Structural alterations in the heart after long-term L-NAME and D-NAME treatment

N(G)-nitro-D-arginine methyl ester (D-NAME), considered as an inactive enantiomer of NAME, is generally used as a negative control for NO synthase inhibition with L-NAME. The aim of this work was to compare the effect of L-NAME (20 and 40 mg/kg/day), and D-NAME (40 mg/kg/day) on hemodynamic and structural parameters in the rat cardiovascular system. After 4 weeks of treatment, blood pressure and left ventricle weight/body weight ratio increased significantly in all studied groups versus control. Myocardial fibrosis (in %) represented 0.94 +/- 0.04 in control, 4.70 +/- 0.39 in L-NAME (20 mg/kg/day), 10.54 +/- 0.91 in L-NAME (40 mg/kg/day) and 5.25 +/- 0.46 in D-NAME (40 mg/kg/day) group. We conclude that in a long-term experiment D-NAME provokes similar changes in cardiovascular system like L-NAME.     

Effect of captopril on cyclic nucleotide concentrations during long-term NO synthase inhibition

The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibitor captopril on cGMP and cAMP concentration in the left ventricle and aorta after NO synthase inhibition by 4-week-lasting N(G)-nitro-L-arginine-methyl ester (L-NAME) treatment. Five groups of rats were investigated: controls, L-NAME in the dose 20 mg/kg/day (L-NAME 20), L-NAME in the dose 40 mg/kg/day (L-NAME 40), captopril in the dose 100 mg/kg/day, L-NAME 40 mg/kg/day together with captopril 100 mg/kg/day. Captopril completely prevented L-NAME-induced hypertension and LV hypertrophy development. Compared to the controls, cGMP concentration in the L-NAME 20 and L-NAME 40 groups was decreased by 13% and 22%, respectively, in the left ventricle and by 27% and 56% in the aorta, respectively. Captopril did not influence this decrease of cGMP concentration. Cyclic AMP concentration in the aorta of L-NAME 20 group increased by 17%. In the L-NAME 40 group, cAMP concentration increased by 17% in the left ventricle and by 34% in the aorta compared to controls. This increase was enhanced in rats given L-NAME together with captopril. Captopril alone had no effect on cAMP concentration. We conclude that captopril does not affect the concentration of cGMP, however, it has more than the additive effect on the cAMP concentration increase in the cardiovascular system during long-term NO synthase inhibition.     

L-NAME-induced protein remodeling and fibrosis in the rat heart

The aim of the present study was to determine whether NO deficiency itself or rather the elevation of systolic blood pressure is responsible for the protein and structural remodeling of the heart during hypertension induced by long-term treatment by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Three groups of rats were investigated. The first group served as control. In the second group L-NAME was given in the dose of 20 mg/kg/day in the drinking water and in the third group L-NAME was given in the dose of 40 mg/kg/day during 4 weeks. While L-NAME treatment in both doses caused essentially the same increase in systolic blood pressure (SBP), NO synthase activity and cGMP concentration in the left ventricle decreased by 17% and 13%, respectively in the 20 mg/kg/day L-NAME group and by 69% and 27%, respectively in the 40 mg/kg/day L-NAME group. The protein profile of the left ventricle in both L-NAME groups was characterized by an increased concentration of metabolic proteins. Nevertheless, a significant increase in the concentration of pepsin-soluble collagenous proteins and the concentration of hydroxyproline in pepsin-insoluble collagenous proteins was found only in the group receiving 40 mg/kg/day L-NAME. The morphometric evaluation revealed a significant increase in myocardial fibrosis in both L-NAME groups. However, this was more pronounced in the 40 mg/kg/day L-NAME group. It is concluded that NO deficiency resulted in significant enhancement of fibrotic tissue growth in proportion to the administered L-NAME dose, while SBP was increased similarly in both L-NAME groups. Thus, NO deficiency rather than hemodynamic changes appears to be crucially involved in collagenous protein and fibrotic tissue changes of the left ventricle in hypertension induced by L-NAME.     

