L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation
Taiming Liu,
Meijuan Zhang,
George T. Mukosera,
Dan Borchardt,
Qian Li,
Trent E. Tipple,
Abu Shufian Ishtiaq Ahmed,
Gordon G. Power,
Arlin B. Blood
Affiliations
Taiming Liu
Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
Meijuan Zhang
Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
George T. Mukosera
Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
Dan Borchardt
Department of Chemistry, University of California, Riverside, CA, 92521, USA
Qian Li
Neonatal Redox Biology Laboratory, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Trent E. Tipple
Neonatal Redox Biology Laboratory, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Abu Shufian Ishtiaq Ahmed
Center for Dental Research, Loma Linda University School of Dentistry, Loma Linda, CA, 92350, USA
Gordon G. Power
Lawrence D. Longo Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
Arlin B. Blood
Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA; Lawrence D. Longo Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA; Corresponding author. 11175 Campus Street, 11121 Coleman, Loma Linda, CA, 92354, USA.
L-NG-Nitro arginine methyl ester (L-NAME) has been widely applied for several decades in both basic and clinical research as an antagonist of nitric oxide synthase (NOS). Herein, we show that L-NAME slowly releases NO from its guanidino nitro group. Daily pretreatment of rats with L-NAME potentiated mesenteric vasodilation induced by nitrodilators such as nitroglycerin, but not by NO. Release of NO also occurred with the NOS-inactive enantiomer D-NAME, but not with L-arginine or another NOS inhibitor L-NMMA, consistent with the presence or absence of a nitro group in their structure and their nitrodilator-potentiating effects. Metabolic conversion of the nitro group to NO-related breakdown products was confirmed using isotopically-labeled L-NAME. Consistent with Fenton chemistry, transition metals and reactive oxygen species accelerated the release of NO from L-NAME. Both NO production from L-NAME and its nitrodilator-potentiating effects were augmented under inflammation. NO release by L-NAME can confound its intended NOS-inhibiting effects, possibly by contributing to a putative intracellular NO store in the vasculature. Keywords: L-NAME, Nitrodilator, L-arginine analogues, Fenton chemistry, Preformed intracellular NO store
