title: SMA-copolymer conjugate of AHPP: a polymeric inhibitor of xanthine oxidase with potential antihypertensive effect.
abstract: In vascular system, superoxide anion (O2(-)) generated by xanthine oxidase (XO) is known to regulate vascular tonus by reacting with, and thus consuming nitric oxide (NO), which determines vasorelaxation. We previously reported the remarkable antihypertensive effect of a potent XO inhibitor, 4-amino -6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP). However, AHPP is insoluble in water, which hamper its in vivo application. Therefore, in this study we prepared a water soluble polymeric conjugate of AHPP, by using a styrene maleic acid copolymer (SMA, SMA-AHPP). SMA-AHPP showed similar inhibitory activity against XO (K(i)=0.25 microM) comparable to native AHPP (K(i)=0.17 microM), while exhibiting good water-solubility, which now made it possible for systemic injection. In vivo experiments were carried out to examine the antihypertensive effect of SMA-AHPP using the spontaneously hypertensive rats (SHR) by i.v. injection (15, 30 mg/kg) or by oral administration (100 mg/kg) of SMA-AHPP. The results showed significantly reduced blood pressures (up to 30% reduction) of SHR rats; this antihypertensive effect continued for at least 24 h after SMA-AHPP administration. These findings strongly suggest the potential value of SMA-AHPP as an antihypertensive agent with sustained in vivo activity, which warrants further investigations.
authors.affiliation: Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Arun K
authors.initials: AK
authors.lastname: Iyer
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda