerk, decreased vibration sense or However, the pathologic basis |of diabetic autonomic pin prick sensation in the feet or hands, or there was neuropathy is still incompletely understood. history of neuropathic pain, foot ulcer, or symptoms compatible with autonomic neuropathy (differential treatment of erectile and cardiovascular dysfunctions diagnosis) including postural hypotension, using oral drugs lies in the substance sildenafil citrate intermittent diarrhea especially nocturnally, (ViagraTM) seems to be a most promising discovery18. epigastria fullness, bladder dysfunction, diminished Sildenafil is a potent and selective inhibitor of the sweating in the legs, gustatory sweating and cyclic guanosine monophosphate (cGMP)-specific hypoglycemic unawareness. The criteria for the phosphodiesterase type 5 (PDE5), which is presence of symptomatic autonomic neuropathy were responsible for the degradation of cGMP in the two or more severe or three or more mild/moderate Sildenafil has a peripheral site of action on Impotence was determined according to the erections. It potently enhances the relaxant effect of method described previously21. Men were considered nitric oxide (NO) on this tissue. When the NO/cGMP candidates for this study when they had complained pathway is activated, as occurs with sexual of erectile dysfunction with diabetic neuropathy for 6 stimulation, inhibition of PDE5 by sildenafil results or more months. All candidates had normal results on in increased corpus cavernosum levels of cGMP. Increased levels of cGMP are involved in smooth hypothalamic pituitary axis as obtained by their muscle relaxation, which in turn leads to penile erection. cGMP is converted back to guanosine monophosphate (GMP), a cGMP precursor, by the alone, oral hypoglycemic agent or insulin. Inquiry action of phosphodiesterase type 5 (PDE5). Sildenafil was made of other drug therapy, angina pectoris, prevents the breakdown of cGMP thereby preventing previous myocardial infarction or cardiac failure, premature detumescence. Furthermore, treatment intermittent claudication, thyroid dysfunction, with sildenafil is well tolerated and is associated with previous sympathectomy or other abnormality that minimal adverse events that rarely cause might predispose to organic impotence such as discontinuation of the treatment. It relaxes vascular neurological disease or previous injury. smooth muscle, resulting in modest reductions in To assess the efficacy and safety of oral blood pressure that are insufficient to stimulate a sildenafil citrate (Viagra TM-Pfizer) in the treatment of reflex increase in heart rate. Sildenafil does not affect erectile dysfunctions in both IDDM and NIDDM the force of cardiac contraction, and cardiac diabetic men with and without neuropathy and in age performance is unaffected. Sildenafil is mildly matched non diabetic controls, subjects home and vasodilating in the coronary circulation and does not clinical practice centers in the local vicinities, were increase the risk of ventricular arrhythmia. Among randomized to receive sildenafil citrate (50 mg), but men with erectile dysfunction treated with sildenafil, not more than once daily, for 12 months. Self- the adverse event profile is similar overall to that in reported ability to achieve and maintain an erection men with comorbid cardiovascular disease (CVD), it for sexual intercourse according to the International is similar between those with and without CAD, and Index of Erectile Function and adverse events were it is similar between those who take and those who recorded according to the method described do not take antihypertensive drugs (regardless of the Pak J Physiol 2006; 2(2)
Erectile and cardiovascular responses were Exactly in a similar manner, values of penile assessed using simultaneous monitoring of penile length and penile pulse amplitude showed a mid shaft circumference & length, penile pulse significant increase (p<0.0005) in both types of amplitude, systemic arterial systolic & diastolic blood sildenafil treated diabetic neuropathic patients when pressures & heart rate during laboratory based erotic compared with the values obtained from untreated stimulation with film and fantasy before and after the patients (Figures 2 & 3). However this difference was sildenafil treatment in all the subjects according to found to be non-significant in both types of diabetic patients without neuropathy before and after oral The degree of erection to erotic film & administration of sildenafil and when compared with fantasy distinguished between neuropathic & non- neuropathic etiologies. The initial approach was tentative so that it was easy for the individuals to decline without embarrassment. If there was apparent willingness, a more definite request was made. All the parameters were statistically analyzed using Student t-test. In all the instances probability (p<0.05) was regarded as statistically significant. The data for the measurement of penile mid shaft circumference in response to film and fantasy before and after the administration of 50 mg of oral dose of sildenafil citrate in 50 IDDM and 50 NIDDM diabetics (with and without neuropathy) and in 50 age matched non diabetic control subjects is shown in Figure- 1. Figure-2: Changes in penile length (mm) before and
after oral administration of sildenafil citrate (50 mg
dose) in response to erotic film and fantasy in insulin
dependent (IDDM) and
non-insulin dependent
(NIDDM) diabetic males (with and without neuropathy)
and in age matched non diabetic control subjects.
