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Year: 2013  |  Volume: 4  |  Issue: 1  |  Page No.: 60 - 64

Tadalafil and Gastrointestinal Relaxivity Effects

Soheila Hekmat, Mehdi Shafiee Ardestani, Seyed E.S. Ebrahimi, Maryam Ravan and Mitra Elmi    

Abstract: Reports suggest the increase in the incidence risk of the coronary heart diseases in diabetic patients. This experiment is carried out to study the differences between inhibitory effects of selective type5 cGMP phophodiestrase inhibitor Tadalafil±dipyridamol on the isolated prepared of ileum of the control and diabetic rats. The diabetic rats were created and kept for 6-8 weeks. A piece of ileum was separated and set up in an organ bath containing physiological salt solution. Contractions were induced by KCl (80 mM) and Tadalafil was added in non-cumulative manner to relax the ileum. Tadalafil induced relaxation of the precontracted isolated ileum preparation in both diabetic and control rats. Relaxation responses in normal and diabetic rats were found similar and there was not any significant differences between EC50 (concentration that results in half-maximal response) of Tadalafil in both control and diabetic rats. Addition of dipyridamol increased the responses to Tadalafil. The present study showed the effectiveness for selective phophodiestrase type5 inhibition to produce equivalent relaxant effect on isolated preparation of ileum obtained from either control or diabetic rats.

Moreno et al., 1996; Javidi et al., 2005; Scognamiglio et al., 2006). Impaired endothelium-dependent relaxation may be a common feature determined in blood vessels of the experimental diabetic animals and in sort I or sort II diabetic patients (Moreno et al., 1996). Researches in experimental animal models designed to research the mechanisms involve in such dysfunctions implicate the varied factors like decreasing in unharness or production of endothelium-derived restful factors like gas (Moreno et al., 1996; Pieper, 1997) area unit being concerned. Among these factors; decreasing within the gas (NO) handiness is of major importance (Pieper, 1997; Van Etten et al., 2002). Nitric oxide may be a noted physiologically necessary treater (Burnett, 1995) that is discharged from vascular epithelium and acts by activating guanylate cyclase, that converts nucleoside triphosphate to cyclic nucleoside monophosphate (cGMP) (Eardley, 1998) cGMP becomes the secondary traveler that causes the graceful muscle relaxation, leading to blood vessel engorgement and penial tumidity (Moreno et al., 1996; Pieper, 1997; Van Etten et al., 2002; Burnett, 1995; Eardley, 1998; Jeremy et al., 1997). Blood flows into the corpora cavernosae and also the bulbous spongiosum engorges the cavernosal areas. High level of the intra-penile gas (NO) can facilitate the relaxations of intra-cavernosal trabeculae, thereby increasing blood flow and penial erection (Burnett et al., 1992; Goldstein et al., 1998; Burnett, 1997). Tadalafil may be a elective matter of cyclic nucleoside monophosphate (cGMP) specific phosphodiesterase sort five (PDE5) Associate in Nursingd is wide used as an oral pharmaceutical for the treatment of male ED.12 Tadalafil will increase the result of NO by by selection inhibiting PDE5 (IC50: three.5 nM) thereby enhances concentrations of cGMP on vascular sleek muscle (Boolell et al., 1996a). Tadalafil may be a PDE5 matter, presently distributed in pill kind for treating ED (ED) and is understood as Cialis and or Adcirca for the treatment of pneumonic blood vessel high blood pressure. it absolutely was at the start discovered by the biotechnology company ICOS and so developed once more and distributed world-wide by Lilly ICOS, LLC, the venture of ICOS Corporation and Eli Lilly and Company. The approved dose for pneumonic blood vessel high blood pressure is forty mg (two 20 mg tablets) once daily (Eardley, 1998; Jeremy et al., 1997; Burnett et al., 1992; Goldstein et al., 1998; Burnett, 1997; Daugan et al., 2003).

