Disease relevance of L-158809

• Lisinopril and L-158,809 controlled BP, prevented proteinuria, and protected PHN animals from renal injury [1].
• In conclusion, L-158,809 was effective in preventing hypertension during the treatment period, in reducing hypertension severity during the withdrawal period, and in persistently decreasing the reactivity of the arteries [2].
• L-158,809 decreased CB chemoreceptor responses to hypoxia in CHF rabbits but not in sham rabbits [3].
• L-158,809 reduced myocyte volume and cross-sectional area significantly after 1 week of treatment with maximal regression of hypertrophy, including reduced cell length, obtained by 4 weeks [4].
• Effect of the novel angiotensin II type 1 receptor antagonist L-158,809 on acute infarct expansion and acute anterior myocardial infarction in the dog [5].

High impact information on L-158809

• METHODS AND RESULTS: In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury [6].
• Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation [6].
• The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells [7].
• PD 123319 completely inhibited 125I-AII binding, with an IC50 of 30 nM, whereas L-158,809 (1 microM) had no significant effect on 125I-AII binding [8].
• METHODS: We measured renal sympathetic nerve activity (RSNA) in response to graded hypoxia before and after intravenous administration of Ang II (20 ng/kg/min, i.v. 30 min) or AT1 receptor antagonist (L-158,809, 0.33 mg/kg, i.v.) in conscious sham and pacing-induced CHF rabbits [3].

Chemical compound and disease context of L-158809

• The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension [9].
• Angiotensin II receptor antagonist, L-158,809, prevents intimal hyperplasia in dog grafted veins [10].
• RESULTS: L-158,809, captopril, and their combination decreased blood pressure and normalised urinary albumin excretion rate in rats with nephritis [11].
• The present study was designed to examine whether the iNOS pathway is pathologically altered in experimental diabetic nephropathy, and whether therapy with angiotensin converting enzyme (ACE) inhibitor (imidapril: I) or angiotensin II type I receptor (AT1) blocker (L-158,809: L), ameliorates these changes [12].

Biological context of L-158809

• CONCLUSION: Perindopril was more effective than was L-158,809 at lowering the blood pressure of adult spontaneously hypertensive rats, and at altering the structure and functioning of the arteries [13].
• Similarly, L-158,809 (4 mg/kg, i.v.) increased cardiac output by 9 +/- 2% and reduced mean arterial pressure and TPR by 4 +/- 1 and 11 +/- 3%, respectively, while the changes in LV dP/dt (+3 +/- 3%), LV fractional shortening (+3 +/- 1%) and heart rate (0 +/- 1%) were not significant [14].
• 5. In the presence of L-NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration-dependent manner by L-158809 (0.05-500 nM) [15].
• Using the AT1 antagonists DuP 753, its metabolite EXP 3174, and L-158,809, [125I]Ang II binding was displaced in a clearly biphasic manner, indicating the presence of two binding sites [16].
• Antagonists of ANG receptor AT(1) (losartan, L-158809, or saralasin), but not an AT(2)-selective blocker (PD-123319), inhibited Bleo-induced apoptosis of either rat AECs (79%, P < 0.01) or A549 cells (83%, P < 0.01) and also reduced the activity of caspase-3 by 52% (P < 0.05) [17].

Anatomical context of L-158809

• L-158,809 treatment in podocytes inhibited the increase in p27(Kip1) mRNA expression by 84%, and protein expression by 89% (P < 0.05). p27(Kip1) mRNA and protein expression in diabetic + ARB glomeruli were also significantly reduced by 78% and 85%, respectively, compared with diabetic glomeruli (P < 0.01) [18].
• DESIGN AND METHODS: Microdialysis probes were placed in the left ventricular (LV) myocardium of eight anaesthetized pigs, three of which were untreated and five treated with the angiotensin II type 1 (AT1) receptor antagonist L-158,809 (10 mg intracoronary) [19].
• The AII blocker study had a similar design, except that the nephropathy was the result of total body irradiation and bone marrow transplantation and the treatments were no treatment or continuous treatment with an AII blocker, L-158,809 (20 mg/l in drinking water) [20].
• Phagocytosis was evaluated by incubating microspheres containing the angiotensin II antagonist, L-158,809, with the macrophages in the presence or absence of the phagocytosis inhibitor cythochalasin D [21].
• The arterial media cross-sectional area and media to lumen ratio were reduced by L-158,809 treatment (0.6 mg/kg dose) [22].

Associations of L-158809 with other chemical compounds

• METHODS: LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg) [9].
• In vitro functional assays utilizing AII-induced aldosterone release in rat adrenal cortical cells demonstrated further that L-158,809 acts as a competitive, high affinity antagonist of AII (pA2 = 10.5) and lacks agonist activity [23].
• The disposition of the angiotensin II receptor antagonist L-158,809 was studied in male rats and female rhesus monkeys [24].
• The selective angiotensin receptor subtype ligands losartan and L-158,809 (AT1), PD 123319 and CGP 42112A (AT2) were inactive [25].
• Prior to TBI the rats were randomized to groups receiving an ACE inhibitor (captopril), an AII type 1 (AT1) receptor antagonist (L-158,809) or no treatment [26].

Gene context of L-158809

• Cells were stimulated with Ang II and the effect was modulated by Ang II type 1 (AT1) and AT2 receptor blockers DUP753 or L-158809 and PD-123319, respectively [27].
• 2. In the absence of NO blockade, the AT1-R antagonist L-158809 (500 nM) antagonized the Ang II-induced vasoconstrictions, while the AT2-R antagonist PD-123319 (500 nM) had no effect [15].
• L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays [28].
• L-158,809 demonstrated a very high selectivity for the AT1 compared to the AT2 receptor subtype (AT2 IC50 greater than or equal to 10 microM) [23].
• L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys [28].

Analytical, diagnostic and therapeutic context of L-158809

• Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty [6].
• Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809 [9].
• The plasma concentrations of L-158,809 varied considerably between monkeys after oral administration [24].
• RESULTS: The average yield of L-158,809 microspheres (10% (w/w)) was 95% of the theoretical loading [29].
• VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys [30].

References