title: Gender differences in tail-skin flushing induced by nitrates and phosphodiesterase type 5 inhibitors in a climacteric mouse model.
abstract: Flushing is one of the most common vasodilation-related adverse effects associated with both nitrates and phosphodiesterase type 5 (PDE5) inhibitors. The present study aimed to investigate the effects of orchidectomy and ovariectomy on isosorbide dinitrate-, sildenafil-, vardenafil- and tadalafil-induced flushing of tail-skin in mice. Both orchidectomy and ovariectomy markedly increased the tail-skin temperature, a good parameter of flushing, induced by isosorbide dinitrate (500 microg/kg, i.p.). These observations suggest that both testosterone withdrawal and estrogen withdrawal are risk factors for isosorbide dinitrate-induced flushing. In contrast, sildenafil (100 mg/kg, p.o.)-, vardenafil (10 mg/kg, p.o.)- and tadalafil (40 mg/kg, p.o.)-induced flushing of tail-skin in mice was aggravated by ovariectomy but not by orchidectomy. Orchidectomized male mice, but not ovariectomized female mice, showed significantly lower levels of PDE5 mRNA expression in tail artery compared with those of sham-operated mice. The present findings suggest that estrogen withdrawal, but not testosterone withdrawal, is a risk factor for PDE5 inhibitor-induced flushing. These gender differences in the vascular adverse reactions of PDE5 inhibitors may be interpreted as occurring due to differences in the levels of PDE5 mRNA expression in peripheral arteries.
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sejima
authors.forename: Koji
authors.initials: K
authors.lastname: Tominaga
authors.forename: Takashi
authors.initials: T
authors.lastname: Egawa
authors.forename: Munehiko
authors.initials: M
authors.lastname: Ikeda
authors.forename: Kohta
authors.initials: K
authors.lastname: Shibuya
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kameyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Shuto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002979:Climacteric / Q000187:drug effects* / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D005260:Female; D005483:Flushing / Q000139:chemically induced*; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D009566:Nitrates / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics; D000068677:Sildenafil Citrate; D012867:Skin / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D000068581:Tadalafil; D013623:Tail; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride
chemical_list: D002243:Carbolines; D007093:Imidazoles; D009566:Nitrates; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5