Use-dependent loss of acetylcholine- and bradykinin-mediated vasodilation after nitric oxide synthase inhibition. Evidence for preformed stores of nitric oxide-containing factors in vascular endothelial cells.
In the present study, we examined the possibility that the endothelium-dependent vasodilators acetylcholine and bradykinin release preformed pools of nitric oxide-containing factors. Successive injections of selected doses of acetylcholine (1.18 +/- 0.3 micrograms/kg IV) or bradykinin (5 micrograms/kg IV) caused reproducible hypotensive and vasodilator responses within sympathetically intact and sympathetically denervated hindlimbs of conscious rats. After administration of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mumol/kg IV), the first injection of acetylcholine or bradykinin produced pronounced depressor and vasodilator responses that, in the case of bradykinin, were greater than those observed before L-NAME administration. However, each successive injection of acetylcholine and bradykinin produced progressively smaller responses, such that the later injections elicited a markedly diminished hypotension and vasodilation. This "use-dependent" loss of endothelium-dependent vasodilation was not due to the diminished vasorelaxant potency of nitric oxide-containing factors because the vasodilator effects of the nitric oxide donor sodium nitroprusside (32 micrograms/kg IV) and the S-nitrosothiol compound S-nitro-socysteine (200 nmol/kg IV) were augmented in the presence of L-NAME. These results suggest that the use-dependent loss of the hemodynamic effects of acetylcholine and bradykinin in L-NAME-treated rats may be due to the release and subsequent depletion of a factor whose synthesis depends on the bioavailability of nitric oxide. Taken together, these results suggest that preformed pools of nitric oxide-containing factors exist within the endothelium of resistance vessels and that endothelium-dependent agonists exert their vasorelaxant effects at least in part by the mobilization of these performed pools.
Davisson
R L
RL
Cardiovascular Center, University of Iowa, Iowa City 52242, USA.
Bates
J N
JN
Johnson
A K
AK
Lewis
S J
SJ
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D007275:Injections, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013562:Sympathectomy; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects*
D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester