title: Effects of cyanamide, an aldehyde dehydrogenase type 2 inhibitor, on glyceryl trinitrate- and isosorbide dinitrate-induced vasodilation in rabbit excised aorta and in anesthetized whole animal.
abstract: The contribution of aldehyde dehydrogenase type 2 (ALDH2) to bioactivation of glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) was systematically examined in excised rabbit aorta and anesthetized whole animal with cyanamide, an ALDH2 inhibitor. In excised aortic preparation, the degree of inhibition by cyanamide in GTN-induced vasorelaxation (concentration ratio, calculated as EC(50) in the presence of cyanamide/EC(50) in the absence of cyanamide; 5.61) was twice that in ISDN-induced relaxation (2.78). However, the degree of inhibition by cyanamide, as assessed by the dose ratio (as described above, but calculated with doses) in anesthetized rabbits was 2.29 in GTN-induced hypotension (assessed by area under the curve (AUC) of 50 mmHg·min) and 7.68 in ISDN-induced hypotension. Thus, the inhibitor was 3 times more potent in ISDN-induced hypotension, a finding in conflict with to that obtained in excised aortic preparation. The rate of increase in plasma nitrite (NO(2)(-)) concentration at certain hypotensive effect (50 mmHg·min of AUC) in the presence and absence of cyanamide (ΔNO(2)(-) ratio) was larger in ISDN-induced hypotension (15.01) than in GTN-induced hypotension (3.28). These results indicate that the bioactivation pathway(s) of GTN is ALDH2-dependent in aortic smooth muscle, while ADLH2-independent mechanism(s) largely take place in the whole body. In contrast, the activation mechanism(s) of ISDN is largely ALDH2-dependent in both aortic smooth muscle and whole body. Plasma NO(2)(-) may be derived from pathways other than the cyanamide-sensitive metabolic route.
authors.affiliation: Department of Pharmacology, School of Nursing, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. ishitaka@kanazawa-med.ac.jp
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Mihoko
authors.initials: M
authors.lastname: Nomura-Nakamoto
authors.forename: Fusae
authors.initials: F
authors.lastname: Abe
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Masuoka
authors.forename: Noriko
authors.initials: N
authors.lastname: Imaizumi
authors.forename: Junko
authors.initials: J
authors.lastname: Yoshida
authors.forename: Tomie
authors.initials: T
authors.lastname: Kawada
authors.forename: Matomo
authors.initials: M
authors.lastname: Nishio
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000758:Anesthesia; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D003484:Cyanamide / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate; D009573:Nitrites / Q000097:blood; D005996:Nitroglycerin; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents
chemical_list: D004791:Enzyme Inhibitors; D009573:Nitrites; D014665:Vasodilator Agents; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate