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Biol Pharm Bull. 2013;36(4):556-63.

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.

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1
Department of Pharmacology, School of Nursing, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. ishitaka@kanazawa-med.ac.jp

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.

PMID:
23546291
[Indexed for MEDLINE]
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