Effect of sildenafil citrate on postprandial gallbladder motility.

Objective: Sildenafil stimulates the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway through inhibition of type 5 phosphodiesterase. NO-cGMP pathway causes smooth muscle relaxation. The aim of this study is to evaluate the effects of sildenafil on gallbladder motility.

Methods: Twenty healthy male volunteers (21-35 years old) participated in this randomized, double blind, crossover, and placebo-controlled study. Oral sildenafil (50 mg) or placebo was randomly dispensed to each volunteer on two consecutive days. After the sildenafil or placebo, a special meal with a high fat content was administered. Gallbladder volume was measured using sonography preprandially and at 5. 15, 30, 60, 120 and 180 minutes postprandially.

Results: Sildenafil showed an inhibitory effect on gallbladder contraction in healthy volunteers that began at 30 minutes. Gallbladder volumes showed significant differences at 30 minutes following the test meal (approximately 50-60 min after the sildenafil intake), between placebo (15.4 [+ or -] 5.1 mL) and the sildenafil groups (19.3 [+ or -] 6.1 mL) (P < 0.05). In addition, gallbladder volume was significantly higher during the refilling phase in the sildenafil group (P < 0.05 at 180 min). Maximal contraction was achieved at 60 minutes in each group.

Conclusions: Sildenafil constituted a significant inhibitory effect on gallbladder discharge in healthy individuals when compared with placebo group. Because of this inhibitory effect, sildenafil consumption for long periods may potentiate risks of gallbladder disorders and gallstone formation resulting from disturbed gallbladder motility.

Key Words: gallbladder diseases, sildenafil citrate, ultrasonography, nitric oxide

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Sildenafil dilates penile arteries through cyclic guanosine monophosphate (cGMP), and penile erection is achieved by increasing penile blood flow. (1-3) Because of these effects, it is widely used for the treatment of erectile dysfunction. (4,5) Its effect takes place via the specific blockage of type 5 phosphodiesterase. This blockage results in an increase of intracellular cGMP and constitutes an inhibitory effect both on the arteriolar smooth muscle cells of corpus cavernosum and on other blood vessel smooth muscle cells of the gut. (6) Sildenafil may be expected to show similar effects on the other smooth muscle-containing organs. It decreases the tonus of the lower esophageal sphincter in normal subjects and patients with achalasia. (7-9) Decreases in gastroduodenal motility and rectal tonus were also shown. (6,8-11) We hypothesize that sildenafil may have inhibitory effects on the smooth muscle of the gallbladder. We aimed to sonographically evaluate the effects of sildenafil and placebo on gallbladder contraction and postprandial volumetric changes.

Methods

Twenty healthy male volunteers (21-35 years old) participated in the study. They were free from any gastrointestinal disturbances, did not take any medication throughout the entire examination period, and gave no history of previous gastric surgery, vagotomy, or diabetes mellitus. Subjects were not permitted to smoke two days before the procedure. Sildenafil and placebo were randomly administered to subjects on two consecutive days. Following an 8 to 12 hour period of fasting, basal gallbladder volume was measured in all subjects. A 50 mg solution of sildenafil (Viagra, Pfizer, NY--USA) in 200 mL water was prepared. Water in same amount was established as a placebo. After the basal gallbladder volume measurement, sildenafil or placebo was provided in its entirety to the subject under close observation. After a waiting period of 10 to 15 minutes, to ensure transit time to plasma, a high fat test meal was eaten by the subject to provide 30 to 40 g of fat intake. Each test meal was consumed within 3 minutes by the subjects. Gallbladder volume was recorded postprandially at 5, 15, 30, 60, 120, and 180 minutes. The subjects were not allowed any other food or liquid intake during the examination. The same procedure was repeated for the placebo and sildenafil groups on different days. Blood pressure and heart rate were measured before and after the procedure, and subjects were encouraged to voice any complaints. Gallbladder volume was measured according to the method of Dodds et al, (12) using real time sonography (Toshiba, Nemio, Tokyo-Japan) and a 3.5 to 6 MHz broadband abdominal transducer. An ellipsoid approximation was used for the calculation of the gallbladder volume, as described by the formula = ([pi]/6) * L * H * W, where V = gallbladder volume, L = gallbladder length, H = gallbladder height, and W = gallbladder width. The best position and location of the transducer for the assessment of gallbladder sizes were determined in each subject and marked on the skin. These marks were used for the following measurements. Longitudinal and cross-sectional diameters of gallbladder were recorded in all three measurements. The mean of these three measurements were used for the assessment of gallbladder volume. Gallbladder contraction (emptying) and relaxation (refilling) plots were obtained from the gallbladder volume and time values. Written informed consent was obtained from every volunteer. The study was carried out in accordance with the Declaration of Helsinki. Values are presented as means and standard deviation. Statistical analyses included the paired, two-tailed student t test. Differences were considered significant when P < 0.05.