Values are means ± S.D.
Figure-1: Changes in penile mid shaft circumference
(mm) before and after oral administration of sildenafil
citrate (50 mg dose) in response to erotic film and
fantasy in insulin dependent (IDDM) and non insulin
dependent (NIDDM) diabetic males (with and without
neuropathy) and in age matched non diabetic control
subjects. Values are means ± S.D.
Figure-3: Changes in penile pulse amplitude (µv) before
A consistent increase in the values of penile and after oral administration of sildenafil citrate (50 mg
circumference in both IDDM and NIDDM diabetic dose) in response to erotic film and fantasy in insulin
patients with neuropathy was observed with a dependent (IDDM) and
non-insulin dependent
significant statistical difference (P<0.0005) after the (NIDDM) diabetic males (with and without neuropathy)
sildenafil treatment, the increase being about 26% and in age matched non diabetic control subjects.
Values are means ± S.D.
Pak J Physiol 2006; 2(2)
types of treated diabetic patients without neuropathy showed a non-significant difference in levels systolic and diastolic blood pressures and heart rate when compared with the untreated patients and their age matched control subjects. An interesting feature in these experiments was about 7% decrease in the values of systolic and diastolic blood pressure and about 6% decrease in the values of heart rate after the oral administration of 50 mg of sildenafil in non-diabetic controls. In addition, no difference was observed when the IDDM and NIDDM values were compared with each other either before or after the oral administration of sildenafil in all groups (data not shown). Figure-4: Changes in systolic blood pressure (mmHg)
before and after oral administration of sildenafil citrate
(50 mg dose) in response to erotic film and fantasy in
insulin dependent (IDDM) and non insulin dependent
(NIDDM) diabetic males (with and without neuropathy)
and in age matched non diabetic control subjects.
Values are means ± S.D.
Figure-6: Changes in heart rate (beat/minute) before
and after oral administration of sildenafil citrate (50 mg
dose) in response to erotic film and fantasy in insulin
dependent (IDDM) and non insulin dependent
(NIDDM) diabetic males (with and without neuropathy)
and in age matched non diabetic control subjects.
Values are means ± S.D.
DISCUSSION
Figure-5: Changes in diastolic blood pressure (mmHg)
Laboratory assessment of erectile response to erotic before and after oral administration of sildenafil citrate
stimuli has been used for many years to assess sexual (50 mg dose) in response to erotic film and fantasy in
preferences as the out come of modification of insulin dependent (IDDM) and non insulin dependent
deviant sexual behavior21, but only one published (NIDDM) diabetic males (with and without neuropathy)
study23 has used this procedure in the investigation of and in age matched non diabetic control subjects.
erectile dysfunction. In the recent years, there has Values are means ± S.D.
