Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation.
The physiological effects of nitroglycerin as a potent vasodilator have long been documented. However, the molecular mechanisms by which nitroglycerin exerts its biological functions are still a matter of intense debate. Enzymatic pathways converting nitroglycerin to vasoactive compounds have been identified, but none of them seems to fully account for the reported clinical observations. Here, we demonstrate that nitroglycerin triggers constitutive nitric oxide synthase (NOS) activation, which is a major source of NO responsible for low-dose (1-10 nM) nitroglycerin-induced vasorelaxation. Our studies in cell cultures, isolated vessels, and whole animals identified endothelial NOS activation as a fundamental requirement for nitroglycerin action at pharmacologically relevant concentrations in WT animals.
Bonini
Marcelo G
MG
Laboratories of Pharmacology and Chemistry and Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. bonini@niehs.nih.gov
Stadler
Krisztian
K
Silva
Sueli de Oliveira
SO
Corbett
Jean
J
Dore
Michael
M
Petranka
John
J
Fernandes
Denise C
DC
Tanaka
Leonardo Y
LY
Duma
Danielle
D
Laurindo
Francisco R M
FR
Mason
Ronald P
RP
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin