Sildenafil is a strong activator of mammalian carbonic anhydrase isoforms I-XIV

ÇOBAN T. A., BEYDEMIR S., Gucin I., EKINCI D., Innocenti A., Vullo D., ...Daha Fazla

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.17, sa.16, ss.5791-5795, 2009 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 17 Sayı: 16
  • Basım Tarihi: 2009
  • Doi Numarası: 10.1016/j.bmc.2009.07.019
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.5791-5795
  • Anahtar Kelimeler: Carbonic anhydrase, Isozymes I-XIV, Sildenafil citrate, Enzyme activator, Piperazine, Proton shuttling, AMINO-ACIDS, ISOZYME-II, THERAPEUTIC APPLICATIONS, INHIBITORS, VITRO, SITE, VII, VA, PHOSPHODIESTERASE-5, DIURETICS
  • Atatürk Üniversitesi Adresli: Evet

Özet

Sildenafil citrate, a phosphodiesterase-5 (PDE5) inhibitor widely used for the treatment of erectile dysfunction was investigated for its interaction with the zinc-enzyme carbonic anhydrase (CA, EC 4.2.1.1), as it has in its molecule a piperazine moiety also found in some CA activators (CAAs). Sildenafil was a potent, low micromolar activator of several CA isozymes, such as CA I, VA and VI (K(A)s in the range of 1.08-6.54 mu M), and activated slightly less the isoforms CA III, IV and VA (K(A)s of 13.4-16.8 mu M). CA isozymes II, IX, XIII and XIV showed activation constants in the range of 27.5-34.0 mu M, whereas the least activated isoforms were CA VII and XII (K(A)s of 72.9-73.0 mu M). Sildenafil citrate was also given orally to Sprague-Dawley rats at 1 mg/kg body weight. Red blood cell CA activity was inhibited in the treated animals at 3-5 h post-administration (in the range of 60-85%), probably due to NO/nitrite formed by PDE5 inhibition or by another, unknown mechanism. Whether CA activation by sildenafil has clinical consequences in humans is beyond the scope of the present work and warrants further studies. (C) 2009 Elsevier Ltd. All rights reserved.