title: Doxazosin treatment causes differential alterations of alpha 1-adrenoceptor subtypes in the rat kidney, heart and aorta.
abstract: We have previously demonstrated that long-term administration of doxazosin, an alpha(1)-adrenoceptor (alpha(1)-AR) antagonist, causes an up-regulation in the expression of alpha(1)-AR subtype mRNAs in the rat genitourinary tract and suggested that these changes may affect long-term effectiveness of alpha(1)-AR antagonists when used to treat the lower urinary tract symptoms of benign prostatic hyperplasia. As chronic administration of alpha(1)-AR antagonists may cause similar alterations in other tissues in which alpha(1)-ARs play a physiologic role, we examined the effects of long-term administration of doxazosin on the expression of alpha(1)-AR subtype mRNAs in several rat tissues. Rats were treated with doxazosin (4 mg/kg/day subcutaneously, supplemented with 4 mg/kg/day orally) for 12 weeks. The cDNA was prepared by reverse transcription of RNA extracted from the rat kidney, heart and aorta. alpha(1A), alpha(1B) and alpha(1D)-AR mRNA expression levels were quantified by real-time reverse transcription polymerase chain reaction. The rank order of expression levels of the alpha(1)-AR mRNAs in rat tissues were: alpha(1A)-AR, kidney > heart > aorta; alpha(1B)-AR, heart > kidney > aorta; alpha(1D)-AR, aorta > kidney = heart. Chronic administration of doxazosin caused an up-regulation in the mRNA level of alpha(1A), alpha(1B) and alpha(1D)-ARs in the rat kidney, heart and aorta, respectively. Our data demonstrate that doxazosin treatment causes differential alterations in the expression of alpha(1)-AR subtype mRNAs in different rat tissues. These findings may provide insight into the long-term effects of alpha(1)-AR antagonists in the treatment of diseases involving tissues whose function is regulated by alpha(1)-ARs.
authors.affiliation: Section of Urology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208041, New Haven, CT 06520, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yono
authors.forename: Harris E
authors.initials: HE
authors.lastname: Foster
authors.forename: David
authors.initials: D
authors.lastname: Shin
authors.forename: Wataru
authors.initials: W
authors.lastname: Takahashi
authors.forename: Mehdi
authors.initials: M
authors.lastname: Pouresmail
authors.forename: Jamshid
authors.initials: J
authors.lastname: Latifpour
mesh_terms: D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers / Q000737:chemistry; D017292:Doxazosin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000317:Adrenergic alpha-Antagonists; D017931:DNA Primers; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D017292:Doxazosin