cyclic-gmp and Glomerulonephritis

Nitric oxide (NO) produced by endothelial NO synthase (NOS) in low concentrations is a unique messenger molecule with key homeostatic functions concerning the prevention of pathological vascular and tissue changes such as increases in blood pressure, platelet degranulation, mononuclear cell infiltration, cell proliferation and extracellular matrix protein accumulation. This is in contrast to high levels of NO derived from inducible NOS which act as detrimental effector molecules and free radicals in immune response. Deficiency in NO's protective signaling actions is a major characteristic in numerous experimental and human disease situations. The main function of the NO signaling pathway is activation of the soluble guanylate cyclase (sGC) enzyme with subsequent generation of cyclic guanosine monophosphate (cGMP) as a second messenger and downstream mediator. In the past, attempts to overcome deficiency in endothelial NO effects were focused primarily on increasing the supply with the NO precursor L-arginine or on the use of directly NO-releasing compounds. The clinical impact of these strategies, however, was rather limited. Recent state-of-the-art studies have revealed that NO signaling is highly regulated at the transcriptional level and that deficiency in NO signaling correlates closely with pathological changes. In parallel efforts, novel pharmacological compounds which specifically enhance NO/cGMP signaling have been developed and have demonstrated remarkable efficacy in experimental disease settings. In this review, we summarize the current state of knowledge on the impairment of NO/cGMP signaling and about its pharmacological stimulation. In the first part, experimental renal fibrosis, i.e. the tandem rat model of acute anti-thy1 glomerulonephritis and progressive anti-thy1 renal fibrosis will serve as a paradigm for introducing this new and exciting field. In the second part, we will address the most recent findings on NO signaling in non-renal diseases. Together, these results point out that deficiency in NO/cGMP is a common key pathway as well as a novel therapeutic target in a number of diseases.

Topics: Animals; Atherosclerosis; Cyclic GMP; Fibrosis; Glomerulonephritis; Heart Failure; Humans; Hypertension, Pulmonary; Kidney; Kidney Diseases; Liver Cirrhosis; Nitric Oxide; Nitric Oxide Synthase Type III; Signal Transduction; Thrombosis

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Cyclic GMP; Dopamine; Glomerular Filtration Rate; Glomerulonephritis; Heart Rate; Humans; Hypertension; Kidney; Middle Aged; Proteinuria; Urination

Matrix expansion and mesangial proliferation are hallmarks of mesangial proliferative glomerulonephritis. Specific inhibition of PDE-5, an enzyme catalyzing the intracellular degradation of cyclic GMP, can be achieved by the inhibitor vardenafil. In this study, we investigated the effects of PDE-5 inhibition in the anti-Thy1 model in the rat in vivo.. After disease induction, rats received 10 mg/kg bw vardenafil twice a day via gavage. On Days 2 and 6, renal biopsies, as well as glomerular isolates, urine and blood samples were taken to compare vardenafil- and placebo-treated groups during the course of disease.. Small amounts of PDE-5 were detected in healthy kidneys, but induced in a typical mesangial pattern during disease (by IHC and WB). Specific PDE-5 inhibition resulted in increased glomerular levels of cGMP. Treated animals demonstrated inhibition of MC proliferation and matrix accumulation while renal function and influx of inflammatory cells were not affected. Due to PDE-5 inhibition, the endogenous TGF-beta-activating protein TSP-1 and the TGF-beta-signalling protein p-smad-2/3 were decreased suggesting this as an antifibrotic mechanism of action of vardenafil in this model.. Considering the availability and safety profile of vardenafil, the beneficial antiproliferative and antifibrotic effect in experimental glomerulonephritis may potentially be applicable to the treatment of mesangial proliferative glomerulonephritis in man.

