Detail Pharmacological studies of NADPH-cytochrome P450 reductase in the vascular biotransformation of glyceryl trinitrate: The effects of flavoprotein inhibition by diphenyleneiodonium sulfate, and of in vivo tolerance Bibliografi Author: McGuire, John Joseph ; Bennett, Brian M. (Advisor) Topik: HEALTH SCIENCES; PHARMACOLOGY|BIOLOGY; ANIMAL PHYSIOLOGY|HEALTH SCIENCES; MEDICINE AND SURGERY Bahasa: (EN )    ISBN: 0-612-38317-2     Penerbit: QUEEN'S UNIVERSITY AT KINGSTON (CANADA)     Tahun Terbit: 1999     Jenis: Theses - Dissertation Fulltext: NQ38317.pdf (0.0B; 0 download) Abstract The efficacy of glyceryl trinitrate (GTN), used by patients suffering from angina pectoris, and congestive heart failure, is limited by the development of tolerance. The biotransformation of GTN to glyceryl-1,2-dinitrate and glyceryl-1,3-dinitrate, and an activator of soluble guanylyl cyclase precedes the therapeutically important relaxation of vascular smooth muscle. In disrupted cells, the cytochromes P450 (CYP) have demonstrated the capacity to mediate NADPH-dependent GTN biotransformation. The effects of CYP inhibitors on the relaxation of isolated blood vessels by GTN have been variable; therefore, the importance of CYP to GTN-induced vasodilation is controversial. The flavoprotein, NADPH-cytochrome P450 reductase (CPR), is required for CYP-mediated drug metabolism, and has been suggested to catalyse GTN biotransformation. This thesis examines the function of vascular CPR with respect to GTN biotransformation. A selective antagonist of CPR was unavailable at the beginning of this research; thus, a flavoprotein inhibitor, diphenyleneiodonium (DPI) was used. DPI caused an irreversible inhibition of GTN action in isolated blood vessels, consistent with inhibition of a GTN-metabolising flavoprotein. In addition, it was found that CPR is a flavoprotein target for DPI in intact blood vessels, and that DPI also inhibits GTN biotransformation in vivo. The inhibition of CPR, and therefore CYP, by DPI accounts for the inhibition of NADPH-dependent GTN biotransformation in disrupted cells. It cannot be concluded that the irreversible inhibition of GTN relaxation of rat aorta is the sole result of inhibition of this flavoprotein, because [125I]-DPI labelling experiments indicated that there were other binding sites for DPI in intact blood vessels. CPR catalyses GTN biotransformation in vitro but this does not result in the formation of an activator of soluble guanylyl cyclase, and the CPR content is not limiting to aortic microsomes-mediated activation of soluble guanylyl cyclase by GTN. The expression/activity of CPR in the aorta from GTN tolerant rats was unchanged compared to that from control animals, and thus reduced CPR expression/activity does not account for GTN tolerance in blood vessels. In conclusion, the function of vascular CPR is to support CYP-mediated GTN biotransformation, and the latter may be unaffected by GTN tolerance. Opini Anda Klik untuk menuliskan opini Anda tentang koleksi ini! Lihat Sejarah Pengadaan  Konversi Metadata   Kembali

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