Significant role of the increase in renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in double transgenic tsukuba hypertensive mice carrying both human renin and angiotensinogen genes. Proximal renal tubular peptide catabolism, ammonia excretion and tubular injury in patients with proteinuria: before and after lisinopril. Rx drugs

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Clin Exp Hypertens. 1998 May;20(4):439-49.
Significant role of the increase in renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in double transgenic tsukuba hypertensive mice carrying both human renin and angiotensinogen genes.

Kai T, Kino H, Sugimura K, Shimada S, Kurooka A, Akamatsu K, Takenaka T, Fukamizu A, Murakami K, Ishikawa K, Katori R.

First Department of Internal Medicine, Kinki University School of Medicine, Osaka-Sayama, Japan.

Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

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Clin Sci (Lond). 1998 Apr;94(4):425-30.
Proximal renal tubular peptide catabolism, ammonia excretion and tubular injury in patients with proteinuria: before and after lisinopril.

Rustom R, Grime JS, Costigan M, Maltby P, Hughes A, Shenkin A, Critchley M, Bone JM.

Regional Renal Unit, Royal Liverpool University Hospital, U.K.

1. Progression to renal failure may be linked to the degree of proteinuria through tubulo-interstitial mechanisms. However, there are no data in man on the kinetics of proximal renal tubular protein catabolism or markers of tubular injury before and after lisinopril. We developed a method to allow such studies, and found increased tubular catabolism of 99mTc-labelled aprotinin (Trasylol) in patients with nephrotic range proteinuria which was associated with increased ammonia excretion. 2. In this study, 10 patients with mild renal impairment (51Cr-EDTA clearance 63.7 +/- 8.3 ml.min-1.1.73 m-2) and heavy proteinuria (8.2 +/- 2.3 g/ 24 h) were given lisinopril (10-20 mg) for 6 weeks. Renal tubular catabolism of intravenous aprotinin was measured before and after lisinopril by renal imaging and urinary excretion of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Fresh timed urine collections were also analysed for ammonia excretion every fortnight from 6 weeks before treatment. Total urinary N-acetyl-beta-D-glucosaminidase and the more tubulo-specific N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme were also measured. 3. After lisinopril proteinuria fell significantly as expected (from 9.5 +/- 1.6 to 4.5 +/- 1.0 g/24 h, P < 0.01). This was associated with a reduction in metabolism over 26 h (from 1.7 +/- 0.1 to 1.2 +/- 0.1% dose/h, P < 0.01) and in fractional degradation of aprotinin (from 0.08 +/- 0.02 to 0.04 +/- 0.007/h, P < 0.04). Ammonia excretion also fell significantly (from 1.2 +/- 0.1 to 0.6 +/- 0.1 mmol/h, P < 0.0001), as did both total urinary N-acetyl-beta-D-glucosaminidase (P < 0.0001) and the N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme (P < 0.015). These observations after lisinopril treatment have not been described previously. There was no significant change in blood pressure nor in glomerular haemodynamics.

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medone.med.osaka-u.ac.jp

BACKGROUND: Unilateral ureteral obstruction (UUO) is a well established experimental model of renal injury leading to interstitial fibrosis. The molecular and cellular mechanism(s) of interstitial fibrosis in UUO are beginning to be elucidated. In the progression of interstitial fibrosis in UUO, up-regulation of collagen synthesis is commonly observed. HSP47 is a collagen-binding stress protein and is thought to be a collagen-specific molecular chaperone, which plays a pivotal role during the biosynthesis and secretion of collagen molecules in the endoplasmic reticulum. The synthesis of HSP47 has been demonstrated to always parallel that of collagen in physiological and pathophysiological conditions. It is well recognized that renin-angiotensin system (RAS) is enhanced in the setting of UUO and that enhanced RAS has been implicated in the pathogenesis of interstitial fibrosis in the obstructed kidneys. METHODS: To investigate the role of HSP47 in the progression of interstitial fibrosis in mouse UUO, the expression of HSP47 was examined by Northern blotting, immunohistochemistry and in situ hybridization in the obstructed kidneys. To test the possible involvement of enhanced RAS on the HSP47 expression, we examined the effects of lisinopril, an angiotensin converting enzyme inhibitor, on interstitial fibrosis. HSP47 and type I collagen mRNA expression. RESULTS: By Northern blot analysis, HSP47 mRNA was significantly up-regulated at 12 hours (about twice that of sham operated kidneys) after the onset of ureteral obstruction, further increased and stayed at the increased level until seven days (about 8 times that of sham operated kidneys). HSP47 mRNA and protein expression were observed in the periglomerular and peritubular interstitial regions of the obstructed kidneys. Distribution of smooth muscle alpha actin and type I collagen immunoreactivity were similar to the HSP47 distribution pattern, suggesting that HSP47 was up-regulated in the myofibroblasts. Lisinopril ameliorated the expansion of cortical interstitium in the obstructed kidneys at four and seven days after ureteral obstruction. HSP47 mRNA expression was suppressed at four and seven days, whereas type I collagen mRNA was suppressed only at seven days after the onset of ureteral obstruction. CONCLUSIONS: These results demonstrate the early and persistent up-regulation of HSP47 during the progression of interstitial fibrosis in mouse UUO kidneys, and further suggest the potential role of HSP47 in the pathogenesis of interstitial fibrosis in the obstructed kidneys. Partial suppression of HSP47 mRNA expression by lisinopril at day 4 and day 7 after ureteral obstruction suggests that there are other immediate trigger(s) that induce the HSP47 mRNA expression. Identification of the molecular mechanism of HSP47 induction during UUO may give an insight into the novel aspects of the molecular pathophysiology of interstitial fibrosis in obstructive nephropathy.

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