Inhibition of brain nitric oxide synthesis enhances and prolongs the hypertensive effect of centrally administered interleukin-1beta in rats

The present study was designed to find out whether brain nitric oxide (NO) influences hemodynamic response to intracerebroventricular (ICV) infusion of interleukin-1 beta (IL-1beta). Mean arterial blood pressure (MAP) and heart rate (HR) were recorded in seven series of experiments performed on conscious Sprague-Dawley rats receiving during 60 min ICV infusion of: 0.9% NaCl (5 microl/h; series 1), IL-1beta (100 ng/h; series 2), NO synthase inhibitor (L-NAME, 1mg/h; series 3), IL-1beta together with L-NAME (series 4), IL-1beta together with inactive isomer of NO synthase inhibitor (D-NAME, 1mg/h; series 5), NO donor (SNAP, 40 microg/h; series 6) and IL-1beta together with SNAP (series 7). ICV infusion of saline did not influence MAP while administration of IL-1beta as well as IL-1beta together with D-NAME elicited a significant, though transient, increase in MAP. In series 4, combined infusion of IL-1beta and L-NAME exerted an increase in MAP, which persisted until the end of the experiment and was significantly higher than in series 2 and 5. In series 7, infusion of SNAP together with IL-1beta abolished the pressor effect of IL-1beta. HR was not significantly altered in any of the experimental series. These results demonstrate that inhibition of NO synthesis in the brain enhances and prolongs the pressor response to IL-1beta, whereas concomitant administration of NO donor abolishes the hemodynamic effect of IL-1beta. Therefore, we conclude that NO generated in the brain is involved in buffering the pressor response to IL-1beta.     

Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions

To test whether nitric oxide (NO) participates in cyclosporine A (CsA)-induced neurotoxicity including convulsions, we examined the effect of an NO synthase inhibitor on convulsions induced by combined treatment with CsA and bicuculline in mice and the effect of CsA on NO production in the dorsal hippocampus using an in vivo microdialysis method in rats. CsA (200 mg/kg, i.p.) significantly increased the intensity of convulsions induced by an intracerebroventricular injection of bicuculline (25 pmol) in mice. This facilitation was blocked by N omega -nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, but not by N omega -nitro-D-arginine methyl ester (D-NAME), an inactive form of L-NAME (10 mg/kg, i.p.). CsA (20-50 mg/kg, i.p.) dose-dependently increased NO 2 - levels in dialysates obtained with microdialysis in the rat dorsal hippocampus. This enhanced NO 2 - formation was blocked by L-NAME but not by D-NAME (50 mg/kg, i.p.). These findings suggest that CsA stimulates NO production and induces convulsions as a result of an interaction between NO and the gamma-aminobutyric acid (GABA) system in the hippocampus.     

Satellite cell activation in stretched skeletal muscle and the role of nitric oxide and hepatocyte growth factor

In the present study, we examined the roles of hepatocyte growth factor (HGF) and nitric oxide (NO) in the activation of satellite cells in passively stretched rat skeletal muscle. A hindlimb suspension model was developed in which the vastus, adductor, and gracilis muscles were subjected to stretch for 1 h. Satellite cells were activated by stretch determined on the basis of 5-bromo-2'-deoxyuridine (BrdU) incorporation in vivo. Extracts from stretched muscles stimulated BrdU incorporation in freshly isolated control rat satellite cells in a concentration-dependent manner. Extracts from stretched muscles contained the active form of HGF, and the satellite cell-activating activity could be neutralized by incubation with anti-HGF antibody. The involvement of NO was investigated by administering nitro-L-arginine methyl ester (L-NAME) or the inactive enantiomer N^G-nitro-D-arginine methyl ester HCl (D-NAME) before stretch treatment. In vivo activation of satellite cells in stretched muscle was not inhibited by D-NAME but was inhibited by L-NAME. The activity of stretched muscle extract was abolished by L-NAME treatment but could be restored by the addition of HGF, indicating that the extract was not inhibitory. Finally, NO synthase activity in stretched and unstretched muscles was assayed in muscle extracts immediately after 2-h stretch treatment and was found to be elevated in stretched muscle but not in stretched muscle from L-NAME-treated rats. The results of these experiments demonstrate that stretching muscle liberates HGF in a NO-dependent manner, which can activate satellite cells. muscle regeneration     

NOS inhibition restores renal responses to atrial distension during pregnancy

Nitric oxide (NO) biosynthesis increases during pregnancy and has been shown to suppress baroreceptor activity. The renal response to a simulated increase in circulating blood volume (atrial distension) is also attenuated at this time. We hypothesized that blocking NO biosynthesis during pregnancy would restore the renal response. Female rats were implanted with indwelling intracardiac balloons and central venous cannulas. After recovery, they were mated, and on day 14 of pregnancy, osmotic minipumps containing the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or its inactive enantiomer N(G)-nitro-D-arginine methyl ester (D-NAME) (120 mg/2 ml at 10 microg/min) were implanted. In response to atrial distension (1 h), urine output increased in the D- and L-NAME-treated virgin rats. During pregnancy (day 20), this response was attenuated in the D-NAME-treated, but not the L-NAME-treated, animals, i.e., after a simulated increase in circulating blood volume, inhibition of NO biosynthesis restored the renal response of pregnant rats to that seen in virgin animals. We conclude that, during normal pregnancy, increased NO biosynthesis blunts the reflex renal response to atrial distension.     

