The relaxation induced by uroguanylin and the expression of natriuretic peptide receptors in human corpora cavernosa.
BACKGROUND
Receptors for natriuretic peptides have been demonstrated as potential targets for the treatment of male erectile dysfunction.


OBJECTIVE
This study investigates the relaxant effects of the atrial natriuretic peptide (ANP) and uroguanylin (UGN), and expression of natriuretic peptide receptors on strips of human corpora cavernosa (HCC).


METHODS
Quantitative analysis of natriuretic receptor expression and relaxation of precontracted strips were used to assess the membrane-bound guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway in HCC strips.


METHODS
HCC was obtained from a cadaver donor at the time of collection of organs for transplantation (14-47 years) and strips were mounted in organ baths for isometric studies.


RESULTS
ANP and UGN both induced concentration-dependent relaxation on HCC strips with a maximal response attained at 300 nM, corresponding to 45.4±4.0% and 49±4.8%, respectively. The relaxation is not affected by 30 µM 1H-[1,2,4]oxaolodiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylate cyclase inhibitor), but it is significantly blocked by 10 µM isatin, a nonspecific particulate guanylate cyclase (pGC) inhibitor. UGN was unable to potentiate electrical field stimulation (EFS) or acetylcholine-induced relaxations. The potential role of pGC activation and cGMP generation in this effect is reinforced by the potentiation of this effect by phosphodiesterase-5 inhibitor vardenafil (55.0±7.5-UGN vs. 98.6±1.4%-UGN+vardenafil; P<0.05). The relaxant effect was also partially (37.6%) blocked by the combination iberitoxin-apamin but was insensitive to glybenclamide. The expression of guanylate cyclase receptors (GC-A, GC-B, GC-C) and the expression of the natriuretic peptide "clearance" receptor (NPR-C) were confirmed by real-time polymerase chain reaction. The exposure of HCC strips to ANP (1 µM) and UGN (10 µM) significantly increased cGMP, but not cyclic adenosine monophosphate (cAMP) levels.


CONCLUSIONS
UGN relaxes HCC strips by a guanylate cyclase and K(ca)-channel-dependent mechanism. These findings obtained in HCC reveal that the natriuretic peptide receptors are potential targets for the development of new drugs for the treatment of erectile dysfunction.
Sousa
Clauber M
CM
Superior Institute of Biomedical Sciences, Ceara State University, Fortaleza, Ceara, Brazil.
Havt
Alexandre
A
Santos
Cláudia F
CF
Arnaud-Batista
F J
FJ
Cunha
Karina M A
KM
Cerqueira
João Batista G
JB
Fonteles
Manassés C
MC
Nascimento
Nilberto R F
NR
D000293:Adolescent; D000328:Adult; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000378:metabolism*; D002102:Cadaver; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D045265:Natriuretic Peptides / Q000378:metabolism / Q000494:pharmacology*; D010413:Penis / Q000187:drug effects / Q000601:surgery*; D017461:Receptors, Atrial Natriuretic Factor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018000:Receptors, Peptide / Q000187:drug effects / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D055815:Young Adult; D000099242:Atrial Natriuretic Factor Receptor B
D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D045265:Natriuretic Peptides; D017461:Receptors, Atrial Natriuretic Factor; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; D000071756:Soluble Guanylyl Cyclase; D000099242:Atrial Natriuretic Factor Receptor B; C084362:uroguanylin