Drugs online research references
Br J Pharmacol. 1999 Feb;126(3):613-20.
Effect of prolonged administration of a urinary kinase inhibitor, ebelactone B on the development of deoxycorticosterone acetate-salt hypertension in rats.
Ito H, Majima M, Nakajima S, Hayashi I, Katori M, Izumi T.
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
The effect of prolonged administration of a carboxypeptidase Y-like kininase inhibitor, ebelactone B (EB) (2-ethyl-3, 11-dihydroxy-4, 6, 8, 10, 12-pentamethyl-9-oxo-6-tetradecenoic 1, 3-lactone), on the development of deoxycorticosterone acetate (DOCA)-salt hypertension was tested. The systolic blood pressure (SBP) of non-treated 6-week-old Sprague-Dawley strain rats was gradually increased by DOCA-salt treatment from 137+/-2 mmHg (n=11) to 195+/-7 mmHg at 10 weeks of age. With daily oral administration of lisinopril (5 mg kg(-1), twice a day), which is an inhibitor of angiotensin converting enzyme, a major kininase in plasma, the development of hypertension was not suppressed. By contrast, administration of EB (5 mg kg(-1), twice a day), completely inhibited the development of hypertension (SBP: 146+/-1 mmHg, n=5, 10 weeks old). The reduced SBP at 10 weeks of age was equal to the SBP before any treatment (142+/-1 mmHg, n=5). Direct determination of mean blood pressure (MBP) in conscious, unrestrained rats confirmed that MBP elevation was completely inhibited by EB. Continuous subcutaneous infusion (5 mg kg(-1) day(-1)) of HOE140, a bradykinin B2 receptor antagonist, restored the elevation of SBP, which was suppressed by EB. The weights of left ventricle of DOCA-salt treated rats 10-weeks-old (0.36+/-0.02 g 100 g body weight(-1), n=11) was significantly reduced by EB (0.27+/-0.01, n=5), as were the sodium levels in serum, cerebrospinal fluid and erythrocyte. These findings suggested that EB is effective in preventing salt-related hypertension presumably by eliminating sodium retention.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10188971&dopt=Abstract
irfmn.mnegri.it
Previous studies showed a renoprotective effect of l-arginine in experimental uremia. Whether this was caused by an increased nitric oxide (NO) release or depended on l-arginine per se is not clear. Here, we evaluated whether chronic administration of an NO donor, molsidomine, controlled systemic blood pressure and renal disease progression and prolonged survival in rats with renal mass reduction (RMR). Rats with RMR received the following daily in the drinking water: group 1 (n = 21), no specific therapy (vehicle); group 2 (n = 12), molsidomine, 120 mg/L; group 3 (n = 9), lisinopril, 25 mg/L; and group 4 (n = 12), reserpine, 5 mg/L, hydralazine, 80 mg/L, and hydrochlorothiazide, 25 mg/L, from day 21 after surgery, when rats had hypertension and proteinuria, until the death of the vehicle-treated rats. Molsidomine normalized systemic hypertension, only partially reduced proteinuria and serum creatinine levels, but significantly prolonged animal survival, particularly in the early stage of the disease. Lisinopril at a similar systemic blood pressure was even better than molsidomine in limiting proteinuria, preserving renal function, and prolonging survival, but triple therapy, despite being effective on blood pressure, offered no renoprotection or prolonged survival. Endothelin-1 (ET-1) levels, formed in excessive amounts by the kidneys of these animals, were reduced by molsidomine and lisinopril, but not by triple therapy. The prolongation of survival by NO donor could be attributed to its effect of reducing ET levels, which in turn may limit the smooth muscle cell proliferation and matrix accumulation responsible for organ and, especially, myocardial fibrosis in uremia.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10196019&dopt=Abstract
irfmn.mnegri.it
In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10203365&dopt=Abstract
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