Topics: Animals; Antibodies, Monoclonal; Biopsy; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Extracellular Matrix; Glomerulonephritis; Imidazoles; Mesangial Cells; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Smad2 Protein; Smad3 Protein; Sulfones; Thrombospondin 1; Thy-1 Antigens; Transforming Growth Factor beta; Triazines; Vardenafil Dihydrochloride

cGMP serves as the main second messenger of nitric oxide (NO). Antifibrotic effects of enhancing renal cGMP levels have recently been documented in experimental acute anti-Thy-1 glomerulonephritis. The present study compares the effects of the cGMP production-increasing soluble guanylate cyclase (sGC) stimulator BAY 41-2272 with those of the cGMP degradation-limiting phosphodiesterase inhibitor pentoxifylline (PTX) in a progressive model of renal fibrosis. At 1 wk after induction of anti-Thy-1-induced chronic glomerulosclerosis (cGS), rats were randomly assigned to groups as follows: cGS, cGS + BAY 41-2272 (10 mg x kg body wt(-1) x day(-1)), or cGS + PTX (50 mg x kg body wt(-1) x day(-1)). BAY 41-2272 and PTX reduced systolic blood pressure significantly. At 16 wk, tubulointerstitial expressions of sGC mRNA and NO-induced cGMP synthesis were increased in untreated cGS animals, whereas their glomerular activity was depressed compared with normal controls. Tubulointerstitial and glomerular cGMP production in response to NO were significantly enhanced in animals treated with BAY 41-2272, but not in those treated with PTX. BAY 41-2272 administration resulted in marked reductions of glomerular and tubulointerstitial histological matrix accumulation, expression of TGF-beta1 and fibronectin, macrophage infiltration, and cell proliferation as well as improved renal function. In contrast, only moderate and nonsignificant renoprotective changes were observed in the cGS + PTX group. In conclusion, increasing renal cGMP production through BAY 41-2272 significantly improved renal NO-cGMP signaling and limited progression in anti-Thy-1-induced chronic renal fibrosis, whereas inhibition of cGMP degradation by PTX was only moderately effective. The findings indicate that pharmacological enhancement of renal cGMP levels by sGC stimulation represents a novel and effective antifibrotic approach in progressive kidney disorders.

Topics: Animals; Blood Pressure; Body Weight; Cell Proliferation; Cyclic GMP; Drinking; Fibrosis; Glomerulonephritis; Guanylate Cyclase; Kidney; Macrophages; Male; Nitric Oxide; Pentoxifylline; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Proteinuria; Pyrazoles; Pyridines; Rats; Rats, Wistar

Activation of soluble guanylate cyclase and generation of cyclic 3',5'-guanosine monophosphate (cGMP) is the main signal transducing event of the L-arginine-nitric oxide pathway. The present study analyzes the expression and activity of the nitric oxide-cGMP signaling cascade in and the effect of the specific soluble guanylate cyclase stimulator Bay 41-2272 on the early injury and subsequent repair phase of acute anti-thy1 glomerulonephritis.. Anti-thy1 glomerulonephritis was induced by OX-7 antibody injection in rats. In protocol 1 (injury), Bay 41-2272 was given starting 6 days before antibody injection. One day after disease induction, parameters of mesangial cell injury (glomerular cell number and inducible nitric oxide synthesis) were analyzed. In protocol 2 (repair), Bay 41-2272 treatment was started one day after antibody injection. On day 7, parameters of glomerular repair [glomerular matrix score, expression of transforming growth factor (TGF)-beta1, fibronectin, and plasminogen-activator-inhibitor (PAI)-1, infiltration with macrophages and fibrinogen deposition (indicating platelet localization)] were determined. In both protocols, tail bleeding time, systolic blood pressure, plasma cGMP levels, glomerular mRNA expression of endothelial nitric oxide synthase (eNOS), alpha1 and beta1 soluble guanylate cyclase, and basal and nitric oxide-stimulated glomerular cGMP production were analyzed.. Bay 41-2272 prolonged bleeding time, reduced blood pressure, and increased plasma cGMP levels in both protocols. In the injury experiment, disease induction increased inducible nitric oxide synthesis and reduced glomerular cell number, while expression and activity of soluble guanylate cyclase was almost completely diminished. Bay 41-2272 did not affect parameters of mesangial cell injury and glomerular soluble guanylate cyclase expression and activity. In the repair protocol, expression and activity of soluble guanylate cyclase was markedly increased by disease. Bay 41-2272 further enhanced soluble guanylate cyclase expression and activity. This went along with significant reductions in proteinuria, glomerular matrix accumulation, expression of TGF-beta1, fibronectin, and PAI-1, macrophage infiltration and fibrinogen deposition as compared to the untreated anti-thy1 animals.. Glomerular nitric oxide signaling via cGMP is markedly impaired during injury of anti-thy1 glomerulonephritis, while it is highly up-regulated during subsequent repair. Further pharmacologic soluble guanylate cyclase stimulation limits glomerular TGF-beta overexpression and matrix expansion, suggesting that the soluble guanylate cyclase enzyme represents an important antifibrotic pathway in glomerular disease.

