The nitric oxide donor SIN-1 is free of tolerance and maintains its cyclic GMP stimulatory potency in nitrate-tolerant LLC-PK1 cells

Burkhard Hinz, Henning Schröder

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Purpose. Using an established cell culture model, the present study investigates whether linsidomine (SIN-1), a spontaneous donor of nitric oxide and active metabolite of the antianginal drug molsidomine, induces tolerance to its own cyclic GMP stimulatory action or shows a diminished response after tolerance induction with glyceryl trinitrate. Methods. Incubations with nitric oxide donors were carried out in LLC-PK1 kidney epithelial cells. Intracellular levels of cyclic GMP, the vasodilatory second messenger of nitric oxide, were determined by radioimmunoassay. Results. A 5-h preincubation with glyceryl trinitrate (0.01-100 μM) led to complete inhibition of a subsequent cyclic GMP stimulation by glyceryl trinitrate but left the cyclic GMP response to SIN-1 unaltered. Similarly, cyclic GMP elevations by the spontaneous nitric oxide donors sodium nitroprusside and spermine NONOate were not affected after pretreatment with glyceryl trinitrate. Moreover, pretreatment with SIN1 (1-1000 μM) had no significant effect on SIN-1-dependent cyclic GMP stimulation. Conclusions. Our results show that in LLC-PK1 cells, SIN-1 is free of tolerance induction and not cross-tolerant to glyceryl trinitrate. This may be due to the spontaneous nitric oxide release from SIN-1, which in contrast to nitric acid esters does not require enzymatic bioactivation and may therefore be unaffected by nitrate tolerance.

Original languageEnglish (US)
Pages (from-to)633-636
Number of pages4
JournalPharmaceutical research
Volume16
Issue number5
DOIs
StatePublished - May 25 1999

Keywords

  • Cyclic GMP
  • Glyceryl trinitrate
  • Molsidomine
  • Nitrate tolerance
  • Nitric oxide
  • SIN-1

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