Acute Nitric Oxide Synthesis Inhibition Research Articles

Pulmonary Microvascular Constriction and Oxidative Stress in the Intact‐ventilated Mouse Lung during Acute Inhibition of Nitric Oxide Synthase

Constitutive nitric oxide (NO) synthesis contributes to maintain low pulmonary vascular resistance in mice, but less is known about its effects on microvasculature at the alveolar level. Given its role in regulating microvascular responsiveness in various species, we determined the effects of acute NO synthesis inhibition on pulmonary arteriolar diameter and oxidative stress in anesthetized, open chest mice with ventilated lungs. NO synthesis was inhibited acutely by injecting L-NAME (0.1 mg/g body wt) into the pulmonary circulation via the right jugular vein. We examined subpleural microvessels (less than 50 μm in diameter) in the right lung, during brief periods when the lungs were statically inflated with O2. NADPH oxidase subunit, p47-phox translocation to the membrane, suggestive of NADPH oxidase activation, was assessed in lung lysates by immunoblot. L-NAME decreased arteriolar diameter by about 14% and increased the translocation of p47-phox compared to saline controls. Our data suggest that constitutive NO production decreases microvascular tone and inhibits NADPH oxidase in the ventilated mouse lung during physiological conditions. This study presents a reliable model for examining the role of NO synthesis in the responses of individual pulmonary microvessels in-vivo, and may provide valuable information on pulmonary microvascular responses to various pathophysiological circumstances.

Hypersensitivity to Thromboxane Receptor Mediated Cerebral Vasomotion and CBF Oscillations during Acute NO-Deficiency in Rats

BackgroundLow frequency (4–12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of thromboxane A2 (TXA2), NO-deficiency is often associated with activation of thromboxane receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations.Methodology/Principal FindingsEffects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats) and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs) both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg iv.) to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl esther (L-NAME, 100 mg/kg iv.) resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA2 synthesis by ozagrel (10 mg/kg iv.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632.Conclusion/SignificanceThese results suggest that hypersensitivity of the TP-receptor – Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency.

Losartan increases NO release in afferent arterioles during regression ofl-NAME-induced renal damage

Inhibition of nitric oxide synthesis (NOS) induces hypertension and heavy proteinuria. Renal structure and function have shown striking improvement after interventions targeting ANG II or endothelin (ET) receptors in rats recovering after long-term NOS inhibition. To search for mechanisms underlying losartan-assisted regression of renal disease in rodents, we measured NO release and contractility to ET in afferent arterioles (AAs) from Sprague-Dawley rats recovering for 2 wk after 4 wk of N(G)-nitro-L-arginine methyl ester treatment. Losartan administration during the recovery period decreased blood pressure (113 ± 4 vs. 146 ± 5 mmHg, P < 0.01), reduced protein/creatinine ratio more (proteinuria decrease: Δ1,836 ± 214 vs. Δ1,024 ± 180 mg/mmol, P < 0.01), and normalized microvascular hypertrophy (AA media/lumen ratio: 1.74 ± 0.05 vs. 2.09 ± 0.08, P < 0.05) compared with no treatment. In diaminofluorescein-FM-loaded AAs from losartan-treated animals, NO release (% of baseline) was increased compared with untreated animals after stimulation with 10(-7) M ACh (118 ± 4 vs. 90 ± 7%, t = 560 s, P < 0.001) and 10(-9) M ET (123 ± 4 vs. 101 ± 5%, t = 560 s, P < 0.001). There was also a blunted contractile response to 10(-7) M ET in AAs from losartan-treated animals compared with untreated animals (Δ4.01 ± 2.9 vs. Δ14.6 ± 1.7 μm, P < 0.01), which disappeared after acute NOS inhibition (Δ10.7 ± 3.7 vs. Δ12.5 ± 2.9 μm, not significant). Contractile dose responses to ET (10(-9), 10(-8), 10(-7) M) were enhanced by NOS inhibition and blunted by exogenous NO (10(-2) mM S-nitroso-N-acetyl-penicillamine) in losartan-treated but not in untreated vessels. Reducing blood pressure similar to losartan with hydralazine did not improve AA hypertrophy, ET-induced contractility, ET-induced NO release, and NO sensitivity. In conclusion, blockade of the local action of ANG II improved endothelial function in AAs, a mechanism that is likely to contribute to the beneficial effects of AT(1a)R antagonism during the recovery of renal function after long-term NOS inhibition in rats.

Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: The roles of nitric oxide and endogenous opioid peptides

The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated. Sham-operated and cirrhotic rats were treated with daily subcutaneous administrations of normal saline (1 ml/kg/day), L-NAME (a non-selective nitric oxide synthase inhibitor, 3mg/kg/day), and naltrexone (20mg/kg/day) during the fourth week after operation. In order to evaluate the effects of acute nitric oxide synthesis inhibition, additional groups of animals were treated by acute intraperitoneal L-NAME injections (3mg/kg). Arrhythmias were induced by intravenous injections of 10 microg/kg epinephrine. Despite QT prolongation (P<0.001), epinephrine induced fewer arrhythmias in cirrhotic rats compared to sham-operated animals (P<0.05). Chronic, but not acute, L-NAME administration corrected the QT prolongation in cirrhotic rats (P<0.001), and restored the susceptibility of cirrhotic rats to arrhythmias (P<0.05). Naltrexone injection without a significant effect on epinephrine-induced arrhythmias corrected QT interval in cirrhotic rats (P<0.001). This study shows that despite QT prolongation, cirrhotic animals are resistant against epinephrine-induced arrhythmias. This resistance is mediated by chronic nitric oxide overproduction.

Role of Nitric Oxide in the Renal Hemodynamic Response to Unilateral Nephrectomy

Reduction of renal mass by unilateral nephrectomy results in an immediate increase in renal blood flow (RBF) to the remnant kidney, followed by compensatory renal hypertrophy. Whether the increase in RBF after unilateral nephrectomy is mediated by nitric oxide (NO) was tested. It was found that immediately after nephrectomy, blood flow to the remaining kidney increased by 8% (P < 0.01), and inhibition of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) blocked the increase in RBF. In addition, 2 d after nephrectomy, there was a 49% increase in RBF (corrected per gram of kidney weight), a 25% increase at 7 and 14 d, and a 16% increase after 28 d. Acute inhibition of NO synthesis with L-NAME in uninephrectomized rats caused a greater decrease in RBF on days 2 and 7 compared with controls, whereas by 14 and 28 d, the response to L-NAME was similar to controls. Urinary excretion of cyclic guanosine monophosphate, a marker for renal NO production, increased 2.5-fold by 2 d after uninephrectomy (P < 0.005) and remained at this level through 28 d. Pretreating rats chronically with a subpressor dose of L-NAME beginning 2 d before nephrectomy blocked the increase in RBF seen at 2 and 7 d and retarded the renal hypertrophy that should have developed by 7 d. It is concluded that after unilateral nephrectomy, immediate and sustained increases in RBF are mediated at least in part by NO. The hypertrophic response to unilateral nephrectomy may be partially initiated by the signal of hemodynamic changes.

Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs.

To test whether the acute reduction of nitric oxide (NO) synthesis causes changes in cardiac substrate metabolism and in the activity of key enzymes of fatty acid and glucose oxidation, we blocked NOS by giving N(omega)-nitro-L-arginine methyl ester (L-NAME; 35 mg/kg iv two times) to nine chronically instrumented dogs. [3H]oleate, [14C]glucose, and [13C]lactate were infused to measure the rate of cardiac substrate uptake and oxidation. Glyceraldehyde-3-phosphate dehydrogenase, acetyl-CoA carboxylase, and malonyl-CoA decarboxylase activities were measured in myocardial biopsies. In eight control dogs, ANG II was infused (20-40 ng x kg(-1) x min(-1)) to mimic the hemodynamic effects of L-NAME. After L-NAME, significant changes occurred for fatty acid oxidation (from 9.8 +/- 0.8 to 7.1 +/- 1.2 micromol/min), glucose uptake (from 12.9 +/- 5.5 to 45.0 +/- 14.2 micromol/min), and oxidation (from 4.4 +/- 1.2 to 19.9 +/- 2.3 micromol/min). ANG caused only a significantly lower increase in glucose oxidation. Lactate uptake increased by more than twofold in both groups. The enzyme activities did not differ significantly between the two groups. In conclusion, the acute inhibition of NO synthesis causes marked metabolic alterations that do not involve key rate-controlling enzymes of fatty acid oxidation nor glyceraldehyde-3-phosphate dehydrogenase.

