Drugs online research references
Eur J Pharmacol. 1993 Apr 6;234(2-3):229-36.
Reduction of myocardial infarct size by ramiprilat is independent of angiotensin II synthesis inhibition.
Hartman JC, Hullinger TG, Wall TM, Shebuski RJ.
Upjohn Laboratories, Kalamazoo, MI 49001.
The angiotensin-converting enzyme inhibitor ramiprilat, the angiotensin II receptor antagonist losartan, angiotensin II, ramiprilat plus angiotensin II, or saline (N = 6 each group), were administered i.v. in anesthetized, open-chest rabbit preparations of acute myocardial ischemia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dtmax, then subjected to 30 min of left anterior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 micrograms/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2.5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of ramiprilat and losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the duration of the experiment. Systemic hemodynamic and +dP/dtmax changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Infarct size/area at risk (%) was significantly lower in rabbits administered ramiprilat only (20 +/- 6%*) or ramiprilat plus angiotensin II (26 +/- 5%*), compared to those receiving saline (41 +/- 6%), angiotensin II (51 +/- 4%), or losartan (52 +/- 4%, mean +/- S.E.M., * P < 0.05). These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8482328&dopt=Abstract
J Clin Invest. 1997 Apr 15;99(8):1926-35.
Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors.
Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA.
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9109437&dopt=Abstract
J Hypertens. 1997 Apr;15(4):421-9.
Kinins and the events influenced by an angiotensin-converting enzyme inhibitor during neointima formation in the rat carotid artery.
Farhy RD, Peterson E, Scicli AG.
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202, USA.
OBJECTIVE: In balloon-injured rat carotid arteries, angiotensin-converting enzyme inhibitors (ACEI) decrease neointima formation, and a kinin receptor antagonist partially reverses this inhibitory effect. We studied which of the events leading to neointima formation are involved in the effects of ACEI and kinins. METHODS: We administered 5 mg/kg per day ramipril, either alone or combined with the kinin receptor antagonist icatibant (Hoe 140), on the days each wave occurred and studied the effects on neointima formation 14 days after balloon injury. Ramipril alone or combined with icatibant had no effect on neointima formation when administered from 2 days before to 3 or 5 days after balloon injury. In contrast, ramipril inhibited neointima formation when administered from day 7 to day 14. Treatment with icatibant had a small effect, which was sufficient to abolish the effects of ramipril (control 0.11 +/- 0.01 mm2, ramipril 0.08 +/- 0.01 mm2; P < 0.05; ramipril plus icatibant 0.09 +/- 0.01 mm2; NS, ramipril plus icatibant versus control). Thus ramipril was not effective when treatment was stopped after 3 or 5 days, but was mildly effective when treatment was administered during the second week. The effect on migration was studied by counting the number of neointimal cells in rats treated from 2 days before to 4 days after injury. Ramipril decreased the number of cells by 93% compared with controls (control 65.0 +/- 13.5 cells/slice, ramipril 4.7 +/- 2.0 cells/slice; P < 0.001), and this effect was blunted significantly by icatibant (19.5 +/- 5.7 cells/slice; P < 0.009, versus ramipril; P < 0.007, versus controls). The influence of treatment on the rate of proliferation (the 5'-bromo-2'-deoxyuridine index) was studied in the media 3 days, and in the neointima 7 and 10 days after balloon injury. Although proliferation peaked in the neointima after 7 days, there were no differences among the groups at any time. Thus neither ramipril nor icatibant affected the rate of proliferation at the times sampled. Ramipril increased cell density (cells/mm2) in the neointima, and this effect was abolished by cotreatment with icatibant (P < 0.05). CONCLUSION: The ACEI needs to be present throughout the experimental period to be most effective. ACEI act on neointima formation in part by inhibiting migration; thus, because ramipril was mildly effective when administered from 7 to 10 days after injury, it is likely that vascular smooth muscle cell migration also occurs continuously. Kinins help mediate roughly 30% of the effect of ACEI on migration. In addition, ACEI, through kinins, affect a process that increases the density of the cells in the neointima, perhaps by decreasing extracellular matrix deposition.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9211177&dopt=Abstract
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