Topics: Animals; Bleeding Time; Blood Pressure; Body Weight; Cyclic GMP; Glomerulonephritis; Guanylate Cyclase; In Vitro Techniques; Isoantibodies; Kidney Glomerulus; Macrophages; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Soluble Guanylyl Cyclase; Transforming Growth Factor beta; Transforming Growth Factor beta1

Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease.. Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control.. Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy.. Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Cyclic GMP; Disease Progression; Drug Combinations; Endothelin-1; Glomerulonephritis; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Systole

Changes in the expression of alternate arginine metabolic pathways have been implicated in the pathogenesis of experimental glomerulonephritis. Agmatine, decarboxylated arginine, has been shown in vitro to suppress both inducible nitric oxide synthase and the rate-limiting enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC). This study was undertaken to determine whether agmatine administration could reduce tissue injury by decreasing nitric oxide, and reduce cell proliferation, by diminishing ODC activity, in experimental mesangial proliferative glomerulonephritis (Thy-1 nephritis). Agmatine treatment (50 mg/kg per d intraperitoneally) in Thy-1 nephritis rats prevented a reduction in GFR at day 1. Agmatine treatment decreased nitric oxide production in Thy-1 nephritis rats by 23% and 41% at days 1 and 4, respectively. Agmatine treatment also reduced ODC activity and glomerular (3)H-thymidine incorporation on days 1, 4, and 7. Histologic evaluation revealed a decline in mesangial cell proliferation and extracellular matrix accumulation associated with agmatine treatment administered before or 24 h after Thy-1 antibody, and this was confirmed by a reduction in the number of cells expressing proliferating cell nuclear antigen on days 4 and 7. These studies provide the first in vivo evidence that agmatine administration can reduce cellular proliferation in Thy-1 nephritis and attenuate the initial reduction in renal function associated with this model.

Topics: Agmatine; Animals; Cell Division; Cyclic GMP; Glomerular Filtration Rate; Glomerulonephritis; Intracellular Membranes; Kidney; Kidney Glomerulus; Male; Nitrites; Ornithine Decarboxylase; Osmolar Concentration; Proteinuria; Rats; Rats, Sprague-Dawley; Thy-1 Antigens

To investigate effects of angiotensin I converting enzyme (ACE) inhibition in experimental nephritis during chronic inhibition of nitric oxide (NO) synthase.. Rats with and without autoimmune Heymann nephritis were treated with a NO synthase inhibitor L-NAME (50 mg/100 ml) and/or an ACE inhibitor captopril (20 mg/100 ml) in drinking water for 12 weeks. Urinary cGMP excretion was used as an indirect measure of NO activity. Blood pressure, urinary albumin, nitrite and nitrate levels, plasma ANP, and plasma renin activity were measured. Kidneys were examined with light microscopy and immunohistochemical methods.. Captopril treatment protected rats receiving L-NAME and none of the captopril-treated rats died. Mortality was greatest in the nephritis-L-NAME (57%) and L-NAME (43%) groups. Captopril normalized cGMP excretion, blood pressure, and prevented partly the appearance of albuminuria. Peritubular infiltration of mononuclear cells was clearly enhanced in the nephritis-L-NAME group (found in 80% of the rats) as compared with the nephritis (20%), L-NAME (40%), and control (0%) groups. The peritubular cell infiltration caused by L-NAME was prevented by captopril treatment. L-NAME-induced hypertension was associated with cardiac hypertrophy and this was prevented by captopril.. NO may play an important renoprotective role in disease progression of chronic membranous glomerulonephritis. Captopril prevents L-NAME-induced hypertension, improves survival, and ameliorates renal damage in this type of nephritis. Dysfunction of renal NO pathways may be an important factor causing progressive renal damage in chronic nephritis. Our results suggest that the dysfunctional renal NO system may be beneficially activated by ACE inhibitors.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Hypertension, Renal; Kidney Tubules; Myocardium; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Organ Size; Rats; Rats, Wistar; Renin

