1，6-二磷酸果糖和左旋精氨酸对心内直视手术期间血清心肌肌钙蛋白T的影响

目的探讨1，6-二磷酸果糖（FDP）和左旋精氨酸（1-Arg）及其联合用药对体外循环期间心肌缺血再灌注损伤的保护作用。方法拟行心内直视手术的先天性心脏病患者40例，随机分为对照组（A组）、Z—Arg组（B组）、FDP组（C组）和联合用药组（D组），每组10例。B组于主动脉开放后给予l-A唱200mg/kg；C组于主动脉阻断前给予FDP200mg／kg；D组联合应用两种药物。分别于主动脉插管时，主动脉开放30min、2h、6h时检测血清心肌肌钙蛋白T（cTnT）、丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。结果各用药组与对照组比较，可最著降低血浆cTnT和MDA的上升幅度，提高SOD活性（JP〈0．05），且D组与B组、C组比较可显著降低血浆cTnT的上升幅度（P〈0．05）。结论1，6．二磷酸果糖和左旋精氨酸对心内直视手术中的心肌保护有良好的作用，联合应用优于两药单用。     

L-arginine levels are diminished in adult acute vaso-occlusive sickle cell crisis in the emergency department

Paediatric studies have demonstrated that l-arginine (l-arg), the precursor to nitric oxide, is diminished in vaso-occlusive crisis (VOC). This study aimed to determine whether l-arginine levels are altered in adult VOC in the emergency department. Plasma l-arg and nitric oxide metabolite (NOx) levels were obtained in adult VOC patients presenting to the emergency department. Fifty patients had significantly low plasma l-arg (29.78 micromol/l +/- 11.21, P < 0.05 vs steady-state control = 41.16 micromol/l +/- 5.04) and significantly low plasma NOx (12.33 micromol/l +/- 10.28, P < 0.05 vs steady-state control = 25.2 +/- 2.6 micro mol/l). Neither l-arg nor NOx levels could predict VOC clinical course.     

Effects of homocysteine on l-arginine transport and nitric oxide formation in human platelets

BACKGROUND: Recent evidence indicates that hyperhomocysteinaemia is an independent risk factor for atherosclerosis, thrombosis and other cardiovascular diseases. This may be secondary to impaired fibrinolysis or increased platelet reactivity. Nitric oxide (NO), a product from l-arginine by NOS and potent antiaggregating agent, plays an important role in the regulation of platelet function. DESIGN: The present study aimed to define the effect of homocysteine on the l-arginine/NO pathway in human platelets. l-Arginine uptake, NO formation and Ca2+ levels were measured. Moreover the homocysteine effect on platelet activation induced by thrombin was tested. RESULTS: Homocysteine causes a concentration-dependent inhibition of l-arginine transport. Results show that homocysteine does not modify the Km parameter, but it significantly decreases the Vmax value. The nitrite and nitrate formation, strictly correlated with the l-arginine transport, also significantly decreased. In contrast, cNOS activity remained unchanged upon homocysteine treatment. In addition homocysteine in a dose dependent manner increased the intracellular Ca2+ concentration and platelet response to thrombin. CONCLUSIONS: Results indicate that the l-arginine/NO pathway is one of the various targets of homocysteine in human platelets. The increased Ca2+ levels associated with reduced NO formation may generate hyperactivation and may contribute to the thrombogenic processes.     

Effects of prolonged oral supplementation with l-arginine on blood pressure and nitric oxide synthesis in preeclampsia

BACKGROUND: Several lines of evidence point to the dysfunction of the endothelial l-arginine-NO system in preeclampsia. We investigated the influence of dietary supplementation with l-arginine on blood pressure and biochemical measures of NO production in women with preeclampsia in prospective, randomized, placebo-controlled study. DESIGN: The 61 preeclamptic women on a standardized low nitrate diet received orally 3 g of l-arginine (n = 30) or placebo (n = 31) daily for 3 weeks as a supplement to standard therapy. The differences between the two groups in systolic (SBP), diastolic (DBP) and mean arterial blood pressures (MAP) as well as in plasma levels of selected aminoacids, plasma concentrations of nitrates/nitrites (NOx) and in 24-h urine NOx excretion were determined. RESULTS: After 3 weeks of treatment, values of SBP, DPB and MAP were significantly lower in the group taking l-arginine as compared with the placebo group (SBP: 134.2 +/- 2.9 vs. 143.1 +/- 2.8; DBP: 81.6 +/- 1.7 vs. 86.5 +/- 0.9; MAP: 101.8 +/- 1.5 vs. 108.0 +/- 1.2 mmHg, P < 0.01). Importantly, treatment with exogenous l-arginine significantly elevated 24-h urinary excretion of NOx and mean plasma levels of l-citrulline. Exogenous l-arginine did not influence plasma concentrations of l-arginine, l-ornithine and methylated arginines (ADMA, SDMA, L-NMMA). CONCLUSIONS: We conclude that in women with preeclampsia, prolonged dietary supplementation with l-arginine significantly decreased blood pressure through increased endothelial synthesis and/or bioavailability of NO. It is tempting to speculate that the supplementary treatment with l-arginine may represent a new, safe and efficient strategy to improve the function of the endothelium in preeclampsia.     