Fig. 1: The chemical structure of dipyridamol versus the Tadalafil

Tadalafil is additionally created and oversubscribed below the name of Tadacip by the Indian drug company Cipla in doses of ten mg and twenty mg. On Gregorian calendar month twenty one, 2003 the Food and Drug Administration has approved tadalafil (as Cialis) purchasable within the u.s. because the third ED prescription (after virility drug change state (Viagra) and vardenafil (Levitra). Cialis’s 36 h effectiveness attained it the nickname, "The Weekend Pill"; like virility drug and vardenafil, tadalafil is suggested as Associate in Nursing ’as needed’ medication. Cialis is that the lonely one amongst the 3 that’s offered as a once-daily medication furthermore. moreover, tadalafil has approved in could 2009 within the u.s. for the treatment of pneumonic blood vessel high blood pressure. In late Gregorian calendar month 2008, Eli Lilly oversubscribed the exclusive rights to commercialize tadalafil for pneumonic blood vessel high blood pressure within the u. s. to United medical specialty for Associate in Nursing direct payment of high charges $150 million (Burnett, 1997; Daugan et al., 2003; Richards, 1991; Boolell et al., 1996a, b).Diabetic men have a quite 3-fold increase within the prevalence of ED (ED) compared by non-diabetic subjects. Oral pharmaceuticals acting through the inhibition of phosphodiesterase in penial vasculature have revolutionized treatment of impotence in diabetic men (Boolell et al., 1996b; Ballard et al., 1998; Dey and Shepherd, 2002). In this study streptozotocin-treated rats were used as Associate in Nursing experimental model of polygenic disorder, since it’s been reportable that intraperitoneal (i.p.) injection of such agent destroys the beta cells of the duct gland, manufacturing endocrine dependent polygenic disorder. Dipyridamol as a non selective PDE matter that is wildly used as Associate in Nursing opposing protoplasm aggregated agent within the clinics inhibits the PDE however from the various web site comparison to virility drug (Billups, 2005). The chemical structures of the mentioned medication were shown in Fig. 1.

The present study was carried out to study the differences in the relaxation induced by Tadalafil in absence or presence of dipyridamol in isolated ileum of control and diabetic rats.


Animals and experimental procedures: These animal experiments were carried out in accordance with recommendations from the Declaration of Helsinki and the internationally accepted principles for the use of experimental animals.

Adult male rats (Sprague Dawly origin) weighting 200-250 g were included in the study and made diabetic by a single i.p. injection of 60 mg kg-1 streptozotocin (STZ) prepared in normal saline as we previously published (Moreno et al., 1996). The state of diabetes was established by testing the urine and blood glucose levels using Uryab-8 tapes (Bakhtar Biochimie Co., Iran) and Glu-cinet kits (Bayer) respectively. A urine glucose concentration of 2% or more was considered to be diabetes (Zheng et al., 2006). Blood glucose levels of the killed diabetic animals were between 500-700 mg dL-1.

The diabetic animals were kept for 6-8 weeks before killing (Zheng et al., 2006). During this time, the diabetic and control animals were allowed free access to food and water.

Rats were killed employing the CO2 cage. The ileum was rapidly removed and carefully dissected free from adhesive tissues. A piece of ileum (1.5-2 mm in length) was set up in 50 mL organ bath containing Krebs solution (at 37°C) bubbled with carbogen (95% O2, 5% CO2). The isotonic contractions of isolated ileum of either control or diabetic rats in oxygenated Krebs solution at 37°C under resting tension of 0.5 mg were recorded with an isotonic transducer and a Washington 400 MD 2R physiograph. Preparation was allowed to equilibrate for at least 60 min, during which the bathing medium was changed every 15 min.

After an equilibrium period, KCl (80 mM) was added to the organ bath. After 5 min Tadalafil at the concentrations of 4, 7.5, 15, 22.5, 30 (μM) was added to the organ bath in non-cumulative manner. The effect of Tadalafil was recorded in percent as the ratio of relaxation achieved by Tadalafil on contractile response curve after adding it to precontracted isolated ileum. In the same procedure the effects of Tadalafil in absence or presence of different doses of dipirydamol on the ileum contractions was respectively investigated.

Solutions and drugs: All the solutions were prepared freshly on the day of experimentation. Tadalafil stock solution was prepared in deionized water and diluted in saline before injection.