Nephrotic syndrome is associated with resistance to the renal actions of atrial natriuretic peptide (ANP). We performed experiments in anesthetized, acutely nephrectomized rats 21-28 days after injection of adriamycin (7-8 mg/kg i.v.) or 9-14 days after injection of anti-Fx1A antiserum (5 ml/kg i.p.) (passive Heymann nephritis; PHN) to test whether extrarenal resistance also occurred. Proteinuria was significantly elevated in both models compared with controls before study. ANP infusion (1 microgram.kg-1.min-1) caused arterial pressure to decrease similarly in control rats, adriamycin-treated rats, and rats with PHN (by 8.2 +/- 1.0, 9.4 +/- 2.3, and 9.0 +/- 2.0%, respectively; all P < 0.05 vs. both baseline and vehicle-infused control rats). In control rats, hematocrit increased progressively to a maximal value 9.5 +/- 0.9% over baseline as a result of the infusion, an increase corresponding to a reduction in plasma volume of 16.1 +/- 0.9%. The ANP-induced increase in hematocrit was preserved in adriamycin-treated rats (9.2 +/- 1.3%) but was markedly blunted in rats with PHN (2.4 +/- 1.3%; P < 0.0001 vs. ANP infusion in control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate was significantly lower in rats with PHN compared with both control and adriamycin-treated rats. Infusion of a subpressor dose of angiotensin II (ANG II, 2.5 ng.kg-1.min-1) fully restored the ANP-induced increase in hematocrit in rats with PHN. This study demonstrates that 1) the hemoconcentrating and hypotensive actions of ANP are preserved in adriamycin-treated rats, 2) the effect of ANP on hematocrit and fluid distribution is blunted in rats with PHN while its hypotensive action is preserved, and 3) low-level ANG II infusion normalizes the hemoconcentrating effect of exogenously infused ANP in rats with PHN. Thus deficient ANG II generation in rats with PHN, but not adriamycin nephrosis, may contribute to extrarenal ANP resistance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Proteins; Blood Volume; Cyclic GMP; Doxorubicin; Glomerulonephritis; Hematocrit; Hemodynamics; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

It has been suggested that renal disease is characterized by the presence of resistance to the natriuretic effects of atrial peptide (ANP). In this study, plasma ANP (pANP) and renal function were evaluated during stepwise infusion of low ANP doses (2, 4, 8, and 16 ng/kg per min) in glomerulonephritic patients with (CRF) or without (GN) moderate renal failure, and in normal subjects (NOR), kept at low-sodium diet (LSD; 35 mEq NaCl/day). To assess the physiological ANP levels, pANP was also measured in the three groups after normal-sodium diet (NSD; 235 mEq NaCl/day). ANP did not affect systemic and renal perfusion at any of the doses tested; a significant increment of GFR was observed only in NOR and GN. The 2-, 4-, and 8-ng/kg doses increased pANP to values overlapping the physiological concentrations measured at NSD; this was associated with a dose-dependent increment of urinary excretion of sodium (UNaV) that reached analogous levels in the three groups. ANP accounted for approximately 40% of the UNaV increment evoked by NSD in patients and in normal subjects. The 16-ng/kg dose led to supraphysiological levels that induced a similar marked enhancement of UNaV (from the basal value of 0.12 +/- 0.02 to 0.42 +/- 0.08 mEq/min in CRF, from 0.13 +/- 0.02 to 0.73 +/- 0.08 in GN, and from 0.09 +/- 0.02 to 0.49 +/- 0.11 in NOR). In CRF, the normal natriuretic response to the highest dose was caused by a larger increase of fractional UNaV that was strictly dependent on the greater pANP increment, as demonstrated by similar changes in the fractional excretion of cGMP, and, in part, on the greater aldosterone decrease. In all groups, ANP also induced a dose-dependent urinary loss of phosphate, potassium, and urea, resulting in a significant 15 to 25% decrease in the plasma levels. Thus, in GN and CRF patients, ANP plays a significant role in the renal handling of sodium; moreover, the achievement of low supraphysiological pANP levels leads to a conspicuous natriuresis associated with unique extranatriuretic effects.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Diet, Sodium-Restricted; Diuresis; Dose-Response Relationship, Drug; Glomerulonephritis; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Natriuresis; Reference Values; Renal Circulation

