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1 This study compares the activity of BMS-180560 (2-butyl-4-chloro-1-[[1-[2-(2H-tetrazol-5-yl)phenyl]-1H-indol-4-yl]methyl]-lH-imidazole-5-carboxylic acid), an insurmountable angiotensin II (All) receptor antagonist, with that of losartan and EXP3174 in functional and biochemical models of AII-receptor activation.2 BMS-180560 selectively inhibited ['25I]-Sar'Ile8AII (['25I]SI-AII) binding to rat aortic smooth muscle (RASM) cell and rat adrenal cortical AT, receptors (Ki = 7.6 ± 1.2 and 18.4 ± 3.9 nM respectively) compared to adrenal cortical AT2 receptors (Ki = 37.6 ± 1.3 JiM). The K, values of BMS-180560 and EXP3174, but not losartan, varied as a function of the BSA concentration used in the assays, indicating that the diacid drugs bound to albumin.3 BMS-180560 (3-300 nM) increased the KD of SI-AII for RASM cell AT, receptors. Only at high concentrations of BMS-180560 (300nM) were Bmax values decreased.4 BMS-1 80560 inhibited AII-stimulated contraction of rabbit aorta with a calculated KB = 0.068 ± 0.048 nM and decreased maximal AlI-stimulated contraction at 1 nM BMS-180560 by 75%. In the presence of 0.1% BSA, a higher KB value (5.2 ± 0.92 nM) was obtained. Losartan behaved as a competitive antagonist with a KB = 2.6 ± 0.13 nM. Contraction stimulated by endothelin-1, noradrenaline, KCl, or the TXA2 receptor agonist U-46619 were unaffected by BMS-180560 (1 nM).5 All stimulated the acidification rates of RASM cells as measured by a Cytosensor microphysiometer with an EC50 of 18 nM. Losartan (30 nM) shifted the All concentration-effect curves in a competitive manner whereas BMS-180560 (0.01 and 0.1 nM) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan and BMS-180560 could be reversed following washout although recovery took longer for BMS-180560. (17-55%). BMS-180560 (3 and 10 nM) increased the EC50 for All and decreased the maximum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS-180560 could be reversed by inclusion of losartan (200 nM) indicating that the inhibition was not irreversible. 7 In conclusion, BMS-180560 is a potent, specific, predominantly competitive, reversible All receptor antagonist, which displays insurmountable receptor antagonism. At concentrations of BMS-180560 which have no effect on receptor number, BMS-180560 produced insurmountable antagonism of AII-stimulated second messenger formation, extracellular acidification, and smooth muscle contraction.

A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.

Abstract-Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (nϭ28) or lisinopril (nϭ33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (Pϭ0.008), ambulatory systolic blood pressure (Pϭ0.004), and ambulatory mean arterial pressure (Pϭ0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (PϽ0.001) increased urinary excretion of atrial natriuretic peptide over 0-to 24-hour (3.8-fold) and 12-to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (PϽ0.001) increased urinary excretion of cGMP over the 0-to 24-and 4-to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. bradykinin, 2 and adrenomedullin 3 ) and inhibition of the production of the vasoconstrictor angiotensin II. The physiological effects of ANP and BNP include vasodilation and inhibition of the renin-angiotensin-aldosterone system. 4 -6 The metabolism of ANP and BNP involves 2 main pathways: an enzymatic degradation by NEP 24.11 7 and a receptor-mediated clearance process via the clearance receptor. 8 NEP 24.11 is widely distributed throughout the body and is particularly present at the level of the brush border membranes in the proximal tubule of the kidney. 9 Inhibition of NEP produces increases in plasma ANP concentrations and urine sodium and volume excretion and a decrease in blood pressure (BP) in deoxycorticosterone acetate-salt uninephrectomized rats. 10,11 NEP inhibitors, when given alone, have not been effective as long-term antihypertensive agents in humans, perhaps because of compensatory reflex renin-angiotensin-aldosterone system activation. 12,13 These limitations may be overcome by VPIs through their additional ability to inhibit ACE and to potentiate the kallikrein-kinin system, resulting in additional vasodilation. 14 Patients with salt-sensitive hypertension (SSH) do not respond as well to ACE inhibitor monotherapy as hypertensive patients who are not salt sensitive. 15 In response to a ...

A comparison of the pilgrimage to Mecca made by Turkish villagers with that made to their natal villages by Turkish immigrants in Europe argues for blurring the boundaries between the categories “sacred” and “secular” as well as those between pilgrim and migrant. It suggests that the hijra (emigration of Muhammed) and the hajj (his pilgrimage home) provide a symbolic model, unavailable for non‐Muslims, that implicitly structures and makes comprehensible the ritualistic and obligatory character of the immigrants' journey home. [Islam, symbolism, pilgrimage, Turkish peasants and immigrants]