Krebs solution had the following composition (in mM); NaCl 118, KCl 4.8, CaCl2 2.5, KH2PO4 1.2, NaHCO3 25, glucose 10. All salts were of analytic grade and were obtained from Merck (Germany).

Statistical analysis: The data were shown as the Mean±SEM. Statistical evaluation of the results was performed by means of t-test (paired) followed by appropriated post hoc test considering the following significant differences: p<0.05.


Tadalafil in non-cumulative manner (4, 7.5, 15, 22.5 to 30 μM) induced relaxation by inhibiting the contractile effect of KCl (80 mM) in the ileum of both control and diabetic rats (Fig. 2, 3).

There was not any significant different between EC50 (concentration that results in half-maximal response) of Tadalafil in both control and diabetic rats, so we concluded that Tadalafil relaxation effect does not have any different diabetic rats in comparison with controls ones (Table 1).

Fig. 2(a-b):
Diagram showing contractile response to KCl (80 mM) and inhibitory effect of Tadalafil in isolated ileum preparation of control (a) and diabetic (b) rat as recorded by the physiograph

Table 1: ED50 values of the Tadalafil in isolated ileum of the control and diabetic rats

Table 2:
Response percentages of Tadalafil in absence and presence of dipyridamol and their appropriated P values resulting from the statistical analysis

Fig. 3:
Dose response curves of Tadalafil in isolated preparations of ileum obtained from control and diabetic rats (n = 6 each)

Fig. 4:
Demonstration the effect of Tadalafil in presence of dipyridamol on the precontracted ileum relaxation

The results also showed the significance differences for Tadalafil to modify the effect of KCl 80 mM in the presence of dipyridamole 10-6 M comparing to the control group (concentration of dipyridamol was equal to 0 M) (Fig. 4). The additional data of these observations was shown in Table 2.



In this study we tried to observe the differences between the effects of Tadalafil on the ileum of diabetic and control rats. It has been reported that streptozotocin can induce diabetes in rats (Moreno et al., 1996) and this model can be used to study the effect of various drugs on diabetes. ED is more prevalent in diabetic patients due to multiple factors such as endothelial damage (Boolell et al., 1996b). Tadalafil, a selective substance of phosphodiesterase kind five, by enhancing the impact of NO, will increase level of cGMP that causes cavernosal sleek muscle relaxation and flow of blood and erectile organ erection (Burnett et al., 1992; Richards, 1991). In diabetic models in step with epithelial tissue harm we have a tendency to catch suppose to lower Tadalafil effects on male erecticle dysfunction. Within the gift study Tadalafil created equivalent relaxation impact on isolated small intestine preparations (precontracted with KCl (80 mM) obtained from management and diabetic rats (Table 1). The results additionally indicate the additional necessary role for dipyridamol as moving drug on NO pathway and PDE (non selective) as a result of its addition caused to vital or non vital improvement within the impact of Tadalafil in relaxation of narrowed small intestine in each traditional and diabetic rats (Table 2). We resulted that polygenic disease didn’t modification the response to Tadalafil considerably. It will make a case for the observation of Dey and Shepherd (2002) on a similar drug. (Boolell et al., 1996b) World Health Organization showed effectiveness of Tadalafil in diabetic patients. This observation any explains by the actual fact that whereas phosphodiesterase kind five is found in tube sleek muscle (Srivastava et al., 1982; Yohannes et al., 2010; Beavo, 1995) the response to virility drug (same drug within the category) isn’t being littered with the epithelial tissue harm seen within the polygenic disease (Moreno et al., 1996). It appears that each medication (Tadalafil and dipyridamol inhibit PDE5 from 2 completely different binding sites and cause to relaxation in narrowed small intestine of traditional and diabetic rats. It ought to be give notice that co-administration of the dipyridamol and virility drug medication has not created any interactions and in some cases like thromboambolic diabetic patients with male erecticle dysfunction the coincidence use of them appears to be necessary and according (Beavo, 1995).


The authors would like to express their deep gratitude to all laboratory technicians for their assistances during the study.

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