Nitric oxide-dependent vasodilation and the regulation of arterial blood pressure.

Conflicting evidence has been reported on the hypothesis that vascular nitric oxide (NO) release is modulated by autonomic influences. Another controversial question is whether an insufficient degree of NO-dependent vasodilation may play a contributory role in the genesis of arterial hypertension. To address these questions we evaluated NO-dependent vasodilation in conscious rats subjected to various experimental manipulations that interfere with autonomic function: chronic chemical sympathectomy (CCSx), acute ganglionic blockade (AGx) and chronic sinoaortic denervation (CSAD). Experiments were also carried out on 6- and 12-week-old spontaneously hypertensive rats (SHR) (i.e. during the pre-hypertensive and the early established hypertensive stage) and in age-matched Wistar-Kyoto (WKY) rats. Nitric oxide-dependent vasodilation was quantified from the extent of blood pressure (BP) elevation in response to acute inhibition of NO synthesis by L-nitromonomethyl-L-arginine (L-NMMA). Chronic chemical sympathectomy was produced by repeated 6-hydroxydopamine injections; AGx was induced by hexamethonium infusion; and CSAD was obtained by aortic nerve section and carotid sinus wall stripping. Nitric oxide synthesis inhibition by L-NMMA was followed by a marked BP elevation in all groups. Rats with CCSx, Agx or CSAD never showed reduced BP responses to L-NMMA compared to intact, control rats. Neither 6- nor 12-week-old SHR had attenuated pressor responses to L-NMMA compared to age-matched WKY rats. In conclusion, the data indicate that (i) in unanaesthetized quietly-behaving rats there is no significant modulation of NO release by autonomic influences and (ii) young SHR have unimpaired NO-dependent vasodilation so it is unlikely that a deficit of vascular NO release plays any etiologic role in the BP elevation of this experimental model.

Effects of Ca(2+) channel activity on renal hemodynamics during acute attenuation of NO synthesis in the rat.

In cultured vascular muscle cells, nitric oxide (NO) has been shown to inhibit voltage-dependent Ca(2+) channels, which are involved in renal blood flow (RBF) autoregulation. Therefore, our purpose was to specify in vivo the effects of this interaction on RBF autoregulation. To do so, hemodynamics were investigated in anesthetized rats during Ca(2+) channel blockade before or after acute NO synthesis inhibition. Rats were treated intravenously with vehicle (n = 10), 0.3 mg/kg body wt N(G)-nitro-L-arginine-methyl ester (L-NAME; n = 7), 4.5 microg. kg body wt(-1). min(-1) nifedipine (n = 8) alone, or with nifedipine infused before (n = 8), after (n = 8), or coadministered with L-NAME (n = 10). Baseline renal vascular resistance (RVR) averaged 14.0 +/- 1.2 resistance units and did not change after vehicle. RVR increased or decreased significantly by 27 and 29% after L-NAME or nifedipine, respectively. Nifedipine reversed, but did not prevent, RVR increase after or coadministered with L-NAME. RBF autoregulation was maintained after L-NAME, but the autoregulatory pressure limit (P(A)) was significantly lowered by 15 mmHg. Nifedipine pretreatment or coadministration with L-NAME limited P(A) resetting or suppressed autoregulation at higher doses. Results were similar with verapamil. Intrarenal blockade of Ca(2+)-activated K(+) channels also prevented autoregulatory resetting by L-NAME (n = 8). These findings suggest NO inhibits voltage-dependent Ca(2+) channels and thereby modulates RBF autoregulatory efficiency.