Peripheral or central administration of nitric oxide synthase inhibitor affects feeding behavior in chicks

We investigated the effect of peripheral or central administration of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, on food intake in layer and broiler chicks (Gallus gallus). The intraperitoneal administration of L-NAME significantly decreased food intake in both broiler and layer chicks while the administration of D-NAME, an inactive form of L-NAME, had no effect. The intracerebroventricular (ICV) injection of L-NAME did not affect food intake in broiler chicks. However, ICV injection of L-NAME increased food intake in layer chicks while the injection of D-NAME had no effect. In addition to this, L-NAME-induced feeding was negated with the co-injection of L-arginine, suggesting that NO acts as a feeding-inhibitor signal in the brain of layer chicks. The present study revealed that administration of NO synthase inhibitor affected food intake in chicks, but the effect might be changed by chick strain and position of the injection.     

The time-dependent effect of Provinols on brain NO synthase activity in L-NAME-induced hypertension

Red wine polyphenols have been reported to possess beneficial properties for preventing cardiovascular diseases but their neuroprotective effects during chronic L-NAME treatment have not been elucidated. The aim of this study was to analyze a time course of Provinols effects on brain NO synthase activity and oxidative damage in L-NAME-induced hypertension. Male Wistar rats, 12 weeks old, were divided into six groups: control groups, groups treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg/day) for 4 or 7 weeks and groups receiving Provinols (40 mg/kg/day) plus L-NAME for 4 or 7 weeks. At the end of the treatment, marker of membrane oxidative damage - conjugated dienes (CD) in the brain and NO synthase activity in the cerebral cortex, cerebellum and brainstem were determined. L-NAME treatment for 4 or 7 weeks led to the increase in blood pressure, elevation of CD concentration and decrease of NO synthase activity in the brain parts investigated. Provinols partially prevented blood pressure rise and elevation of CD concentration. Comparing to the L-NAME treated group, Provinols increased NO synthase activity after 4 weeks of treatment. However, the prolonged Provinols treatment for 7 weeks had no effect on NO synthase activity decreased by L-NAME treatment. In conclusion, Provinols partially prevents L-NAME induced hypertension via the different mechanisms depending on the duration of treatment. Prevention of oxidative damage in the brain with modulating effect on NO synthase activity is suggested.     

Chronic low-dose L-NAME treatment increases nitric oxide production and vasorelaxation in normotensive rats

N(G)-nitro-L-arginine methyl ester (L-NAME) is a non-specific nitric oxide (NO) synthase inhibitor, commonly used for the induction of NO-deficient hypertension. The aim of this study was to investigate the effect of chronic low-dose administration of L-NAME on NO production, vascular function and structure of the heart and selected arteries of rats. Adult male Wistar rats were treated with L-NAME in the dose of approximately 1.5 mg/kg/day in drinking water for 8 weeks. Basal blood pressure (BP) of rats (determined by tail-cuff) was 112+/-3 mm Hg. The low-dose administration of L-NAME significantly elevated BP measured on the third and sixth week of treatment vs. controls by approximately 9 % and 12 %, respectively. After this period, BP of L-NAME-treated rats returned to the control values. The relative left ventricular mass, heart fibrosis and collagen III/collagen I ratio were not affected by L-NAME. Similarly, there were no alterations in the cross-sectional area and wall thickness/diameter ratio of the aorta and the femoral artery of L-NAME-treated rats. NO synthase activity (determined by conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline) was not altered in the hypothalamus of L-NAME-treated rats. Interestingly, chronic low-dose L-NAME treatment significantly elevated NO synthase activity in the left ventricle and aorta, increased endothelium-dependent acetylcholine-induced vasorelaxation and reduced serotonin-induced vasoconstriction of the femoral artery. The data suggest that chronic low-dose L-NAME treatment can increase NO production and vasorelaxation in normotensive rats without negative structural changes in the cardiovascular system.     