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min). Thirty min after the onset of the infusion, plasma ANP concentration was increased to the same extent in both normal and nephritic rats, compared with their respective hydropenic controls. Despite this increase, UcGMPV was significantly less in nephritic rats after the saline infusion. Accumulation of cGMP by isolated glomeruil and IMCD cells from nephritic rats after incubation with ANP and RNP was also significantly reduced, compared with normal rats. This difference was not related to differences in either density or affinity of renal ANP receptors, but was abolished when accumulation of cGMP was measured in the presence of 10(-3) M isobutylmethylxanthine or Zaprinast, two different inhibitors of cyclic nucleotide phosphodiesterases (PDE). Infusion of Zaprinast into one renal artery in nephritic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. Furthermore, cGMP-PDE activity was increased in IMCD cell homogenates from nephritic compared with normal rats (388 +/- 32 versus 198 +/- 93 pmol/min per mg protein, P < 0.03). These results indicate that blunted volume expansion natriuresis accompanied by cellular resistance to ANP in vitro occurs in an immunologic model of renal injury. The resistance is not related to an alteration in ANP release or binding to its renal receptors, but is suppressed by PDE inhibitors and is associated with increased renal cGMP. PDE activity, thus suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium

Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Glomerular Filtration Rate; Glomerulonephritis; In Vitro Techniques; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Natriuresis; Peptide Fragments; Phosphodiesterase Inhibitors; Purinones; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

Hypotension is frequently encountered during hemodialysis (HD). One of the main factors of the HD-induced hypotension is acute reduction of circulating plasma volume by water removal, which is induced by the poor plasma refilling from the extravascular space into vessels. The determinants of plasma refilling, however, have not been clearly identified. Recently, we devised a mathematical model of water transport in HD patients, which can estimate the plasma-refilling coefficient (Kr) during HD. In the present study, we evaluated the factors determining plasma refilling by using this model. In 13 patients undergoing regular HD, the changes of Kr during HD were calculated from the model. Levels of ANP, cGMP, cAMP, endothelin, angiotensin II and vasopressin were measured before and after HD. Kr fell from 750.4 +/- 558.0 to 112.8 +/- 81.9 ml/mm Hg/h during HD. The rate of water removal during HD showed no significant correlation with the changes of Kr. Among the hormones and nucleotides measured here, plasma ANP level and cGMP were significantly correlated with Kr (r = 0.78, p < 001 and r = 0.62, p < 0.01, respectively). Our findings suggest that severe reduction in the level of serum ANP during HD, which is induced by water removal, plays some role in HD-induced hypotension through the attenuation of plasma refilling in HD patients.

Topics: Adult; Aged; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Blood Vessels; Cyclic AMP; Cyclic GMP; Endothelins; Female; Fluid Shifts; Glomerulonephritis; Hematocrit; Hemodynamics; Humans; Male; Middle Aged; Nephrosclerosis; Plasma; Polycystic Kidney Diseases; Renal Dialysis; Vasopressins; Water

Effects of nitric oxide (NO) synthase inhibition on blood pressure and on the course of Heymann nephritis was examined in rats. L-NG-nitroarginine-methylester (L-NAME, 10 mg/100 ml in the drinking water for 12 weeks) was used as an inhibitor of NO synthase. Urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of NO, was used as an indirect estimate of NO activity. Rats were divided into the following groups: control, nephritis, L-NAME, and nephritis-L-NAME. Urinary cGMP excretion was lower in the nephritis group (p < 0.05) and in the nephritis-L-NAME group (p < 0.005) compared with controls. Plasma atrial natriuretic peptide (ANP) levels were elevated in the nephritis (p < 0.001) and in the nephritis-L-NAME groups (p < 0.05. L-NAME treatment alone did not have any effect on plasma ANP levels. Blood pressure rose progressively in all L-NAME-treated rats. Most marked albuminuria developed in the nephritis-L-NAME group. No differences in the immunohistological findings were observed between the nephritis and the nephritis-L-NAME groups. NO synthase inhibition causes hypertension and aggravates albuminuria in chronic nephritis. Moreover, nephritis itself may decrease then production of cGMP either as a consequence of blunted NO activity or, in addition, because of ANP resistance. It appears that NO synthase inhibition does not change the immunological course of Heymann nephritis but rather the increased hemodynamic load makes the course of nephritis worse.