Chronic exercise reduces platelet activation in hypertension: upregulation of the L-arginine-nitric oxide pathway

Nitric oxide (NO) inhibits platelet function and plays a key role in the regulation of cardiovascular homeostasis. Essential hypertension is characterized by an increased risk of thrombus formation, and by an inhibition of intraplatelet NO bioactivity. We have previously shown that membrane transport of l -arginine is a rate-limiting step for platelet-derived NO synthesis. This study examined the effects of exercise on the platelet l -arginine–NO pathway and aggregation and systemic inflammation markers in 13 sedentary hypertensive patients subjected to 60 min of training activity (exercise group), predominantly aerobic, three times a week for a period of 12 weeks. Six sedentary hypertensive patients participated in the control group. After 12 weeks, l -arginine transport was significantly increased and associated with increased platelet NO synthase activity and cGMP levels and reduced platelet aggregation. Moreover, exercise training reduced plasma concentrations of fibrinogen and C-reactive protein and blood pressure. The control group did not change their previous intraplatelet l -arginine–NO results and systemic inflammatory markers levels. Thus, exercise training reduces inflammatory responses, restores NO synthesis in platelets and thereby contributes to the beneficial effects of exercise in hypertension. The present study adds exercise as a new tool to reduce morbidity and mortality associated with platelet activation in hypertension.     

Erectile and endothelial dysfunction in Type II diabetes: a possible link

Aims/hypothesis: The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. Methods: We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the l-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. Results: Mean erectile score and HbA_{1 c} were 10.5 ± 5.8 and 8.3 ± 1.6 % in patients with erectile dysfunction, and 24.0 ± 0.7 and 6.8 ± 1.4 % in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA_{1 c} and erectile function score in patients with erectile dysfunction (r = –0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to l-arginine was lower (p < 0.05–0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05–0.02). Indices of coagulation activation (F1 + 2 and d-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds, as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA_{1 c}, MBP response to l-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. Conclusion/interpretation: Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation. [Diabetologia (2001) 44: 1155–1160] Received: 18 April 2001 and in revised form: 21 April 2001     

The antinociceptive activity of Muntingia calabura aqueous extract and the involvement of L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in its observed activity in mice

The present study was carried out to investigate on the possible involvement of L-arginine/nitric oxide/cyclic guanosine monophosphate (L-arginine/NO/cGMP) pathway in the aqueous extract of Muntingia calabura (AEMC) leaves antinociception in mice assessed by abdominal constriction test. The AEMC, obtained by soaking the dried leaves in distilled water (DH(2)O) (1 : 2; w/v) for 24 h, was prepared in concentrations of 10%, 50% and 100% that were approximately equivalent to doses of 27, 135 and 270 mg/kg, and administered subcutaneously (s.c.) 5 min after pre-treatment (s.c.) of mice with DH(2)O, L-arginine (20 mg/kg), N(G)-monomethyl-L-arginine acetate (L-NMMA; 20 mg/kg), N(G)-nitro-L-arginine methyl esters (L-NAME; 20 mg/kg), methylene blue (MB) (20 mg/kg), respectively. The AEMC was found to exhibit a concentration-dependent antinociception after pre-challenge with DH(2)O. Interestingly, pre-treatment with L-arginine was found to block significantly (P < 0.05) the AEMC antinociception but only at the highest concentration (100%) of AEMC used. On the other hand, pre-treatment with L-NAME was found to significantly (P < 0.05) enhance the low concentration but inhibit the high concentration AEMC antinociception. MB was found to significantly (P < 0.05) enhance AEMC antinociception at all concentrations used. Except for the higher concentration of AEMC used, co-treatment with L-NAME was found to insignificantly and significantly (P < 0.05) reverse the L-arginine effect when given alone or with low concentration AEMC, respectively. In addition, co-treatment with MB significantly (P < 0.05) reversed the L-arginine effect when given alone or with 10% concentration AEMC but failed to affect the activity of the rest of concentrations used. As a conclusion, this study has demonstrated the involvement of L-arginine/NO/cGMP pathway in AEMC antinociception.     