Nitric oxide regulation of lingual blood flow in the rat.

The purpose of this study was to determine the role of nitric oxide in the maintenance of basal lingual blood flow in the anesthetized rat. By using laser-Doppler flowmetry, blood flow was measured from the tongue before and after treatment with the nonselective inhibitor of nitric oxide synthase, L-NAME (0.2, 2.0, and 20 mg/kg), or the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (40 mg/kg). Other groups of rats were treated with saline, D-NAME (2.0 mg/kg), L-arginine (200 mg/kg), L-arginine + L-NAME (200 + 2.0 mg/kg), or the 7-nitroindazole vehicle. L-NAME produced a dose-related depression in blood flow in the tongue (concurrent with increased arterial blood pressure), which was attenuated by prior administration of L-arginine. Lingual blood flow depression was not seen after administration of the inactive stereoisomer, D-NAME. In addition, the neuronally specific nitric oxide synthase inhibitor, 7-nitroindazole, failed to produce a significant depression of lingual blood flow. These results suggest that the tonic release of nitric oxide from the vascular endothelium plays an important role in maintaining basal blood flow in the tongue and that neuronally released nitric oxide is not involved in maintaining basal circulation in this vascular bed.     

Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide

The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4 )M), NOS blocking agent N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and L-NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O(2) consumption was determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and L-NAME treated rabbits. SNAP in controls caused a reduction in O(2) consumption (SNAP 5.9+/-0.6 vs. control 8.4+/-0.8 ml O(2)/min/100 g) and a rise in cyclic GMP (SNAP 18.3+/-3.8 vs. control 10.4+/-0.9 pmol/g). After chronic L-NAME treatment, SNAP caused no significant changes in O(2) consumption (SNAP 7.1+/-0.8 vs. control 6.4+/-0.7) or cyclic GMP (SNAP 14.2+/-1.8 vs. control 12.1+/-1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7+/-20.0 SNAP vs. 34.4+/-2.5 pmol/mg/min base), while this increase was blunted after L-NAME (115.9+/-24.5 SNAP vs. 24.9+/-4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O(2) consumption. This was related to reduced guanylyl cyclase activity after chronic L-NAME. These results suggest that, unlike many receptor systems, the NO-cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.     

Roles of endogenous prostaglandins and nitric oxide in inhibitions of gastric emptying and accelerations of gastrointestinal transit by escins Ia, Ib, IIa, and IIb in mice

We reported previously that escins Ia, Ib, IIa, and IIb, isolated from horse chestnuts, inhibited the 30-min gastric emptying (GE) in mice. In this study, the effects of escins Ia-IIb on gastrointestinal transit (GIT), and the roles of endogenous prostaglandins (PGs) and nitric oxide (NO) in the effects of escins Ia--IIb on GE and GIT were investigated in fasted mice. Escins Ia-IIb (12.5-50 mg/kg, p.o.) dose-dependently accelerated GIT. Both GE inhibitions and GIT accelerations by escins Ia-IIb (25 mg/kg) were markedly attenuated by pretreatment with indomethacin (10 mg/kg, s.c., an inhibitor of PGs synthesis). Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p., an inhibitor of constitutive and inducible NO synthase) attenuated the effects of escins Ia-IIb on GIT, but not on GE. The effect of L-NAME was reversed by L-arginine (600 mg/kg, i.p., a substrate of NO synthase), but not by D-arginine (900 mg/kg, i.p., the enantiomer of L-arginine). The GIT accelerations of escins Ia-IIb were not attenuated by pretreatment with D-NAME (10 mg/kg, i.p., the enantiomer of L-NAME) or dexamethasone (5 mg/kg, i.p., an inhibitor of inducible form of NO synthase). The results suggest that endogenous PGs play an important role in both GE inhibitions and GIT accelerations, and constitutive NO is involved in the GIT accelerations, by escins Ia--IIb in mice.     

