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

Haroldo Alfredo Flores Toque, Edson Antunes, Cleber E. Teixeira, Gilberto De Nucci

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objectives: 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 μmol/L) caused relaxation of urethral rings contracted with phenylephrine (10 μmol/L), with higher potency (P <0.01) in U+ (pEC50 7.77 ± 0.09) compared with U- (pEC50 6.84 ± 0.19) preparations. The NO synthesis inhibitor Nω-nitro-L-arginine methyl ester (100 μmol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 μmol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 μmol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca2+-induced contractions in K+ depolarized rings were significantly attenuated by BAY 41-2272 (1 μmol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 μmol/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 μmol/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.

Original languageEnglish (US)
Pages (from-to)711-715
Number of pages5
JournalUrology
Volume72
Issue number3
DOIs
StatePublished - Sep 1 2008

Fingerprint

Cyclic GMP
Urethra
Nitric Oxide
Rabbits
Calcium
Soluble Guanylyl Cyclase
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Phosphodiesterase 5 Inhibitors
Urothelium
Nitric Oxide Donors
Nitroglycerin
Phenylephrine
Baths
Electric Stimulation

ASJC Scopus subject areas

  • Urology

Cite this

@article{85d5a475c0764d53890d60c96c1d734f,
title = "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",
abstract = "Objectives: 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 μmol/L) caused relaxation of urethral rings contracted with phenylephrine (10 μmol/L), with higher potency (P <0.01) in U+ (pEC50 7.77 ± 0.09) compared with U- (pEC50 6.84 ± 0.19) preparations. The NO synthesis inhibitor Nω-nitro-L-arginine methyl ester (100 μmol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 μmol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 μmol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca2+-induced contractions in K+ depolarized rings were significantly attenuated by BAY 41-2272 (1 μmol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 μmol/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 μmol/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.",
author = "{Flores Toque}, {Haroldo Alfredo} and Edson Antunes and Teixeira, {Cleber E.} and {De Nucci}, Gilberto",
year = "2008",
month = "9",
day = "1",
doi = "10.1016/j.urology.2007.12.031",
language = "English (US)",
volume = "72",
pages = "711--715",
journal = "Urology",
issn = "0090-4295",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - 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

AU - Flores Toque, Haroldo Alfredo

AU - Antunes, Edson

AU - Teixeira, Cleber E.

AU - De Nucci, Gilberto

PY - 2008/9/1

Y1 - 2008/9/1

N2 - Objectives: 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 μmol/L) caused relaxation of urethral rings contracted with phenylephrine (10 μmol/L), with higher potency (P <0.01) in U+ (pEC50 7.77 ± 0.09) compared with U- (pEC50 6.84 ± 0.19) preparations. The NO synthesis inhibitor Nω-nitro-L-arginine methyl ester (100 μmol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 μmol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 μmol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca2+-induced contractions in K+ depolarized rings were significantly attenuated by BAY 41-2272 (1 μmol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 μmol/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 μmol/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.

AB - Objectives: 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 μmol/L) caused relaxation of urethral rings contracted with phenylephrine (10 μmol/L), with higher potency (P <0.01) in U+ (pEC50 7.77 ± 0.09) compared with U- (pEC50 6.84 ± 0.19) preparations. The NO synthesis inhibitor Nω-nitro-L-arginine methyl ester (100 μmol/L) or the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) (10 μmol/L) had no effect on BAY 41-2272 responses in U+ or U- rings. The phosphodiesterase-5 inhibitor vardenafil (0.1 μmol/L) potentiated the relaxant effects of BAY 41-2272 in both U+ (10-fold) and U- (sevenfold) tissues. Ca2+-induced contractions in K+ depolarized rings were significantly attenuated by BAY 41-2272 (1 μmol/L) in an ODQ-insensitive manner. BAY 41-2272 (0.03-0.3 μmol/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 μmol/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.

UR - http://www.scopus.com/inward/record.url?scp=50249155414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50249155414&partnerID=8YFLogxK

U2 - 10.1016/j.urology.2007.12.031

DO - 10.1016/j.urology.2007.12.031

M3 - Article

C2 - 18359064

AN - SCOPUS:50249155414

VL - 72

SP - 711

EP - 715

JO - Urology

JF - Urology

SN - 0090-4295

IS - 3

ER -