Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis. Angiotensin-converting enzyme inhibition and compliance of the carotid artery in normotensive and hypertensive rats. Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE). Rx drugs

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J Pharmacol Toxicol Methods. 1999 Apr-Jun;41(2-3):69-73.
Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis.

Wapstra FH, van Goor H, de Jong PE, Navis G, de Zeeuw D.

Groningen Institute of Drug Studies (GIDS), Department of Medicine, State University, University Hospital, The Netherlands.

Nephrosis induced by doxorubicin (adriamycin) is an experimental model of glomerulosclerosis with relative stable proteinuria which is commonly used for pharmacological intervention studies. It is induced by a single or a double dose of doxorubicin, with doses that vary considerably among investigators from 2 to 7.5 mg/kg. Intervention studies with ACE-inhibitors in this model have provided conflicting results. We hypothesized that these discrepancies might be due to different properties of the doxorubicin model, related to the dose of doxorubicin used to induce proteinuria. We tested this hypothesis by inducing doxorubicin nephrosis with 1, 2 and 3 mg/kg, and evaluating the response to intervention with lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg/ kg dose resulted in a proteinuria of 684+/-215 mg/24 h and 736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment with lisinopril 2 mg/kg/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in the 2-mg/kg doxorubicin group, whereas in the 3-mg/kg doxorubicin group, proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control rats, proteinuria remained stable. Renal damage developed in both time control groups, with a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/-41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lower glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05), whereas the 3-mg/kg group showed no significant reduction (56+/-29, NS). In conclusion, the dose of doxorubicin used to induce nephrosis is an important determinant not only of the severity of the ensuring renal damage, but also of the response to intervention by ACE-inhibition. These findings have an impact on the interpretation of intervention studies in this model.

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J Hum Hypertens. 1989 Jun;3 Suppl 1:57-62.
Angiotensin-converting enzyme inhibition and compliance of the carotid artery in normotensive and hypertensive rats.

Levy BI, Benessiano J, Poitevin P, Safar ME.

INSERM Unit 141, Hopital Lariboisiere, Paris, France.

To investigate the effects of local application of an angiotensin-converting enzyme inhibitor on the mechanical properties of the arterial wall, the volume/pressure relationship (from 25 to 175 mmHg) in the in vivo isolated carotid artery was measured in normotensive (WKY) and spontaneously hypertensive rats (SHR). The compliance of the carotid artery (CC) was calculated, for each level of pressure, as the slope of the the volume/pressure curve. The carotid artery was less compliant in the SHR strain than in normotensive rats. This rigidity was partly related to an increased tone of the arterial smooth muscle in SHR compared with the WKY. Local incubation with lisinopril (2.3 micrograms/ml) produced a significant increase in the compliance of the carotid artery in both normotensive and hypertensive rats; CC was increased by 23% in WKY rats and by 14% in SHR. Since the goal of antihypertensive treatment may be not only to reduce blood pressure (BP) but also to improve the mechanical properties of the arterial system, the direct effect of lisinopril on the arterial wall may have a major beneficial role.

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Br J Clin Pharmacol. 1989;28 Suppl 2:115S-130S; discussion 130S-131S.
Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

Cushman DW, Wang FL, Fung WC, Grover GJ, Harvey CM, Scalese RJ, Mitch SL, DeForrest JM.

Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin-converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose-response and time-course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized 'equiactive' oral doses employed for time-course studies were: SQ 29,852 (1.0), 100 mg kg-1; captopril (3.5), 30 mg kg-1; enalapril (12), 20 mg kg-1; fosinopril (13), 25 mg kg-1; zofenopril (20), 10 mg kg-1; lisinopril (24), 10 mg kg-1; and ramipril (51), 5 mg kg-1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short-lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long-lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

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