Exercise conditioning attenuates the hypertensive effects of nitric oxide synthase inhibitor in rat

Many individuals with cardiovascular diseases undergo periodic exercise conditioning with or with out medication. Therefore, this study investigated the interaction of exercise training and chronic nitric oxide synthase (NOS) inhibitor (Nitro-L-Arginine Methyl Ester, L-NAME) treatment on blood pressure and its correlation with aortic nitric oxide (NO), antioxidant defense system and oxidative stress parameters in rats. Fisher 344 rats were divided into four groups: (1) sedentary control, (2) exercise training (ET) for 8 weeks, (3) L-NAME (10 mg/kg, subcutaneous for 8 weeks) and (4) ET + L-NAME. Blood pressure (BP) was monitored weekly for 8 weeks with tail-cuff method. The animals were sacrificed 24 h after last treatments and thoracic aortic rings were isolated and analyzed. Exercise conditioning resulted in a significant increase in respiratory exchange ratio (RER), aortic NO production, NO synthase activity and inducible iNOS protein expression. Training significantly enhanced aortic GSH levels, GSH/GSSG ratio and up-regulation of aortic CuZn-SOD, Mn-SOD, catalase (CAT) glutathione peroxidase (GSH-Px) activity and protein expression and significantly decreased aortic lipid peroxidation. Chronic L-NAME administration resulted in a significant depletion of aortic NO, NOS activity, endothelial (eNOS) and iNOS protein expression, GSH level, GSH/GSSG ratio, down-regulation of aortic antioxidant enzyme activities and protein expressions. Aortic xanthine oxidase (XO) activity significantly increased with increased lipid peroxidation and protein oxidation after L-NAME administration. The biochemical changes were accompanied by increased in BP. Interaction of training and chronic NOS inhibitor treatment resulted in normalization of BP and aortic antioxidant enzyme activity and protein expression, up-regulation of aortic GSH/GSSG ratio, NO levels, Mn-SOD protein expression, depletion of GSSG, protein oxidation and lipid peroxidation. The data suggest that training attenuated the oxidative injury caused by chronic NOS inhibitor treatment by up-regulating the NO and antioxidant systems and lowering the BP in rats.     

Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat

Recent studies have shown that nitric oxide (NO) biosynthesis increases in pregnancy and that inhibition of nitric oxide synthase (NOS) induces some pathological processes characteristic of preeclampsia. The current project sought to study the effect of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microg x min(-1), sc for 7 days) on plasma volume, plasma atrial natriuretic factor (ANF), plasma endothelin-1 (ET), and plasma renin activity (PRA) during gestation in conscious rats. NOS inhibition caused mean arterial pressure to increase in both virgin and 21-day pregnant rats. Plasma volume fell in the pregnant rats [L-NAME, 4.5 +/- 0.3 mL x 100 g(-1) body wt. (n = 7) vs. D-NAME, 6.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 10); P < 0.05] but not in the virgin rats [L-NAME, 4.3 +/- 0.1 mL x 100 g(-1) body wt. (n = 6) vs. D-NAME, 4.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 8)]. There was no effect of NOS inhibition on plasma ANF levels or PRA in either the virgin or pregnant rats. However, L-NAME did decrease plasma ET levels in the pregnant rats [L-NAME, 19.6 +/- 1.6 pg x mL(-1) (n = 8) vs. D-NAME, 11.6 +/- 2.5 pg x mL(-1) (n = 9); P < 0.05]. Our results confirm that NO is involved in cardiovascular homeostasis in pregnancy; NOS inhibition selectively reduces plasma volume in pregnant rats, thus mimicking a major pathophysiological perturbation of preeclampsia. However, it does not induce the hormonal changes characteristic of preeclampsia, namely the decrease in PRA and increase in plasma ET and ANF levels.     

Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension

The effects of the red wine polyphenolic compounds (Provinol) on hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular remodeling were investigated after chronic inhibition of nitric oxide (NO) synthase by administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats. Rats were divided into four groups: a control group, a group treated for 4 wk with L-NAME (40 mg x kg(-1) x day(-1)), and two groups treated with L-NAME followed by 3 wk of either spontaneous recovery or recovery with Provinol treatment (40 mg x kg(-1) x day(-1)). Administration of Provinol produced a greater readiness of the decrease in blood pressure than that in the spontaneous recovery group. Provinol significantly depressed myocardial fibrosis and expedited the decrease in aortic cross-sectional area, the increase in endothelium-dependent relaxation, and the decrease in contraction of the aorta. These effects of Provinol were associated with a greater increase of NO synthase activity in the left ventricle and the aorta. The present study provides evidence that Provinol accelerates the regression of blood pressure and improves structural and functional cardiovascular changes produced by chronic inhibition of NO synthesis.     

