TY - JOUR
T1 - Endothelium-independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium
AU - Dodd, Jeffrey M.
AU - Zheng, Gemin
AU - Silverman, Howard S.
AU - Lakatta, Edward G.
AU - Ziegelstein, Roy C.
PY - 1997
Y1 - 1997
N2 - 1. The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient presser response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath. 2. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mM) initiated an additional contraction of prostaglandin F(2α)-preconstricted rings with endothelium which was sustained throughout the period of L-NAME exposure (+234 ± 39% at 15 min). In contrast, addition of DPI (5 μM) to rings with endothelium produced a transient initial contraction (+111 ± 27% at 2 min) followed by a more sustained relaxation (-27 ± 19% at 15 min, P < 0.001 vs L-NAME). 3. The contraction to DPI was also observed in rings without endothelium, was abolished by L-NAME pretreatment, and was unaffected by the α-adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either L-NAME or with the ATP-sensitive potassium channel blocker glibenclamide. 4. The endothelium-independent relaxation to DPI was inhibited at 23°C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue. 5. Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium-independent, temperature-dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its presser effect in vivo despite sustained NOS inhibition.
AB - 1. The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient presser response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath. 2. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mM) initiated an additional contraction of prostaglandin F(2α)-preconstricted rings with endothelium which was sustained throughout the period of L-NAME exposure (+234 ± 39% at 15 min). In contrast, addition of DPI (5 μM) to rings with endothelium produced a transient initial contraction (+111 ± 27% at 2 min) followed by a more sustained relaxation (-27 ± 19% at 15 min, P < 0.001 vs L-NAME). 3. The contraction to DPI was also observed in rings without endothelium, was abolished by L-NAME pretreatment, and was unaffected by the α-adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either L-NAME or with the ATP-sensitive potassium channel blocker glibenclamide. 4. The endothelium-independent relaxation to DPI was inhibited at 23°C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue. 5. Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium-independent, temperature-dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its presser effect in vivo despite sustained NOS inhibition.
KW - Diphenyleneiodonium
KW - Endothelium
KW - Guanylate cyclase
KW - Nitric oxide synthase
KW - Vasodilatation
UR - http://www.scopus.com/inward/record.url?scp=0030903363&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030903363&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0701014
DO - 10.1038/sj.bjp.0701014
M3 - Article
C2 - 9138692
AN - SCOPUS:0030903363
VL - 120
SP - 857
EP - 864
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 5
ER -