been increasing recognition that many cases of In contrast, an inverse relationship was erectile dysfunctions are due, at least in part, to found when systolic and diastolic blood pressures and physical factors. This has led to a renewed interest in heart rate values were measured in the same group of the physiological mechanism of normal erection and search for methods of investigating erectile function neuropathic treated patients showed a significant that may have diagnostic value. Evidence indicates decrease (p<0.025) in the values of systolic and that erection may involve the activation of several diastolic blood pressure (Figures-4 and 5) and comparatively a more significant decrease (P< 0.005) parasympathatically mediated arterial vasodilatation, in values of heart rate (Figure-6). However, both there may also be active reduction of venous Pak J Physiol 2006; 2(2)
drainage25 and the active closure of intra cavernosal after the oral administration of 50 mg of sildenafil arterio-venous shunts 26. None of the established (Viagra) in both IDDM and NIDDM diabetic methods of investigating penile dysfunction is wholly neuropathic patients. However this difference was satisfactory. The most widely used techniques for found to be non-significant in both types of diabetic laboratory studies are either concerned with patients without neuropathy before and after oral physiological state of non-erect penis e.g. administration of sildenafil and when compared with measurement of penile blood pressure27-28 or involve invasive procedures such as xe non washout25, arteriography and artificial erection29-30 and the usual determinant of the quality of an erection. Based on non-invasive method of investigating the erect penis published evidence it is suggested that a penile is to measure erections during sleep. However, this rigidity of >70% is adequate for sexual intercourse33. does necessitate over night observation of the Because sildenafil is believed to exert its beneficial effects by inhibiting the phosphodiesterase type-V In a study laboratory based procedure for enzyme and, therefore, increasing the intracellular monitoring penile diameter and dorsal penile arterial levels of cGMP in the corporal smooth muscle, it pulse during presentation of erotic stimuli has been would not be expected to produce an erectile described in the normal subjects10. The results response when used in the absence of a drive on the indicate the aspects of the erectile response, which nitric oxide-cGMP pathway. This drive can be may be vulnerable to different pathological provided by physiological mechanisms that can be processes31. The etiology of erectile impotence initiated by visual or other forms of sexual associated with diabetes mellitus has been reported to stimulations. As such, sildenafil may be expected to be neuropathic abnormality in the male genital organ enhance relaxation of the corpus cavernosal smooth and/or vascular change in the corpora cavernosa. muscle, which in turn increases blood flow into the However, the diagnostic assessment and the cavernosal spaces, thus leading to increased treatment of the neuropathic factor has been intracavernosal pressure, a key factor in producing an impended by the lack of an objective laboratory test. Sildenafil citrate relaxes vascular smooth Our results suggest that oral administration muscle, resulting in modest reductions in blood of sildenafil improves the quality of erection in both pressure that are insufficient to stimulate a reflex IDDM and NIDDM neuropathic group of patients. increase in heart rate. These blood pressure We thus conclude that sildenafil citrate is an effective reductions are similar for healthy men and men with first-line therapy for erectile dysfunction in diabetic coronary artery disease (CAD) or who use men with impotence of neuropathic etiology. These antihypertensive drugs. Sildenafil does not affect the results further explains, how to manage sexual force of cardiac contraction, and cardiac performance disorders as part of diabetic care, and suggests rules is unaffected. Sildenafil is mildly vasodilating in the for sildenafil’s prescription in diabetic neuropathic coronary circulation and does not increase the risk of ventricular arrhythmia. During exercise and recovery, In contrast to above mentioned findings we sildenafil does not cause clinically significant found a decrease in the values of systolic and alterations in hemodynamic parameters in men with diastolic blood pressures (P<0.025) and heart rate CAD, and it has no negative effects on coronary (P<0.005) in both types of diabetic neuropathic oxygen consumption, ischemia, or exercise patients after the sildenafil treatment, where as this difference was found to be non significant in both types of non neuropathic diabetics when compared designed to compare the efficacy of sildenafil citrate with their respective control subjects. A decrease in on erectile and cardiovascular responses to erotic pressure responses and heart rate after the sildenafil stimulations in IDDM and NIDDM diabetics (with treatment in IDDM and NIDDM diabetic neuropathic and without neuropathy) and in age matched non- patients is probably due to a decrease in peripheral diabetic controls. The stimuli utilized were fantasy resistance due to overall greater severity of and film. Both of these stimuli produced striking neuropathy in these individuals with sympathetic and differences between those in whom neuropathic and parasympathetic damage rather than from the effect induced erectile factors were likely to under lie their of parasympathetic damage in particular. In this context, Jackson36 observed in one couple tested, that Our results indicated that during the period administration of beta-adrenergic receptor antagonist of erotic stimulation to film and fantasy penile mid prior to intercourse reduced the pressure response in shaft circumference, penile length, and penile pulse both sexes. This can be taken as an alternative amplitude exhibited a significant increase (P<0.0005) interpretation of our results. Our data indicate that Pak J Physiol 2006; 2(2)
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Address For Correspondence:
Dr. Syed Tabrez Ali, Associate Professor, Department of Physiology, Faculty of Medicine and Medical Sciences,
Umm-al-Qura University, P.O. Box 7607, Makkah, Saudi Arabia
E-mail: shazali_2004@hotmail.com

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