Cardiovascular system of offsprings of hypertensive rats with defective nitric oxide production

The question was addressed of how nitric oxide synthase (NO synthase) inhibition-induced hypertension in rat parents would affect the cardiovascular system in their offsprings. Two experimental groups were set up: Group I -- offsprings of parents who had both been administered NO synthase inhibitor L-nitro-arginine methyl ester (L-NAME 40 mg/kg/day) for 5 weeks, the treatment of dams continued till week 12. Group II -- offsprings fed by dams administered L-NAME after delivery only for a period of 4 weeks. Control age-matched offsprings formed the third group. Blood pressure and heart rate in parents and in 3-week-old offsprings were determined noninvasively. In the offsprings, body and heart weight were measured and the heart/body weight ratio (HW/BW) was calculated. The NO synthase activity, and also ornithine decarboxylase activity as a marker of polyamine production, were determined in the heart. The acetylcholine-induced relaxation of aortic rings was also followed. A marked blood pressure increase with a tendency to a decreased heart rate was found in the offsprings of Group I. A significant decrease in heart weight and body weight with a decreased HW/BW ratio indicated cardiac hypotrophy that contrasted with the decrease in NO synthase activity and increase in ornithine decarboxylase activity in the heart. Noteworthy was also the finding of completely preserved relaxation of the aorta to acetylcholine. Offsprings of Group II were similarly characterized by significantly higher blood pressure, a tendency to decreased heart rate, a decrease in heart weight, but not of the HW/BW ratio. The contrasting findings of heart weight decrease on the one hand and NO synthase activity decrease and ornithine decarboxylase increase on the other, were also found in this group. Full relaxation of the aorta to acetylcholine was preserved. It can be concluded that remarkable alterations in the cardiovascular system were found in offsprings of hypertensive NO compromised parents.     

A possible role of nitric oxide in the regulation of dopamine transporter function in the striatum.

Brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) on striatal dopamine (DA) release in the anesthetized rat. Systemic administration of L-NAME (10 mg/kg, i.p.) significantly decreased the resting release of DA. The peak effect (23% decrease) was reached 45 min after injection. The inactive enantiomer D-NAME (10 mg/kg, i.p.) or the vehicle (saline, 5 ml/kg i.p.) had no effect on the striatal DA level. Neither treatment altered significantly the concentration of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). To investigate the possible involvement of the DA uptake system L-NAME was injected also in the presence of the DA uptake inhibitor nomifensine. Local application of nomifensine (10 microM in the dialysate medium) increased the extracellular concentration of DA to about eight-fold of the basal value and stabilized it at this higher level. Under these conditions L-NAME (10 mg/kg, i.p.) was not able to alter the striatal DA level. Neither nomifensine nor L-NAME caused any change in the level of DOPAC and HVA. Our data suggest that endogenously produced nitric oxide may influence the activity of the DA transporter which effect may have special importance in the regulation of extracellular transmitter concentration in the striatum.     

The effect of diabetes and sex on nitric oxide-mediated cardiovascular dynamics

Diabetes is associated with impaired cardiovascular responses that are especially prominent in females. Since nitric oxide (NO)-mediated effects on cardiovascular dynamics are altered in diabetes, we evaluated the effect of L-NAME, a nitric oxide synthase (NOS) antagonist, on mean arterial pressure (MAP), heart rate (HR), and selective vascular flows in both male and female normal and diabetic rats as an index of NO activity. Rats were made diabetic using streptozotocin and maintained for 5-6 weeks. Following anesthesia with urethane/alpha-chloralose, the femoral artery and vein were cannulated for recording and sampling, and flow probes were placed on the iliac, renal, and superior mesenteric arteries. A bolus infusion of L-NAME (10mg/ kg) resulted in a rapid +52% and +68% increase in MAP in normal female and male rats, respectively. However, diabetic females' and males' responses were significantly lower (44% and 45%, respectively) when compared with their normal counterparts. The decreased HR in response to the peak pressor effect of L-NAME was more prominent in normal females compared with normal males (-14% vs 2%). The results in diabetic females and males were equivalent (-6% vs -9%, respectively). L-NAME decreased the conductance (flow/MAP) an average of 65% in all three vascular beds in normal female rats. In diabetic females, the iliac and superior mesenteric responses to L-NAME were less, and the renal conductance was contrastingly increased 23%. The response to L-NAME was comparable (-62%) in the renal and superior mesenteric and less (-40%) in the iliacs of normal versus diabetic males. We concluded that diabetes is associated with a decreased pressor response to NOS inhibition. And the impaired constriction response of the renal vessels noted in female diabetic rats may provide a basis for the increased renal pathology observed in diabetic humans.