Glyceryl Trinitrate Distribution and the "Remarkable Tolerance"
1992 (English)Doctoral thesis, comprehensive summary (Other academic)
To study the distribution of glyceryl trinitrate (GTN), a gas chromatographic method was developed for simultaneous determination of GTN and its dinitrate metabolites in 'plasma and tissues. The distribution of GTN and 1 ,3-g1yceryl dinitrate (1,3-GDN) and 1,2-glyceryl dinitrate (1,2-GDN) was studied in GTN tolerant and nonto1erant rats. An extensive distribution of GTN and GDNs was found, and the highest level of GTN was observed in the adipose tissue of both tolerant aud nontolerant animals. This subcutaneous depot of GTN might affect the pharmacokinetics of the drug. Generally higher concentrations of GTN were found in tissues studied (except for the liver), as compared with blood. Furthermore, high levels of GTN and GDNs were found in the brain, and an increase in cGMP level was also observed there, which might mediate side effects, such as headache, head throbbing and dizziness. The formation of the metabolites 1,3-GDN and 1,2-GDN in plasma werefound to be dependent on the GTN concentration.
Long-term administration of GTN was shown to result not only in tolerance, i.e. reduced response to a given dose on repeated administration, but in a decreased elimination rate of GTN, 1,3-GDN, and 1,2-GDN in plasma. Moreover, GTN tolerance was found to reduce both the maximal relaxation and the potency of GTN. An increase in cGMP was found in tolerant vessels, although this was more marked in nontolerant vessels. The cGMP levels noted in vessels do not correlate with tissue GTN levels in rats.
Autoradiographic studies show a rapid and homogeneous distribution of radioactivity after iv [14C]-GTN in mice aud rat. Cytochrome P-450 and esterases were found to be involved in the distribution of radioactivity.
The present thesis shows that the phosphodiesterase inhibitor dipyridamole can not reverse GTN tolerance in healthy volunteers. Based on this and on previous studies on GTN tolerance, it was concluded that GTN tolerance in humans can only be reversed by applying "nitrate free intervals".
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1992. , 68 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 358
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-27548Local ID: 12209ISBN: 91-7870-649-1OAI: oai:DiVA.org:liu-27548DiVA: diva2:248100
1992-05-14, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Henning, Matts, Docent
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.2009-10-082009-10-082012-07-19Bibliographically approved