Topics: Albuminuria; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Blood Pressure; Complement C3; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Immunoglobulin G; Immunohistochemistry; Kidney Glomerulus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Renin; Time Factors

The vasoconstrictor peptide endothelin-1 (ET1) has only recently been characterized and its effects are at present largely speculative. It has been hypothesized that ET1 acts on mesangial cells to cause vasoactive changes which might ultimately contribute to the development of glomerulosclerosis. Opposite to ET1, nitric oxide (NO) inhibits mesangial cell contraction and proliferation. NO activates soluble guanylic acid cyclase and the final product, cyclic GMP (cGMP), has been recently used as a marker of NO action. Urinary levels of ET1 and cGMP were detected in 58 patients with biopsy-proven glomerulonephritis (GN), including 36 IgA nephropathy (IgAGN), 30 with normal and 6 with impaired renal function, 10 patients with non-IgA mesangial GN and 12 pts with membranous GN (MGN) with normal renal function. Compared to normal controls (0.019 +/- 0.006 ng/min), urine ET1 levels were significantly higher in patients with normal renal function having IgAGN (0.035 +/- 0.017, p < 0.01), MGN (0.028 +/- 0.013, p < 0.05), non-IgA mesangial GN (0.027 +/- 0.012, p < 0.05) and those with IgAGN and renal failure (0.032 +/- 0.011, p < 0.01). However no difference was found between MGN patients and normals by deleting MGN cases with mild to moderate mesangial proliferation. The mean value of urinary cGMP in IgAGN patients with renal failure (0.186 +/- 0.117 nmol/min) was lower (p < 0.05) than that of each group with normal renal function (IgAGN: 0.378 +/- 0.010 nM/min; MGN: 0.338 +/- 0.064 nmol/min, non-IgAGN: 0.436 +/- 0.168 nmol/min). The same significant differences were obtained by correcting cGMP values for creatinine urinary excretion. Urinary ET/cGMP ratio (assumed as an index of the relative balance between vasoconstrictor and vasorelaxing factors) was found to be higher than normal (0.570 +/- 0.010 ng/nmol) both in IgAGN patients with normal renal function (0.103 +/- 0.064 ng/mol, p < 0.05), and in those with renal failure (0.203 +/- 0.108 ng/nmol, p < 0.02). Urinary cGMP values were not related to plasma levels of atrial natriuretic peptide (ANP). These data show that hyperexcretion of ET1 occurs in a number of patients with mesangial proliferative GN. In some of them, mainly those with established glomerular damage, the local production of ET1 is not counter-balanced by adequate cGMP biosynthesis.

Topics: Adult; Cyclic GMP; Endothelins; Glomerular Filtration Rate; Glomerulonephritis; Humans; Kidney; Middle Aged; Radioimmunoassay

Blood volume, blood pressure, plasma concentrations of atrial natriuretic peptide (ANP), cyclic 3',5'-guanosine monophosphate (cGMP), angiotensin II, aldosterone, and arginine vasopressin (AVP), and urinary excretion rates of cGMP, sodium, and water were determined before and after infusion of human albumin 20%, 3.5 ml/kg body-weight to 12 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 1); and before and after frusemide injection, 0.75 mg/kg to 15 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 2). In Study 1 blood volume was expanded to the same degree in patients (8.8 and 7.5%, medians, after 90 and 180 min) and controls (8.6 and 6.1%). ANP was enhanced in the patients (5.9 to 11.0 pmol/l, P less than 0.01) and the controls (4.9 to 7.1 pmol/l, P less than 0.01), but the elevated level was protracted in the patients simultaneously with a delayed sodium excretion. Plasma cGMP increased, aldosterone decreased and AVP was unchanged in both groups, whereas angiotensin II decreased in the patients (P less than 0.01), but not in the controls. In Study 2 blood volume was reduced to a smaller extent in the patients than in the controls (8.9% versus 9.9%, P less than 0.05). ANP an cGMP decreased, and angiotensin II, aldosterone and AVP increased in both patients and controls. In conclusion, patients with glomerulonephritis respond to albumin- and frusemide induced changes in blood volume with essentially the same counter-regulatory changes in ANP, angiotensin II, aldosterone and AVP as do healthy subjects. The more protracted increase in ANP and the decrease in angiotensin II after albumin, and the smaller blood volume reduction after frusemide suggest an abnormal regulation of blood volume in glomerulonephritis.

Topics: Adult; Albumins; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Diuresis; Female; Furosemide; Glomerulonephritis; Humans; Male; Middle Aged; Natriuresis

Topics: Chronic Disease; Cyclic AMP; Cyclic GMP; Glomerulonephritis; Humans; Immunoglobulin G; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plant Extracts; Plants, Medicinal; Rosette Formation