The role of heart rate in the modulation of the decreased cardiac output induced by acute nitric oxide synthesis inhibition in anaesthetized dogs.

1. The role of the heart rate modulating the decrease in cardiac output induced by the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was investigated in anaesthetized dogs. This was achieved in dogs in which a positive pacemaker (PM) cable was located at the right ventricle. 2. The haemodynamic events were evaluated: mean arterial blood pressure (MABP), systemic vascular resistance index (SVRI), stroke volume index (SVI), heart rate (HR) and cardiac index (CI). 3. The infusion of L-NAME (0.01-10 mg kg(-1)) in the animals with the PM off caused a dose-dependent rise in MABP and SVRI, accompanied by significant decreases of HR and SVI. A resulting decrease in CI was observed at all doses of L-NAME used. 4. In the animals with the PM on, HR was maintained stable. Under this condition, the increase in MABP and SVRI as well as the decrease in SVI induced by the L-NAME infusion did not significantly differ from the PM-off animals. However, the resulting decreased CI was markedly attenuated compared to PM-off animals but significant decreases in CI were still observed at higher doses of L-NAME. 5. The results suggest that HR plays an important role in the L-NAME-mediated decreased cardiac output but other factors might also be involved.

Effect of Acute Nitric Oxide Synthesis Inhibition on Kidney Function in Experimental Renovascular Hypertension 1796

Nitric oxide plays an important role in regulating renal hemodynamics. We compared the responses of anesthetized two kidney, one clip renovascular hypertensive rats to acute mean arterial pressure [MAP] elevations caused by either the nitric oxide synthesis inhibitor L-NAME 8 mg/kg IV (n = 8) or by infrarenal aortic constriction [CONST] (n = 6). Results are mean ± SE and *P < 0.05 vs pretreatment measurements. Pretreatment MAP was 125± 2 mmHg, rising to 149 ± 4* mmHg after L-NAME and to 146± 2* mmHg after CONST. L-NAME reduced plasma concentrations of the nitric oxide metabolites, nitrite/nitrate (28 ± 1 vs 19 ± 3* umol/L) while CONST had no significant effect on these levels (28 ± 1 vs 29 ± 2 umol/L). In unclipped kidneys, L-NAME did not significantly alter glomerular filtration rate (1.2 ± 0.2 vs 1.0± 0.2 ml/min per g kidney wt), decreased renal plasma flow (2.6± 0.1 vs 1.6 ± 0.3* ml/min per g kidney wt), increased urine flow (12 ± 3 vs 47 ± 12* ul/min per g kidney wt), and did not significantly affect urine nitrite/nitrate excretion (2.5 ± 0.3 vs 3.0± 0.5 nmol/min per g kidney wt); while CONST did not significantly alter either glomerular filtration rate (0.9 ± 0.1 vs 0.9 ± 0.1 ml/min per g kidney wt) or renal plasma flow (2.9 ± 0.1 vs 2.8 ± 0.3 ml/min per g kidney wt) and increased both urine flow (10 ± 3 vs 39± 9* ul/min per g kidney wt) and urine nitrite/nitrate excretion (2.1± 0.2 vs 4.3 ± 0.4* nmol/min per g kidney wt). Inclipped kidneys, both L-NAME and CONST did not significantly affect glomerular filtration rate (L-NAME 0.8 ± 0.1 vs 1.0 ± 0.2 ml/min per g kidney wt; CONST 0.8 ± 0.1 vs 0.9 ± 0.1 ml/min per g kidney wt) and increased renal plasma flow (L-NAME 1.9 ± 0.3 vs 2.5± 0.3* ml/min per g kidney wt; CONST 2.2 ± 0.3 vs 2.7 ± 0.2* ml/min per g kidney wt), urine flow (L-NAME 8 ± 3 vs 38 ± 11* ul/min per g kidney wt; CONST 7 ± 3 vs 31 ± 7* ul/min per g kidney wt) and urine nitrite/nitrate excretion (L-NAME 1.8 ± 0.3 vs 3.2± 0.5* nmol/min per g kidney wt; CONST 1.4 ± 0.2 vs 2.9 ± 0.3* nmol/min per g kidney wt). Our results suggest that the influence of nitric oxide on kidney function varies with renal perfusion pressure and that plasma and urine nitrite/nitrate measurements can be used as indices of nitric oxide activity in vivo.

