Drugs online research references
J Pharmacol Exp Ther. 2000 Nov;295(2):621-6.
Protective effect of omapatrilat, a vasopeptidase inhibitor, on the metabolism of bradykinin in normal and failing human hearts.
Blais C Jr, Fortin D, Rouleau JL, Molinaro G, Adam A.
Faculte de Pharmacie, Universite de Montreal, Montreal, Quebec, Canada.
Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left ventricular membranes prepared from normal donor hearts (n = 7), and hearts from patients with an ischemic (n = 11) or dilated (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased the half-life of BK (P <.01), but the effect was similar for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P <.01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes (P <.05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11046097&dopt=Abstract
Exp Nephrol. 2001;9(1):60-4.
Intrarenal renin-angiotensin system contributes to tubular acidification adaptation following uninephrectomy.
Amorena C, Damasco C, Igarreta P, MacLaughlin M.
Instituto de Investigaciones Cardiologicas, Facultad de Medicina, Universidad de Buenos Aires, Argentina.
BACKGROUND/AIMS: Reduction in renal mass by uninephrectomy induces a functional compensation in the remnant kidney. The activity of the angiotensin-converting enzyme (ACE) as well as renin mRNA in the proximal convoluted tubule (PCT) of uninephrectomized (UNx) rats increases. The aim of this work was to determine whether the increased activity of the local renin-angiotensin system (RAS) participates in the adaptation of renal function after uninephrectomy. METHOD: We utilized normal two-kidney (2K) and 3-week UNx rats to study the activity of the ACE in vesicles obtained from luminal membranes of proximal tubular cells and the acidification kinectics in PCTs using micropuncture techniques. RESULTS: The converting enzyme activity was significantly larger in UNx (5.87+/-0.69 nmol x min(-1) x mg protein(-1)) than in 2K rats (2.43+/-0.13 nmol x min(-1) x mg protein(-1); p<0.05). The acidification rate constant (kappa) in PCT of 2K rats was 0.18+/-0.02 s(-1) and in UNx rats 0.30+/-0.04 s(-1) (p<0.001). In UNx rats, microperfusion with 10(-5) M ramipril or 10(-5) M losartan decreased kappa to 0.19+/-0.02 and 0.18+/-0.02 s(-1), respectively, but had no effect on 2K rats. Luminal steady-state pH (pH(infinity)) was the same in 2K and UNx rats, and was not modified by addition of 10(-5) M ramipril or 10(-5) M losartan in both groups. The proximal H(+) flux (J(H(+))), calculated from pH(infinity) and kappa, was 1.12 nmol x cm(-2) x s(-1) in 2K rats and, 1.77 nmol. cm(-2). s(-1) in UNx rats (p<0.001). In 2K rats, this value was not changed by 10(-5) M ramipril or 10(-5) M losartan, but in UNx rats J(H(+)) decreased 25 and 30% with ramipril or losartan, respectively (p<0.001). CONCLUSIONS: These data suggest that the increase in the local RAS activity could be an adaptive change that contributes to maintain the homeostasis of body fluids after uninephrectomy. Copyright 2000 S. Karger AG, Basel
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11053982&dopt=Abstract
med.de
Coronary artery disease is still the no. 1 killer in the developed countries and must thus be detected and treated at an earlier stage. If coronary artery disease is advanced, patients have to be examined regarding the need for revascularization. For secondary prevention, of course, an optimal change of life style and optimal medical treatment of risk factors is mandatory. Independent of the optimal risk factor modification, all of these patients (according to the rules of evidence-based medicine) should take ASA, statins, beta blockers and ACE-inhibitors, if no contraindications or intolerance are present. Therefore, the problem in secondary prevention is not how to identify these patients, but rather how to fulfill their needs. In our own survey in patients with known coronary artery disease referred for PTCA (including patients with post myocardial infarction previous PTCA or bypass surgery), only 89% were on ASA (or clopidogrel), 51% on lipid lowering drugs (46% on statins), 65% on beta blockers, and only 43% had an ACE-inhibitor (MUNICH data in Figures 1 to 4). The analysis of published literature is also depicted in Figures 1 to 4. Until 1996, patients with known coronary artery disease took ASA in only 26% of the cases but later on it was 77 to 100% (Figure 1). Lipid lowering drugs (especially statins) are prescribed in only 13 to 77% (Figure 2), beta blockers in only 30 to 80% (Figure 3) and ACE-inhibitors in only 10 to 72% (Figure 4). In 2 major studies, a decrease in the rate of intake of these drugs during the follow-up years has been documented. The "ideal tablet" for secondary prevention contains ASA (100 mg), a statin (e.g. for most statins 40 to 80 mg), a beta blocker (e.g. metoprolol 100 mg or bisoprolol 10 mg) and an ACE-inhibitor (e.g. ramipril 10 mg). So this ideal "SPM" ("secondary prevention mix") tablet contains 160 to 300 mg of drugs. In conclusion, the analysis of published data for Europe and the USA shows that--in contrast to the statements of politicians and health care insurance companies--we are not overtreating but rather undertreating our patients regarding medications for secondary prevention.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11076320&dopt=Abstract
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