Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz

Mikiya Nakatsuka, K. Nakatsuka, Y. Osawa

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase (NOS) activity in vitro and in vivo. In in vitro studies with the use of a cytosolic fraction from penile tissue, the inactivation was found to depend on NADPH, time, and the concentration of guanabenz. The L-, but not the D-, isomer of arginine could protect from the inactivation, suggesting an active site-directed event. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (K(i)) and a pseudo first-order inactivation constant (k(inact)) of 38.5 μM and 0.179 min-1, respectively. In in vivo studies, guanabenz was shown to inhibit penile cytosolic NOS activity in a dose- and time-dependent manner. Treatment of rats with guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately one-half in the NOS activity of the penile cytosolic fraction with a concomitant loss in the amount of immunodetectable NOS protein. Treatment for 4 days at a dose of 0.5 mg/kg/day showed a similar decrease in activity, whereas a dose of 0.05 mg/kg/day showed no effects. Due to the multitude of processes that are regulated by NO, the inactivation of NOS is a potential mechanism to be considered in a variety of biological effects associated with drugs.

Original languageEnglish
Pages (from-to)497-501
Number of pages5
JournalDrug Metabolism and Disposition
Volume26
Issue number5
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

Guanabenz
Metabolism
Nitric Oxide Synthase
NADP
Isomers
Arginine
Rats
Catalytic Domain
Tissue
Kinetics
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz. / Nakatsuka, Mikiya; Nakatsuka, K.; Osawa, Y.

In: Drug Metabolism and Disposition, Vol. 26, No. 5, 1998, p. 497-501.

Research output: Contribution to journalArticle

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