Avaliação da ação composto do IWP-051, um estimulador da guanilato ciclase na musculatura lisa cavernosa de humanos

Abstract

Deficiency of nitric oxide (NO) has been implicated as one of the main mechanisms of Endothelial dysfunction and erectile dysfunction. The search for new medications must be important to lessen the burden of this disease. The study evaluated the relaxation, in vitro, induced by a new Guanylate Cyclase stimulator (IWP-051) into strips of corpora cavernosa, taken from non-living human organ donor for transplantation. The strips were immersed in tissue baths in Krebs solution (pH7 .4, 37° C). They were contracted in 80 mm K + solution, and later again with Phenylephrine (PE 10 µm) and concentration-response curves (10-12 to 10-4M) were obtained. Initially the drug was compared with Tadalfil. To clarify the mechanism by which this drug promotes relaxation, the following experiments were carried out:, effect of an inhibitor of nitric oxide syntase (NOS), L-NAME (100 µm); addition of ODQ (10µM), an inhibitor of the soluble Guanylate Cyclase; evaluation of relaxation achieved with the contraction with 80 mm K +; Glibenclamide (10 µm), a potassium ion channel blocker ATP-dependent (KATP). It was observed, during the experiments the presence of spontaneous contractions, and the effect of the drug on those contractions were studied. It was also measured the phosphorylation of VASP, and measurement of GMPc concentration. The substance caused an EMAX relaxation in smooth muscle of the corpus cavernosum (EMAX = 107.37 % ± 2.98%. and pEC50=6.289+/- 0.09787). Comparing IWP-051 with tadalfil, there were no difference between both EMAX (p = 0.0817) or pEC50 (p=0.1823). Although there was no inhibition of the maximal relaxation with the addition of L-NAME, a right shift of the relaxation curve of the drug was observed (p<0.0001), reducing the potency in 10 times. The same results were observed when adding ODQ (10µM) into the bath (p<0.001). The EMAX achieved in concentration-response curve with 80 mm K + was about 20% lower than the curve with PE (10 µm) (p < 0.001). The addition of 10-5M of IWP-051 abolished all spontaneous contractions. There was no inhibition or blockade of the maximum effect of the drug with Glibenclamide (10 µm) (p> 0.05). The addition of IWP-051 in HCC strips increased the phosphorylation of VASP by 3 times compared with the control (DMSO), and the effect was reduced by the addition of ODQ (p<0.05) .GMPc measurement also increased in the presence of IWP-051 by 3 times and was also partially abolished by adding ODQ (p<0.05) Iwp-051 is a sGC stimulator, it produces a powerful relaxation of the smooth muscle of the corpus cavernosum. It depends on NOS to improve your potency, It acts by activating the soluble guanylate Cyclase. It seems that it does activate potassium channels, and it do not act throurgh KATP. It abolishes spontaneous contraction.