Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase.
OBJECTIVE
The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment.


METHODS
We investigated whether high dose isosorbide mononitrate (ISMN) or pentaerythrityl tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg(-1) d(-1) for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg(-1) d(-1) for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite.


RESULTS
Western blots of rabbit aortic rings showed similar protein levels of sGC alpha1- (P=0.2790) and beta1-subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN-treated mice (P=0.0961 for alpha1 and P=0.3709 for beta1). The activities of isolated sGC in response to SNAP (1 microM-1 mM) were identical in aortae of ISMN-treated rabbits (P=0.0775) and lungs of PETN-treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN.


CONCLUSIONS
These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo.
Oppermann
M
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Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-Universität, Düsseldorf, Germany.
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Suvorava
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Kojda
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D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010417:Pentaerythritol Tetranitrate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D021122:Protein Subunits / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D020030:Nitric Oxide Donors; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate