The Nitric Oxide Donor SIN-1 Is Free of Tolerance and Maintains Its Cyclic GMP Stimulatory Potency in Nitrate-Tolerant LLC-PK1 Cells |
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Authors: | Hinz Burkhard Schröder Henning |
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Institution: | (1) Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06099 Halle (Saale), Germany |
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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 M) 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 SIN-1 (1–1000 M) 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. |
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Keywords: | nitrate tolerance nitric oxide cyclic GMP SIN-1 molsidomine glyceryl trinitrate |
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