Results

The results are summarized in the Table. Preprandial gallbladder volumes before placebo (33.6 [+ or -] 9.0 mL) and sildenafil (32.4 [+ or -] 11.4 mL) were not significantly different (P = 0.478). Although it was not significant, more of a decrease was observed in gallbladder volume measured at 5 and 15 minutes after placebo than during the same time frame after sildenafil (Fig. 1). However, the difference was not statistically significant (P = 0.057 for 5 and P = 0.132 for 15 min). Thirty minutes after the test meal (50-60 min after the sildenafil intake), there was a significant difference between gallbladder volumes of placebo (15.4 [+ or -] 5.1 mL) and sildenafil groups (19.3 [+ or -] 6.1 mL) (P = 0.009). Maximal gallbladder emptying was achieved at 60 minutes, both in placebo (15.05 [+ or -] 5.39 mL) and sildenafil (17.76 [+ or -] 6.85 mL) groups. Although the gallbladder volume of the sildenafil group was greater than placebo at 60 minutes, this difference was not significant (P = 0.059). In our study, the measurements that were taken before 60 minutes were the values of gallbladder contraction phase. In both groups, the increasing gallbladder volumes after 60 minutes, as measured at 120 and 180 minutes (Fig. 1), imply refilling of the gallbladder was started after 60 minutes. While gallbladder volume did not show any significant difference at 120 minutes between placebo and sildenafil groups (P = 0.187), a statistical difference was assessed at 180 minutes (P = 0.011). The excess of gallbladder volume at this stage is thought to result from the inadequate emptying at contraction phase. In all measurements taken after the test meal, all values of post sildenafil gallbladder volume were higher than post placebo ones. Gallbladder emptying was lower, while refilling was higher after sildenafil (Fig. 1).

Post sildenafil systolic blood pressures were moderately lower than the corresponding basal values. Diastolic pressure did not show any significant difference. No change in blood pressure or heart rate was noted after placebo. Six subjects complained of mild headache and one complained of headache requiring pain relief after sildenafil. Eight subjects had mild flushing after sildenafil intake. No complaint was reported after placebo intake.

Discussion

In the present study we show that sildenafil causes gallbladder tonus decrease and significantly slows down gallbladder emptying. In addition, post sildenafil gallbladder refilling was higher in late phase. To our knowledge, this is the first demonstration of the effect of sildenafil on gallbladder contraction. Gallbladder motility is controlled by neural and hormonal mechanisms which interact with each other. (13) Cholecystokinin, a proximal gut hormone, is the primary stimulant mediator for gallbladder contraction. (14,15) It is released from small bowel mucosal cells when gastric content rich in fatty acids and amino acids reaches the small bowel. It is the main determiner for the postprandial gallbladder discharge. Cholecystokinin starts gallbladder contraction by affecting the preganglionic cholinergic nerves. (15) Nitrous oxide (NO) is an essential inhibitory neurotransmitter for the gastrointestinal tract which is produced either by smooth muscle cells directly or by the stimulation of nonadrenergic-noncholinergic (NANC) vagal neurons. (16,17) NO increases intracellular and plasma concentrations of cGMP. (18,13) cGMP then phosphorylates other intracellular signaling molecules that make smooth muscle cells less excitable. (7) IV infusion of NO-donor glyceryl trinitrate slows down gastric emptying by reducing the gastric tonus in healthy individuals. (19) NO is the basic neurotransmitter released from NANC inhibitory neurons that cause constriction of sphincter of Oddi in gallbladder contraction phase and relaxation of the gallbladder in the late postprandial phase. (18)