L-arginine fails to protect against myocardial remodelling in L-NAME-induced hypertension

BACKGROUND: We investigated whether the substrate for nitric oxide synthesis L-arginine is able to modify hypertension and left ventricular hypertrophy development induced by chronic blockade of nitric oxide synthase activity by NG-nitro-L-arginine-methyl ester (L-NAME). MATERIAL AND METHODS: Four groups of rats were investigated: control, L-arginine 1.5 g kg-1, L-NAME 40 mg kg-1, and L-NAME +L-arginine in corresponding doses. Systolic blood pressure was measured by non-invasive tail-cuff plethysmography each week. After 4 weeks, the animals were sacrificed and hydroxyproline and coenzyme Q9 and Q10 concentrations in the left ventricle, and nitric oxide synthase activity in the left ventricle, kidney and brain were investigated. RESULTS: In the L-NAME group, nitric oxide synthase activity was decreased in the left ventricle, kidney and brain, and hypertension, left ventricular hypertrophy and fibrosis developed. Heart remodelling was associated with the decrease of coenzyme Q9 and Q10 concentrations in the left ventricle. Simultaneous treatment with L-NAME and L-arginine prevented nitric oxide synthase activity diminution in the left ventricle but not in the kidney and brain, and completely failed to prevent hypertension, left ventricular hypertrophy and fibrosis. Nevertheless, l-arginine prevented the diminution of coenzyme Q9 and Q10 concentrations in the left ventricle. CONCLUSIONS: We conclude that L-arginine failed to prevent hypertension, left ventricular hypertrophy and fibrosis development despite restoration of nitric oxide synthase activity in the left ventricle. However, L-arginine prevented the diminution of coenzyme Q levels in the left ventricle.     

Inhibition of L-arginine transport by reactive oxygen species in rat anococcygeus muscle

The effect of L-arginine on nitrergic transmission and its alteration with reactive oxygen species (ROS) were investigated. L-arginine potentiated the relaxation response induced by electrical field stimulation in rat anococygeus muscle. This effect was inhibited by L-lysine, a cationic amino acid using y+ L and y+ transport systems in a similar way with L-arginine. The neutral amino acid L-leucine, which uses only y+ L system as a transport mechanism, inhibited this potentiation at only low frequency stimulation. Electrolysis of the physiological solution did not change the responses to electrical field stimulation, but inhibited the potentiation elicited by L-arginine that was prevented in the presence of mannitol and N-acetyl-L-cysteine. In conclusion, L-arginine is transported via y+ system predominantly to potentiate the relaxation response to nitrergic nerve stimulation in rat anococcygeus muscle. ROS, primarily hydroxyl radicals inhibited L-arginine-induced potentiation probably by interacting with the y+ amino acid transport system.     

Role of nitric oxide in the CBF autoregulation during acute stage after subarachnoid haemorrhage in rat pial artery

The present study was aimed to identify whether endogenously produced nitric oxide (NO) plays a role in preservation of cerebral blood flow (CBF) autoregulation in rat pial artery during the acute stage after subarachnoid haemorrhage (SAH). During the acute stage after SAH, the lower limit of CBF autoregulation significantly shifted to the higher arterial blood pressure in association with suppressed vasodilatation in response to acute hypotension, which was accompanied by significantly increased expression of endothelial nitric oxide synthase mRNA and increased production of superoxide anion in cerebral vessels. SAH-induced increase in superoxide production was further enhanced under pretreatment with N-nitro-L-arginine methyl ester in the cerebral vessels. Following additional administration of L-arginine (100 mg/kg, i.p.), the haemodynamic alterations were significantly restored in association with significantly reduced superoxide level in the cerebral vessels. In line with these findings, rats that received polyethylene glycol superoxide dismutase and catalase or Mn(III) tetrakis (4-benzoic acid) porphyrin chloride showed recovery of impaired autoregulatory vasodilation in response to acute hypotension. Thus, it is suggested that NO endogenously produced is importantly implicated in the preservation of CBF autoregulation during the acute stage after SAH via its capability to scavenge superoxide anion.