Role of AT1 receptors in the renal papillary effects of acute and chronic nitric oxide inhibition.

Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1 angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1 receptor blocker losartan did not modify the decreases in RBF or PBF secondary to L-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.

Renal nerves do not mediate vasoconstrictor responses to acute nitric oxide synthesis inhibition in conscious rats.

Nitric oxide is a physiologically important peripheral and renal vasodilator. The studies presented here were conducted in the conscious, chronically catheterized, unstressed rat to investigate whether NO interacts with renal efferent sympathetic nerve activity in control of blood pressure, renal vascular resistance, and sodium excretion. Renal clearance studies were conducted in normal rats with innervated kidneys and in a separate group of rats with chronic, bilateral renal denervation. Acute systemic inhibition of NO synthesis with n-nitro L-arginine methyl ester (L-NAME) leads to hypertension, renal vasoconstriction, and natriuresis in rats with intact renal nerves. Chronic renal denervation does not diminish the pressor and renal vasoconstrictor response to NO synthesis inhibition, although the natriuretic response is prevented. Stimulation of renal NO synthesis with the substrate L-arginine produces selective renal vasodilation and a marked osmotic diuresis in the innervated kidney. Renal denervation has little impact on the responses to L-arginine. These studies suggest that in the normal, conscious, chronically catheterized rat in which the sympathetic nervous system is operating at basal levels, renal nerve activity does not contribute to the pressor or renal vasoconstrictor response to NO inhibition or the renal vasodilator response to NO stimulation. These observations contrast with earlier observations made under conditions of stress-induced activation of renal nerve activity.

Acute inhibition of nitric oxide synthesis induces anxiolysis in the plus maze test

The involvement of nitric oxide (NO) in anxiety was investigated in rats, using the elevated plus maze test. Acute, but not chronic, systemic treatment with N ω-nitro- l-arginine methyl ester ( l-NAME, 10 and 60 mg·kg −1), an inhibitor of NO synthase, increased the time spent by the rats in the open arms. Both the acute and chronic treatments with l-NAME inhibited NO synthase in endothelial cells and in the central nervous system, as shown by the increase in mean arterial pressure and decreased NO synthase activity in brain tissue. Chronic treatment with l-NAME also decreased the serum nitrate levels. The anxiolysis induced by acute l-NAME treatment is unlikely to be due to hypertension, since two-kidney one-clip hypertension in non- l-NAME-treated rats failed to significantly change exploratory behaviour in the elevated plus maze. These results indicate that acute inhibition of NO synthesis decreases anxiety in rats. © 1997 Elsevier Science B.V. All rights reserved.

Dissociation between the increase in systemic vascular resistance induced by acute nitric oxide synthesis inhibition and the decrease in cardiac output in anesthetized dogs.

The decrease in cardiac output (CO) that follows nitric oxide (NO) synthesis inhibition is thought to be the result of an increase in systemic vascular resistance (SVR). We investigated whether sodium nitroprusside (SNP) and iloprost prevent the decrease in CO induced by short-term administration of N omega-nitro-L-arginine methyl ester (L-NAME) in anesthetized dogs. The left femoral artery and vein were cannulated for mean arterial blood pressure (MABP) measurement and drug administration, respectively. A Swan-Ganz thermodilution catheter was inserted into the right femoral vein and allowed the determination of CO and the calculation of SVR, expressed as the cardiac index (CI) and the index of systemic vascular resistance (ISVR), respectively. L-NAME (0.01-10.0 mg/kg; n = 13) induced dose-dependent increases in MABP and in the ISVR. These changes were accompanied by significant decreases in both the CI and the heart rate. SNP (1 microgram/kg/min; n = 6) virtually abolished L-NAME-induced hypertension and significantly attenuated both the increase in the ISVR (< 3.0 mg/kg) and the decrease in CO. Iloprost (50 ng/kg/min; n = 6) also abolished L-NAME-induced hypertension and markedly attenuated the increase in SVR. However, the decrease in CO was not prevented by this vasodilator. These results clearly demonstrate that the increase in SVR is not the major factor accounting for the decrease in CO after short-term NO synthesis inhibition in anesthetized dogs.

