Lymarenko I. The search of novel potential detrusor-selective compounds among guanidine derivatives.

The effects of the a novel fluorine-containing analogues of pinacidil on bladder contractile function were examined in vitro on isolated bladder strips and on vascular tone in vitro on isolated aorta rings. The most selective compound for detrusor tissue was investigated in vivo. K+ produced concentration-related contractions of rat detrusor muscle strips. The presence of 60 mM K+ solution induces tonic contractions of the all preparations. All new fluorine-containing analogues of pinacidil concentration-dependently decreased contractions evoked by 60 mM K+. Low concentrations of K+ (15 mM) enhanced the already existing spontaneous activity. All new fluorine-containing analogues of pinacidil caused a concentration-dependent decrease in contractions amplitude and frequency evoked by 15 mM K+. The tested compounds inhibited KCl- and phenylephrine - induced contraction of the rat aortic rings in a concentration-dependent manner. It was shown, that all novel fluorine-containing analogues of pinacidil wereless potent than pinacidil as a vascular smooth muscle relaxant. The differences between the EC50 values for the compound PF-5 - mediated relaxation of the rat bladder strips and the EC50 obtained for the relaxation of the rat aorta rings by this agent indicate that compound PF-5 demonstrated selectivity for detrusor smooth muscle over isolated thoracic aorta rings.The effects of the PF-5 and pinacidil on urinary bladder activity in vivo were evaluated in urethane-anesthetized female Wistar rats. Both compounds decreased intravesical pressure after intraperitoneal administration in a dose-dependent manner. It was shown that experimental compound (1 mg/kg) inhibites the micturition reflex in the rat but does not alter arterial pressure. Preincubation of preparations with glibenclamide (3 mM) depressed the relaxant effect of compound PF-5. Glibenclamide caused a rightward shift in the concentration-response curve for the relaxant effect of the tested compound.