[FIGURE 1 OMITTED]

Sildenafil increases the relaxant effect of NO by inhibiting type 5 phosphodiesterase. Type 5 phosphodiesterase decreases the effectiveness of NO-cGMP pathway via degradation of intracellular cGMP. (13,20) Various studies have shown the inhibitory effects of sildenafil in some parts of the gastrointestinal system. Sildenafil significantly decreases the tonus of the lower esophageal sphincter in normal individuals, patients with esophageal motor disorders, and with nutcracker esophagus. (7,9,21) Therefore, it is suggested that this medicine may be helpful for the treatment of achalasia and nutcracker esophagus. (7,9) Bortolotti et al (10) showed inhibition of gastroduodenal motility by sildenafil. Fritz et al (11) reported that sildenafil reduces rectal muscle tone in healthy subjects and patients with irritable bowel syndrome. In our study, sildenafil revealed similar effects on the smooth muscle of the gallbladder. It slowed down gallbladder emptying by the inhibitory effect on contractility. This effect was more pronounced at 30 and 60 minutes, at which sildenafil reaches maximal plasma concentrations after oral intake in the fasting state. (22) The NO-cGMP pathway relaxes the gallbladder smooth muscle in the refilling phase by means of NANC nerves in normal conditions. In our study, the significant difference between post placebo and post sildenafil gallbladder volumes at the refilling phase (180 min) may be due to lesser gallbladder emptying at the contraction phase in the sildenafil group and the increasing effect of sildenafil on the dilating effects of NANC nerves. The effect of sildenafil on gallbladder motility is presumably carried out two ways: first, increase of intracellular cGMP by the inhibition of type 5 phosphodiesterase and relaxation of smooth muscle cells at postprandial gallbladder contraction phase (direct effect); and second, decrease of cholecystokinin release resulting from inhibition of gastroduodenal motility (indirect effect). Disruption of gallbladder motility facilitates the formation of gallstones. Gallbladder motility is frequently disrupted in high risk cases for gallstone formation, including pregnancy, obesity, diabetes mellitus, gastric surgery, and somatostatin therapy. (23) Besides, both small bowel and whole gut transit times are extended in gallstone patients. (24) Three mechanisms have been described for gallstone formation: first, increased rate of cholesterol crystal nucleation; (25) second, cholesterol super saturation of gallbladder bile; (26) and third, reduced gallbladder emptying. (27) Delayed gallbladder emptying and reduced muscle contractility occurs in chronic calculus, gallstone, or cholecystitis. (28,29) Impairment of gallbladder contractility may contribute to the etiopathology of acalculous cholecystitis. (30)

According to our study, sildenafil decreases gallbladder emptying by its inhibitory effect on gallbladder smooth muscle contractility. Previous studies have shown that it causes prolonged small bowel transit time and inhibition of gastroduodenal motility. Sildenafil use for long periods of time may possibly have some risk for gallbladder diseases, including increased risk for cholecystitis due to delayed emptying of the gallbladder, although this has not been confirmed. In addition, impaired gallbladder emptying with long-term use of sildenafil may result in gallbladder stone formation. This suggestion requires further evaluation, especially in long-term sildenafil users.

References

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2. Umans JG, Levi R. Nitric oxide in the regulation of blood flow and arterial pressure. Annu Rev Physiol 1995;57:771-790.

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17. Kuiken SD, Vergeer M, Heisterkamp SH, et al. Role of nitric oxide in gastric motor and sensory functions in healthy subjects. Gut 2002;51:212-218.

