In Vitro Evaluation of Indomethacin, Ketoprofen, Diclofenac and Celecoxib on Erectile Function

NA Nour El-Din, AM Senbel, MM Mohy El-Din. Faculty of Pharmacy-Alexandria University, Alexandria, Egypt

Non-steroidal anti-inflammatory drugs (NSAIDs) act via inhibition of the cyclooxygenase (COX) enzyme and inhibition of prostaglandins (PGs) synthesis. Despite the important role played by PGs in the control of erection peripherally (1), the potential contribution of NSAIDs in erectile function in experimental animals has not been investigated, knowing that PGE1 (alprostadil) has been widely used for the treatment of erectile dysfunction. To our knowledge, only one clinical study reported that the use of NSAIDs increased the risk of erectile dysfunction (2). Additionally one animal study reported that indomethacin, and to a lesser extent diclofenac, significantly inhibited erectile responses, while celexocib failed to produce such effect (3). The current study was designed to explore the effect of some NSAIDs with different COX1/COX2 selectivities on erectile response in experimental animals in-vitro. Corpus cavernosum strips were prepared from New Zealand White rabbits as previously described (4). Each drug was incubated with the preparation for 10 minutes, then the tissue was contracted with 10 µM phenylephrine (PE). Values are represented as mean ± SEM. The analysis of variance (ANOVA) followed by Dunnett’s post-test were used for comparison. The criterion for statistical significance was set at the 0.05 level. Each experiment was repeated 6-7 times.

Indomethacin, diclofenac and celecoxib caused a significant dose-dependent potentiation of the relaxation caused by electric field stimulation on PE-precontracted strips at almost all the frequencies tested (2, 4, 8 and 16 Hz). Ketoprofen (which is the most COX-1 selective) failed to produce any significant effect. Three doses of each drug were tested (5, 25 and 100 µM). On the other hand indomethacin, diclofenac and celecoxib caused potentiation of the relaxation caused by higher doses of ACh (10-5 and 10-4 µM) but not on lower doses of ACh (10-8 to10-6 µM), while ketoprofen did not produce any significant effect. 10-4 µM ACH caused 43±4.84% relaxation. This value increased to 73±9.07%, 72±9.45% and 59±5.98% after indomethacin, diclofenac and celecoxib treatment, respectively. All drugs were used in 25 µM concentration. Meanwhile, all the tested drugs did not have any significant effect on the relaxation induced by sodium nitroprusside .

In summary, indomethacin, diclofenac and celecoxib potentiated electric field stimulation-induced as well as ACh-induced relaxation, which is contrary to the reported inhibitory effect of NSAIDs on the erectile response in-vivo. In accordance with our results, it was previously reported that COX-2 is the predominant COX isoform in the adult rat male reproductive system (5). Biochemical and pharmacological studies are in process to investigate the mechanisms underlying these effects and the relationship between these effects and the COX-1/COX-2 selectivity of different NSAIDs. Additional studies will be performed to assess the differential effects of NSAIDs on the vasculature, smooth muscle contractility and blood flow in the penis.

(1) Khan MA et al, Prostaglandins Leukot Essent Fatty Acids 60(3):169, 1999

(2) Shiri R et al, J Urol 175(5):1812, 2006

(3) Senbel AM, World J Urol 29(4):523, 2010

(4) Holmquist F et al, J Physiol 449:295, 1992

(5) MCKanna JA et al, Am J Physiol 275:R227, 1998