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 language | English (US) |
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Pages (from-to) | 633-636 |
Number of pages | 4 |
Journal | Pharmaceutical research |
Volume | 16 |
Issue number | 5 |
DOIs | |
State | Published - 1999 |
Bibliographical note
Copyright:Copyright 2007 Elsevier B.V., All rights reserved.
Keywords
- Cyclic GMP
- Glyceryl trinitrate
- Molsidomine
- Nitrate tolerance
- Nitric oxide
- SIN-1