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20. Steers WD. Viagra, after one year. Urology 1999;54:12-17.

21. Rhee PL, Hyun JG, Lee JH, et al. The effect of sildenafil on lower esophageal sphincter and body motility in normal male adults. Am J Gastroenterol 2001;96:3251-325,7.

22. Madsen JL, Sondergaard SB, Fuglsang S, et al. Effect of sildenafil on gastric emptying and postprandial frequency of antral contractions in healthy humans. Scand J Gastroenterol 2004;39:629-633.

23. Harrington K, Bomzon A, Sharkey KA, et al. Differential sensitivities of the sphincter of Oddi and gallbladder to cholecystokinin in the guinea pig: their role in transsphincteric bile flow. Can J Physiol Pharmacol 1992;70:1336-1341.

24. Scott RB, Eidt PB, Shaffer EA. Regulation of fasting canine duodenal bile acid delivery by sphincter of Oddi and gallbladder. Am J Physiol 1985;249:622-633.

25. Holan KR, Holzbach RT, Hermann RE, et al. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 1979;77:611-617.

26. Admirand WH, Small DM. The physicochemical basis of cholesterol gallstone formation in man. J Clin Invest 1968;47:1043-1052.

27. Fisher RS, Stelzer F, Rock E, et al. Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci 1982;27:1019-1024.

28. Behar J, Lee KY, Thompson WR, et al. Gallbladder contraction in patients with pigmentand cholesterol stones. Gastroenterology 1989;97:1479-1484.

29. Fisher RS, Rock E, Mahmud LS. Cholinergic effects on gallbladder emptying in humans. Gastroenterology 1985;89:716-722.

30. Parkman HP, James AN, Bogar LJ, et al. Effect of acalculous cholecystitis on gallbladder neuromuscular transmission and contractility. J Surg Res 2000;88:186-192.</p> <pre> Happiness is that state of consciousness which proceeds from the achievement of one's values. --Ayn Rand </pre> <p>Bumin Degirmenci, MD, Murat Acar, MD, Ramazan Albayrak, MD, Aylin Yucel, MD, Alpay Haktanir, MD, Reha Demirel, MD, and Ender Ellidokuz MD

From the Departments of Radiology, Public Health, and Gastroenterology, Kocatepe University Faculty of Medicine, Afyon, Turkey.

Reprint requests to Bumin Degirmenci, MD, Department of Radiology, Kocatepe University Faculty of Medicine, Afyon, Turkey. Email: [e-mail]

Accepted November 28, 2005.

RELATED ARTICLE: Key Points

* Sildenafil citrate is widely used for the treatment of erectile dysfunction because of its relaxant effect in vascular smooth muscle cells by inhibiting type 5 phosphodiesterase.

* It has been shown that sildenafil produces a similar effect in the smooth muscles of the esophagus, stomach, and rectum in the gastrointestinal tract.

* A comparable relaxant effect of sildenafil is expected in the gallbladder wall smooth muscle.

* Relaxation of the smooth muscle of the gallbladder wall decreases postprandial emptying in gallbladder.

Table. Postprandial gallbladder volumes after placebo and sildenafil

                           Volume (mL)
Time (min)  Placebo              Sildenafil            P value

  0         33.66 [+ or -] 9.00  32.41 [+ or -] 11.42   0.478
  5         21.20 [+ or -] 7.73  26.34 [+ or -] 12.46   0.057
 15         17.41 [+ or -] 7.51  20.18 [+ or -] 8.60    0.132
 30         15.49 [+ or -] 5.18  19.33 [+ or -] 6.13    0.009
 60         15.05 [+ or -] 5.39  17.76 [+ or -] 6.85    0.059
120         16.98 [+ or -] 5.91  19.57 [+ or -] 9.92    0.187
180         18.27 [+ or -] 5.84  22.44 [+ or -] 5.93    0.011

Results are expressed as mean [+ or -] SD.