Inhibitory actions of diphenyleneiodonium on endothelium-dependent vasodilatations in vitro and in vivo.
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 x 10(-8)-3 x 10(-6) M) concentration-dependently inhibited acetylcholine (ACh)-induced relaxation in preconstricted rat thoracic aortic rings, with an IC50 of 1.8 x 10(-7) M and a maximal inhibition of nearly 100%. DPI (3 x 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 x 10(-7) M) on ACh-induced relaxation was prevented by pretreatment with NADPH (5 x 10(-3) M) and FAD (5 x 10(-4) M) but not L-arginine (L-Arg, 2 x 10(-3) M). Pretreatment with NADPH did not alter the inhibitory effect of NG-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 x 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 N0-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.
Wang
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Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Poon
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Poon
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Pang
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D000109:Acetylcholine / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005182:Flavin-Adenine Dinucleotide / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D009249:NADP / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D009599:Nitroprusside / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
D009861:Onium Compounds; D005182:Flavin-Adenine Dinucleotide; D009599:Nitroprusside; D019335:Nitroarginine; D000001:Calcimycin; D009249:NADP; C007517:diphenyleneiodonium; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D009247:NADH, NADPH Oxidoreductases; D000109:Acetylcholine