Increased cyclic guanosine monophosphate synthesis and calcium entry blockade account for the relaxant activity of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in the rabbit penile urethra.
OBJECTIVE
To study the direct relaxant activity of 5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine (BAY 41-2272) in the rabbit penile urethra and to investigate its modulatory effect on nitric oxide (NO)-mediated responses.


METHODS
Urothelium-intact (U+) and denuded (U-) rings were mounted in 10-mL organ baths for isometric force recording. Intracellular cyclic guanosine monophosphate (cGMP) levels were quantified with specific kits.


RESULTS
BAY 41-2272 (0.0001 to 10 micromol/L) caused relaxation of urethral rings contracted with phenylephrine (10 micromol/L), with higher potency (P <0.01) in U+ (pEC(50) 7.77 +/- 0.09) compared with U- (pEC(50) 6.84 +/- 0.19) preparations. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (100 micromol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 micromol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 micromol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca(2+)-induced contractions in K(+) depolarized rings were significantly attenuated by BAY 41-2272 (1 micromol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 micromol/L) increased the amplitude and duration of electrical field stimulation-induced relaxations (1 to 32 Hz), as well as those evoked by the NO donor glyceryl trinitrate (0.0001 to 10 micromol/L). BAY 41-2272 induced ODQ-resistant increases in cGMP levels above baseline (approximately twofold) in both U+ and U- rings.


CONCLUSIONS
BAY 41-2272 relaxes penile urethra in a synergic fashion with NO. Targeting soluble guanylate cyclase with BAY 41-2272 may represent a new therapy in the management of voiding disturbances associated with impaired NO-cGMP signaling.
Toque
Haroldo A Flores
HA
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
Antunes
Edson
E
Teixeira
Cleber E
CE
De Nucci
Gilberto
G
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010413:Penis / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D001743:Urinary Bladder / Q000187:drug effects
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D011188:Potassium; D002118:Calcium