Pharmacokinetic‐pharmacodynamic profile of systemic nitric oxide‐synthase inhibition with L‐NMMA in humans

Mayer, Bernd; Mensik, Christa; Krishnaswami, Sriram; Derendorf, Hartmut; Eichler, Hans‐Georg; Schmetterer, Leopold; Wolzt, Michael

doi:10.1046/j.1365-2125.1999.00930.x

Cited by 65 publications

(56 citation statements)

References 27 publications

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“…A role of increased NO synthesis, release of NO, or altered NO sensitivity by training is also supported by our results obtained in the ocular vasculature. NO is an important regulator of ocular blood flow, and the choroidal vasculature is particularly sensitive to changes in NO production (31). We have previously demonstrated that the ocular responsiveness to L-NMMA is reduced in patients with long-standing type 1 diabetes (12), which is compatible with the results of the present study.…”

Section: Fuchsjä Ger-mayrl and Associatessupporting

confidence: 82%

Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes

et al. 2002

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OBJECTIVE -Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training.RESEARCH DESIGN AND METHODS -The study included 26 patients with type 1 diabetes of 20 Ϯ 10 years' duration and no overt angiopathy; 18 patients (42 Ϯ 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 Ϯ 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N G -monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise.RESULTS -Training increased peak oxygen uptake (VO 2max ) by 13% after 2 months and by 27% after 4 months (P ϭ 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 Ϯ 1.1 to 9.8 Ϯ 1.1% (P ϭ 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 Ϯ 0.9% before training and by 13.4 Ϯ 1.5% after 4 months of training (P ϭ 0.02). VO 2max , FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise.CONCLUSIONS -Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.

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Section: Fuchsjä Ger-mayrl and Associatessupporting

confidence: 82%

Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes

et al. 2002

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“…L-NMMA is cleared predominantly by hepatic amino acid pathways, with a minor amount of renal clearance at higher doses (31). In healthy adults, the mean elimination half-life of a 3 mg/kg L-NMMA dose is about 1 hour (26,32). In contrast, septic adults have a longer elimination half-life (2-3 hours) (31).…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

et al. 2005

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Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [N G -monomethyl-L-arginine (L-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L-NMMA in newborns born at Ͻ28 weeks' gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h). Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h) plus a 72-hour L-NMMA infusion]. Thirty-eight newborns received three additional indomethacin doses (without L-NMMA) and served as a comparison group. Ninety-two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L-NMMA infusions were limited in dose and duration by acute side effects. Doses of 10 -20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at Ͻ28 weeks' gestation. However, the combined administration of L-NMMA and indomethacin was limited by acute side effects in this treatment protocol. Studies in premature animals demonstrate that prolonged, tight constriction of the ductus arteriosus is necessary to produce ischemia of the ductus wall, anatomic remodeling, and permanent closure (1-3). A persistent patent ductus arteriosus (PDA) in premature infants is due in large part to the increased sensitivity of the ductus to endogenous vasodilators like prostaglandins. Prostaglandin synthesis inhibitors, such as indomethacin, are the only drugs currently approved for treatment of PDA. Unfortunately, a three-dose course of indomethacin frequently fails to close the PDA in infants of Ͻ28 weeks gestational age (GA). Previous studies have shown that infants delivered before 28 weeks GA who still have evidence of ductus flow on Doppler examination (performed after a standard three-dose course of indomethacin), are unlikely to eliminate Doppler flow through their ductus even if a prolonged six-dose indomethacin course is administered (2).

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“…Saline or L-NMMA (1 ml) was continuously injected for 30 min via the right femoral vein, starting from myocardial ischemia until reperfusion. All rats were further injected intraperitoneally (ip) with L-NMMA or saline every 12 h for a period of 48 h. 39 …”

Section: Animals and Mirmentioning

confidence: 99%

Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia Reperfusion

Yamamoto

Maeda

Hirose

et al. 2008

Circ J

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lthough therapeutic intervention or coronary artery bypass grafting can recover coronary blood flow, myocardial damage after blood flow reperfusion, namely myocardial ischemia reperfusion (MIR) injury, remains to be resolved. Among the factors affecting MIR, oxidative stress might play an important role in both the myocardial injury and the cardiac events after reperfusion therapy. 1 Oxidative stress induced by superoxide generated via the xanthine oxidase system and infiltrating inflammatory cells is the major proposed mechanism of MIR progression. [2][3][4][5] We have reported that reactive oxygen species (ROS) influence the opening of the mitochondrial permeability transition pore in myocardial cells, which led to progression of myocardial infarction (MI) in a rat MIR model. 6 Moreover, total nitric oxide (NO) synthesis in the reperfused heart was increased in previous investigations. 7-9 Physiological concentrations of NO produced from endothelial NO synthase (eNOS) or NO donors exert significant cardioprotective effects, whereas the reaction between NO and ROS produces peroxynitrite and results in oxidative and nitrative tissue injury. [7][8][9][10][11][12][13] Evidence from several model systems supports the notion that NO radicals cause myocardial damage in MIR, 7,8,[12][13][14][15] whereas a small amount of NO exerts a cytoprotective effect in the reperfused heart. 11,12,16,17 The dynamics of oxidative stress up to 48 h after MIR remain unclear because of the difficulties associated with monitoring oxidation in vivo. This period is considered critical in both cardiac surgery and therapeutic intervention, so more sensitive and reliable markers of in vivo oxidative stress are required.Bilirubin is an intrinsic antioxidant that quenches radicals under several inflammatory conditions. 18-21 Its synthesis is regulated by the rate-limiting enzyme, heme oxygenase-1 (HO-1), which is rapidly induced by oxidative stress and inflammatory reactions caused by factors such as cytokines, ischemia and NO. [22][23][24][25][26][27][28][29] Bilirubin generates several hydrophilic metabolites called biopyrrins upon oxidation and these can be detected using the anti-bilirubin monoclonal antibody 24G7. 30,31 Biopyrrins are immediately excreted in urine because of their hydrophilic properties and thus can reflect the severity of oxidative stress. 25,[32][33][34][35][36][37][38] Biopyrrin synthesis reflects NO radicals, 25 so urinary biopyrrin levels can indicate ongoing changes in oxidative stress in vivo and thus function as a marker of oxidative stress.The time course of urinary and tissue biopyrrin levels in rat models of cardiac transplantation and hepatic ischemia reperfusion has been investigated. 25,32 A cardiac transplantation study showed that levels of urinary biopyrrins become more rapidly and sensitively elevated than either urinary 8-hydroxy-2'-deoxyguanosine or serum troponin-T during Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia ReperfusionMasaki Yamamoto, MD; Hironori Maeda, MD; Nobuyuki...

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Pharmacokinetic‐pharmacodynamic profile of systemic nitric oxide‐synthase inhibition with L‐NMMA in humans

Cited by 65 publications

References 27 publications

Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes

Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes

Combined Treatment With a Nonselective Nitric Oxide Synthase Inhibitor (L-NMMA) and Indomethacin Increases Ductus Constriction in Extremely Premature Newborns

Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia Reperfusion

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