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Inhibitory actions of diphenyleneiodonium on endothelium‐dependent vasodilatations in vitro and in vivo
Author(s) -
Wang YongXiang,
Poon Christina I.,
Poon Ken S.,
Pang Catherine C.Y.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13947.x
Subject(s) - sodium nitroprusside , acetylcholine , in vivo , chemistry , nitric oxide , inhibitory postsynaptic potential , vasodilation , endothelium derived relaxing factor , nitroarginine , nitric oxide synthase , pharmacology , in vitro , ic50 , endothelium , biophysics , biochemistry , endocrinology , biology , microbiology and biotechnology , organic chemistry
1 This study examined the in vitro and in vivo inhibitory effects of diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, on endothelium‐dependent vasodilatations. 2 DPI (3 × 10 −8 –3 × 10 −6 m ) concentration‐dependently inhibited acetylcholine (ACh)‐induced relaxation in preconstricted rat thoracic aortic rings, with an IC 50 of 1.8 × 10 −7 m and a maximal inhibition of nearly 100%. DPI (3 × 10 −6 m ) also completely inhibited the relaxation induced by the calcium ionophore, A23187 but not by sodium nitroprusside (SNP). The inhibitory effect of DPI (3 × 10 −7 m ) on ACh‐induced relaxation was prevented by pretreatment with NADPH (5 × 10 −3 m ) and FAD (5 × 10 −4 m ) but not l ‐arginine ( l ‐Arg, 2 × 10– 3 m ). Pretreatment with NADPH did not alter the inhibitory effect of N G ‐nitro‐ l ‐arginine on ACh‐induced relaxation. 3 The inhibitory effect of DPI on ACh‐induced relaxation in the aortae lasted >4 h after washout. In contrast to pretreatment, post‐treatment (1 h later) with NADPH (5 × 10 −3 m ) reversed only slightly the inhibitory effect of DPI. 4 In conscious rats, DPI (10 −5 mol kg −1 ) inhibited the depressor response to i.v. infused ACh, but not SNP. However, it caused only a transient pressor response which was previously shown to be due completely to sympathetic activation. 5 Thus, DPI is an efficacious and ‘irreversible’ inhibitor of endothelium‐dependent vasodilatation in vivo and in vitro. The mechanism of the inhibition may involve antagonism of the effects of FAD and NADPH, co‐factors of NO synthase. However, unlike the N G ‐substituted arginine analogues (another class of NO synthase inhibitors), DPI‐induced suppression of endothelium‐dependent vasodilatation in vivo does not lead to a sustained rise in blood pressure.