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Clin Exp Pharmacol Physiol. 1994 Feb;21(2):133-5.
Effects of enalapril and Dup753 on renin synthesis in mice with one hydronephrotic kidney.

Zhang Y, Morgan T.

Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.

1. Renin synthesis and secretion were investigated in mice with one hydronephrotic kidney. 2. Enalapril and Dup753 stimulated renin synthesis to a similar extent in the hydronephrotic and normal kidney. 3. Hydronephrosis did not prevent an increase in renin mRNA caused by enalapril and Dup753. 4. The results therefore indicate that the macula densa does not appear to be crucial for renin synthesis in the kidney under the inhibition of angiotensin II. 5. Thus angiotensin II plays an important role controlling renin gene expression in both the normal and hydronephrotic kidneys.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8039266&dopt=Abstract




Br J Pharmacol. 1997 Dec;122(8):1694-701.
Comparative effects of the dual metallopeptidase inhibitor, MDL 100,240 and of enalaprilat on regional and on cardiac haemodynamics in conscious, hypertensive, transgenic ((mRen-2)27) rats.

Gardiner SM, Kemp PA, Brunner-Ferber F, Bennett T.

School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, France.

1. Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350-450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin-converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg-1, 3 mg kg-1 h-1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)-receptor antagonist, Hoe 140 (1 mg kg-1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin. 2. Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (-54 +/- 9 mmHg) was greater than that of enalaprilat (-38 +/- 4 mmHg), because the former caused a significantly greater reduction in cardiac index. 3. Between 8-24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds. 4. There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug. 5. These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.

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J Am Soc Nephrol. 1996 Oct;7(10):2202-12.
Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.

Morrissey JJ, Ishidoya S, McCracken R, Klahr S.

Department of Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to minimize fibrosis of the kidney tubulointerstitium in several diseases. In addition to lowering angiotensin II levels, ACE inhibitors can increase kinin levels and subsequently increase nitric oxide formation. To determine whether nitric oxide generation is a component of the beneficial effect of ACE inhibitors on renal fibrosis, enalapril, enalapril plus NG-nitro-L-arginine methyl ester (L-NAME) or L-arginine was administered to rats that had undergone unilateral ureteral obstruction (UUO). Ureteral obstruction caused significant increases in interstitial volume, monocyte macrophage infiltration, interstitial collagen IV and alpha-smooth muscle actin expression, transforming growth factor-beta 1 mRNA, collagen IV mRNA, and tissue inhibitor of metalloproteinase-1 mRNA. Enalapril treatment significantly blunted the increase in all parameters during UUO. Cotreatment of the animals with enalapril and L-NAME reversed the beneficial effect of enalapril in the obstructed kidney for all parameters. Treatment of animals with UUO with L-arginine significantly blunted the increase in all parameters except for transforming growth factor-beta 1 mRNA expression. In the enalapril- plus-L-NAME-treated animals, there were modest but significant increases in monocyte/macrophage infiltration of the interstitium and glomerulus, and collagen IV and alpha-smooth muscle actin expression in the interstitium of the contralateral unobstructed kidney. The urine nitrite concentration was significantly increased by either enalapril or L-arginine treatment, whereas L-NAME significantly reduced urine nitrite concentration. These results suggest that treatment modalities that increase nitric oxide formation have a beneficial effect on the progression of cellular and molecular parameters of tubulointerstitial fibrosis caused by obstruction of the ureter.

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