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

Abstract

Objective: To investigate effects of angiotensin I converting enzyme (ACE) inhibition in experimental nephritis during chronic inhibition of nitric oxide (NO) synthase. Methods: 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. Results: 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. Conclusions: 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.

Renoprotective Mechanisms of Angiotensin II Antagonism in Experimental Chronic Renal Failure

“…Natriuretic peptides activate receptors linked to particulate guanylate cyclase while NO acts through receptors linked to soluble guanylate cyclase. In our previous studies [7,10] and the present experiment we have been unable to correlate changes in circulating natriuretic peptide levels to changes in urinary cyclic GMP excretion in Heymann nephritis rats treated with either the ACE inhibitor captopril or AT1 receptor antagonist L-158,809. This does not exclude, however, possible alterations in generation and/ or inactivation of cGMP itself.…”

“…We have previously shown that urinary cGMP excretion is decreased, consistent with deficient NO production, during the chronic phase of Heymann nephritis in the rat [7]. Moreover, treatment with an ACE inhibitor resulted in increased urinary excretion of cGMP in nephritic rats suggesting that the dysfunctional NO system may be activated by ACE inhibition [10]. It was therefore of interest to study the effects of an angiotensin antagonist on urinary cGMP excretion and the expression of AT1 and AT2 receptors in this experimental model of chronic nephritis.…”

“…We have previously shown that urinary cGMP excretion is decreased during the chronic phase of Heymann nephritis (HN) in the rat, consistent with deficient NO production [7,10]. In this model of chronic nephritis, treatment with an ACE inhibitor resulted in increased urinary excretion of cGMP suggesting that the dysfunctional NO system may be activated by ACE inhibition [10]. The mechanism behind this effect remained unclear, however.…”

Effects of Captopril on Cardiac and Renal Damage, and Metabolic Alterations in the Nitric Oxide-Deficient Hypertensive Rat

“…Duarte et al [18] showed that the SH-containing ACE inhibitor captopril at a high dose level of 50 mg/kg inhibited proteinuria in obese Zucker rats, a model of non-insulin-dependent diabetic hypertensive rats. In rats with and without autoimmune Heymann nephritis and treated with L -NAME, captopril partly prevented albuminurea and inhibited the L -NAME-enhanced peritubular mononuclear cell infi ltration in rats with nephritis [21] . Fortepiani et al [22] showed that captopril at a dose of 60 mg/kg was effective treatment for the NO-defi cient arterial hypertension and renal vasoconstriction, though it was not enough to overcome the blunted renal pressure diuresis response associated with the chronic defi ciency of NO.…”

“…Inhibition of the renin-angiotensin system by ACE inhibitor captopril was shown to protect against renal damage induced by chronic hypertension, diabetes or irradiation [18,[20][21][22][23][24] . Duarte et al [18] showed that the SH-containing ACE inhibitor captopril at a high dose level of 50 mg/kg inhibited proteinuria in obese Zucker rats, a model of non-insulin-dependent diabetic hypertensive rats.…”