Molecular mechanisms regulating urogenital expression of nitric oxide synthase in spontaneously hypertensive rats.
OBJECTIVE
Although doxazosin, but not nifedipine, can partially prevent a decrease in urogenital expression of nitric oxide synthase (NOS) in spontaneously hypertensive rats (SHRs), the mechanisms involved in the regulated expression of NOS are not known. Therefore, we identified differential gene expression profiles in SHRs to elucidate the molecular mechanisms regulating urogenital expression of NOS.


METHODS
SHRs and normotensive Wistar-Kyoto (WKY) rats received doxazosin (30 mg/kg/day) or nifedipine (30 mg/kg/day) orally for 4 weeks. Microarray expression data of key transcripts were verified by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis.


RESULTS
RT-PCR data, in accord with the microarray analysis, indicated that untreated SHRs had lower mRNA expression levels of cAMP responsive element binding protein 1 (Creb1) in the pelvic ganglion and vascular endothelial growth factor A (Vegfa) and kinase insert domain protein receptor (Kdr) in the penis, and higher mRNA expression levels of brain derived neurotrophic factor and neurotrophin 3 (Ntf3) in the bladder and Ntf3, Rho-kinases (Rock1 and Rock2) and caveolin 1 (Cav1) in the penis than untreated WKY rats. In SHRs, doxazosin and nifedipine caused a significant decrease in penile expression of Rock1 and Rock2, whereas the differential alterations in urogenital expression of Creb1, Vegfa, Kdr and Cav1 were attenuated by treatment with doxazosin, but not nifedipine.


CONCLUSIONS
Our data suggest that differential alterations in the expression of several genes related to pathways that mediate NOS expression in the urogenital tissues of SHRs, which can be attenuated by doxazosin treatment, may play an important role in regulating urogenital expression of NOS.
Yono
Makoto
M
Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Yoshida
Masaki
M
Yamamoto
Yasuhiro
Y
Imanishi
Aya
A
Fukagawa
Atsushi
A
Latifpour
Jamshid
J
Eto
Masatoshi
M
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017292:Doxazosin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014566:Urogenital System / Q000187:drug effects / Q000201:enzymology*
D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D019001:Nitric Oxide Synthase; D009543:Nifedipine; D017292:Doxazosin