Chronic Inhibition of Nitric Oxide Synthase in Heymann Nephritis

Abstract

Effects of nitric oxide (NO) synthase inhibition on blood pressure and on the course of Heymann nephritis was examined in rats. L-N^G-nitroarginine-methylester (L-NAME, 10 mg/l00 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 the 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.

Renoprotective Effects of Captopril in Hypertension Induced by Nitric Oxide Synthase Inhibition in Experimental Nephritis

“…In our previous studies with a low dose of L -NAME (10 mg/100 ml) we were unable to show an increase in heart weight in spite of high blood pressure [19]. Arnal et al [36]have observed that blockade of NO synthase for 8 weeks induced hypertension without left ventricular hypertrophy in most rats whereas severe hypertension was associated with left ventricular hypertrophy.…”

“…We also found elevated urinary NO – 2 /NO – 3 levels in nephritic rats which may be reflecting the general inflammation process. We have repeatedly shown that urinary cGMP excretion is decreased during the chronic phase of HN, indicating deficient NO production in chronic nephritis [19]. The changes in urinary cGMP levels did not correlate with changes in ANP levels.…”

“…Rats (9–11 weeks of age, n = 38) were immunized with purified kidney brush border antigen to induce Heymann nephritis (HN), as described earlier [18, 19]. HN in rats is a chronic nephropathy closely resembling idiopathic membranous glomerulonephritis in man.…”

Inhibitory Effects of Ligustrazine, a Modulator of Thromboxane-Prostacycline-Nitric Oxide Balance, on Renal Injury in Rats with Passive Heyman Nephritis

“…Some observations revealed that induction of iNOS in rats with IC glomerulonephritis was complement-dependent [38, 39, 40]. Chronic blockade of NO synthesis in rats with Heymann nephritis can produce systemic hypertension and glomerular damage [18]. In the experiment, we detected the expression of glomerular iNOS mRNA in all the 3 groups at day 7 after various treatments and found that glomerular iNOS mRNA was expressed in the PHN model rats, but that the amount of iNOS mRNA with densitometry analysis was markedly lower than that in the PHN + ligustrazine group.…”

“…PHN rats have renal TxA 2 increase accompanied (or not) by the decrease of 6-keto-PGF 1α , suggesting that the pathogenesis of PHN is associated with the unusual metabolism of arachidonic acid (AA) on the GEC membrane mediated by sublytic C5b-9 [15, 16, 17]. Several findings have shown that inhibition of TxA 2 synthesis and promotion of PGI 2 or NO could lead to a partial reduction in proteinuria in experimental membranous nephropathy [18, 19]. In order to study deeply the pathologic factors of PHN and further prevent and treat the nephritis, we selected to give the PHN rats Chinese traditional medicine – ligustrazine [20, 21, 22], and then investigated its effects on the metabolism of AA, excretion of urinary protein, glomerular injury and NO synthesis.…”