Drugs online research references
J Pharmacol Exp Ther. 1997 Nov;283(2):661-5.
Renin vs. angiotensin-converting enzyme inhibition in the rat: consequences for plasma and renal tissue angiotensin.
Allan DR, Hui KY, Coletti C, Hollenberg NK.
Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
To compare the effects of a potent rat renin inhibitor peptide (RIP) and angiotensin-converting enzyme (ACE) inhibitor on the intrarenal and plasma renin-angiotensin systems, anesthetized Sprague-Dawley rats were treated with an infusion of vehicle, ramipril or graded doses of the rat RIP (acetyl-His-Pro-Phe-Val-statine-Leu-he-NH2) for 30 min. Kidney and plasma samples were processed rapidly, and angiotensin peptides were separated by high-pressure liquid chromatography before measurement by a double-antibody radioimmunoassay. Blood pressure fell identically, by approximately 15 mm Hg, after either the RIP or ACE inhibitor. Plasma Ang II was 83 +/- 20 fmol/ml in vehicle-treated rats and fell to 28 +/- 3 fmol/ml with ramipril (10 mg/kg), the dose-response zenith. Plasma Ang II was significantly lower, 9 +/- 2 fmol/ml, with the highest RIP dose used. Control renal tissue Ang II was 183 +/- 18 fmol/g, fell with ramipril to 56 +/- 6 and then fell to a similar level (47 +/- 10 fmol/g) after RIP. Ang I/Ang II ratios indicated the expected sharp drop in Ang I conversion after ramipril in plasma and tissue. RIP did not influence conversion rate in plasma but was associated with an unanticipated fall in Ang I conversion in renal tissue, perhaps reflecting local aspartyl protease inhibition, which contributes to normal Ang II formation. Also unanticipated was a rise in tissue Ang I concentration during RIP administration. Renin inhibition is more effective than ACE inhibition in blocking systemic Ang II formation, supporting studies suggesting that quantitatively important non-ACE-dependent pathways participate in Ang II formation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9353383&dopt=Abstract
Nephrol Dial Transplant. 1996 Jun;11(6):1003-11.
Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure.
Amann K, Nichols C, Tornig J, Schwarz U, Zeier M, Mall G, Ritz E.
Departments of Pathology Heidelberg and Darmstadt, Department of Internal Medicine Ruperto Carola University, Heidelberg, Germany.
BACKGROUND. Experimental renal failure causes structural alterations of the kidney. It is still unresolved how these changes are modified by antihypertensive treatment. Purpose of the study. To examine the effects of different antihypertensive agents (ramipril, nifedipine, moxonidine) mainly on glomerular geometry, cell number, cell morphology, and capillarization, in a subtotal nephrectomy model of renal failure. MATERIAL AND METHODS. Sham-operated male SD rats and subtotally nephrectomized (SNX) ad libitum-fed rats were examined. Groups of 8-10 SNX rats were left untreated or were treated with ramipril (0.5 mg/kg b.w. per day), nifedipine (20 mg/kg b.w. per day) or moxonidine (10 mg/kg b.w.per day) respectively. After perfusion fixation the kidneys were examined using stereological techniques. RESULTS. Systolic blood pressure (by tail plethysmography) was 110+/-13 mm Hg in sham-op and 119+/-9 in SNX. It was effectively and comparably reduced below normal values by ramipril (89+/-11 mmHg), nifedipine (98+/-23 mmHg) and moxonidine (92+/-11 mmHg). The glomerulosclerosis index (SI) was significantly increased in SNX versus sham-op; it was similarly decreased by ramipril and moxonidine but less so by nifedipine. Vascular damage (preglomerular vessels) was reduced by all treatments whereas tubulointerstitial damage was signficantly reduced only by ramipril and moxonidine. Mean glomerular tuft volume was increased in SNX compared to sham-op. controls and was normalized only by ramipril treatment. Glomerular cells were differentially affected the three antihypertensive agents. After subtotal nephrectomy an increase in podocyte volume and mesangial cell number per glomerulus was noted. Nifedipine, and to a lesser extent ramipril, prevented mesangial cell hyperplasia. In contrast, only the ACE inhibitor ramipril, but not nifedipine or moxonidine prevented podocyte abnormalities, particularly podocyte hypertrophy. CONCLUSIONS. (i) Despite comparable reduction in systolic blood pressure, different classes of antihypertensive agents had diverse effects on renal damage in subtotally nephrectomized rat. This observation is consistent with specific, non-hemodynamic actions of anti-hypertensives. (ii) Glomerular and tubulointerstitial damage are prevented by treatment with ACE inhibitors and antisympathotonic agents, but not with the calcium antagonist nifedipine. In contrast, renal vascular changes were also prevented by nifedipine. (iii) Only ACE inhibitors effectively inhibited podocyte hypertrophy and mesangial cell hyperplasia. Whether the superior effect of ACE inhibitors on glomerulosclerosis is related to inhibition of glomerular growth and podocyte hypertrophy as well as preservation of podocyte structure, or whether these findings are merely a passive reflection of greater efficacy, remains unresolved.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8671960&dopt=Abstract
Ann Thorac Surg. 1995 Sep;60(3):789-92.
The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors.
Hartman JC.
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
BACKGROUND. The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. The objective of these investigations was to examine the roles of bradykinin, angiotensin II, and nitric oxide in the cardioprotective effects of ramiprilat. METHODS. Anesthetized, open-chest rabbits were instrumented for production of myocardial ischemia (30 minutes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with either saline solution, ramiprilat (50 micrograms/kg), the bradykinin2 receptor antagonist HOE 140 (1 microgram/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg-1.min-1), the angiotensin II receptor antagonist losartan (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 micrograms.kg-1.min-1), or ramiprilat + NG-nitro-L-arginine methyl ester. RESULTS. Among all treatment groups myocardial infarct size was reduced significantly below saline control only by ramiprilat (-54%) and ramiprilat + angiotensin II (-37%). Pretreatment with HOE 140 or NG-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither stimulation nor antagonism of angiotensin II receptors altered infarct size from the saline control level. Also, when isolated neonatal rat cardiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mumol/L) and bradykinin (10 nmol/L) improved cell viability (approximately 60%), and the protective effect of both agents was reversed by administration of HOE 140 (10 mumol/L). CONCLUSIONS. These results indicate that the in vivo cardioprotective effect of ramiprilat can be abolished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II receptor activity. The potential bradykinin-sparing property of ramiprilat may promote increased bradykinin-stimulated nitric oxide production leading to cardioprotection. Part of the cardioprotective effects of ramiprilat/bradykinin/nitric oxide may occur locally as demonstrated by the in vitro results using isolated cardiomyocytes.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7545893&dopt=Abstract
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