Comparative effects of sildenafil, phentolamine, yohimbine and L-arginine on the rabbit corpus cavernosum.
Penile erection involves relaxation of smooth muscle of corpus cavernosum and associated arterioles. Sildenafil, a highly selective inhibitor of phosphodiesterase type 5, is effective in the treatment of erectile dysfunction. The aim of this study is to investigate the effect of sildenafil on smooth muscle of the rabbit corpus cavernosum (RCC) and to compare its effect with those of phentolamine, yohimbine and L-arginine. The effects of sildenafil, phentolamine, yohimbine and L-arginine were studied on the response of the RCC to electrical field stimulation (EFS) as well as on the phenylephrine (PE, 3 x 10(-6) M)-induced tone. EFS caused transient, frequency-dependent relaxation of the RCC that was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 x 10(-5) M). Sildenafil (1 x 10(-9)-1 x 10(-6) M) and phentolamine (1 x 10(-9)-1 x 10(-6) M) enhanced the EFS-induced relaxation in a concentration-dependent manner with ED50 of 0.056 +/- 0.004 and 0.572 +/-0.035 microM at 8 Hz, respectively, yohimbine (3 x 10(-7)-3 x 10(-5) M) and L-arginine (3 x 10(-6)-3 x 10(-4) M) did not show significant effects (ED50 at 8 Hz = 35.84 +/-2.24 and 2.164 +/- 0.174 microM, respectively). Sildenafil (1 x 10(-9) and 1 x 10(-8) M) potentiated the EFS-induced relaxation caused by L-arginine (3 x 10(-5) m). Sildenafil, phentolamine, yohimbine and L-arginine reduced the PE-induced tone to different extents; the ED50 values were 0.81 +/- 0.097, 0.49 +/- 0.025 and 13.97 +/- 1.10 microM, respectively. Maximum concentration of L-arginine used failed to produce 50% relaxation (ED20 = 221.82 +/- 15.71 microM). The muscle relaxant effects of different combinations of sildenafil and L-arginine on PE-induced tone did not differ significantly from the sum of the individual effects. The results demonstrate that sildenafil, when compared to other drugs used in penile erection dysfunction, shows the highest potency on the nitrergic transmission in the RCC. On the other hand, phentolamine was found to possess the highest potency in inducing relaxation of RCC proving that its action is independent on the stimulated neurogenic system. In addition, the combination of less effective doses of sildenafil and L-arginine has a potential advantage on erectile functions. The importance of this combination remains to be solved clinically.
Sharabi
F M
FM
Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, El-Khartoom Square, Alexandria, Egypt. fmsharabi@hotmail.com
Daabees
T T
TT
El-Metwally
M A
MA
Senbel
A M
AM
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000379:methods; D007172:Erectile Dysfunction / Q000188:drug therapy; D006145:Guanethidine / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019335:Nitroarginine / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D010646:Phentolamine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D015016:Yohimbine / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D010656:Phenylephrine; D019335:Nitroarginine; D015016:Yohimbine; D001285:Atropine; D001120:Arginine; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D010646:Phentolamine; D006145:Guanethidine