Relationship between sympathetic nervous system activity, baroreflex and cardiovascular effects after acute nitric oxide synthesis inhibition in humans

To examine the cardiovascular effects of acute systemic nitric oxide synthesis inhibition in humans in relation to the possible involvement of changes in sympathetic nervous system activity or in the baroreceptor reflex. Placebo or NG-monomethyl-L-arginine (250 mg by intravenous infusion for 5 min) was administered to seven healthy male volunteers according to a random, double-blind sequence. Blood pressure and heart rate were measured non-invasively using a Finapres device from 20 min before to 80 min after starting infusion; beat-to-beat variability of blood pressure, pulse interval and systolic blood pressure and pulse interval covariation were assessed by means of spectral and sequence analysis methods. Under basal conditions and 15 min and 60 min after infusion, we measured stroke volume and indices of cardiac systolic and diastolic function by echocardiography, forearm blood flow by strain-gauge venous occlusion plethysmography, and plasma catecholamine levels. Compared with placebo, administration of NG-monomethyl-L-arginine caused a transient increase in blood pressure and reduction in heart rate. Stroke volume and indices of cardiac function did not change significantly, whereas cardiac index and forearm blood flow were significantly reduced after 15 min. Spectral analysis of blood pressure and pulse interval showed a significant reduction of power spectral density in the low frequencies (0.03-0.15 Hz) that persisted 60 min after infusion. The plasma noradrenaline level was significantly reduced after 15 min. No change in baroreflex engagement or sensitivity was detected by the cross-spectral or the sequence method. Acute systemic nitric oxide synthesis inhibition transiently increases blood pressure and reduces heart rate and cardiac index. The acute hypertensive response to NG-monomethyl-L-arginine is dependent neither on sympathetic nervous system activity, which is probably reduced as a consequence of baroreceptor reflex activation, nor on baroreceptor reflex sensitivity, which is not impaired.

C22 - Cardiovascular effects of acute nitric oxide synthesis inhibition in man

C22 - Cardiovascular effects of acute nitric oxide synthesis inhibition in man

Consequences of acute nitric oxide synthesis inhibition in experimental glomerulonephritis.

To assess the functional relevance of the enhanced glomerular nitric oxide (NO) synthesis during acute nephrotoxic serum (NTS) nephritis, a NO synthesis inhibitor (NOI) NG-monomethyl-L-arginine was administered to normal (N + NOI) and acutely nephritic (NTS + NOI) Munich-Wistar rats, and systemic and glomerular hemodynamic responses were contrasted with those observed in vehicle-treated normal and nephritic (NTS) controls. Urinary protein excretion rates were equal in normal and N + NOI rats but were markedly elevated in NTS animals and further increased in NTS+NOI. NO inhibition in normal animals (normal versus N + NOI) led to reductions in glomerular plasma flow rate and the glomerular capillary ultrafiltration coefficient (Kf) and elevations in afferent and efferent arteriolar resistances and net transcapillary hydraulic pressure difference (delta P), as well as an increase in systemic arterial pressure. The increase in delta P offset the falls in glomerular plasma flow rate and Kf, and GFR was preserved. Directionally similar responses in efferent resistance occurred in NTS + NOI compared with NTS, however, afferent resistance was not further affected by NOI. Additionally, although Kf was severely depressed in the NTS group (approximately 60% versus normal), it was not further depressed by NOI treatment. Polymorphonuclear cell (PMN) infiltration/glomerulus was mildly increased in N + NOI over normal. In contrast, PMN number in NTS + NOI rats was diminished as compared with NTS.(ABSTRACT TRUNCATED AT 250 WORDS)