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  • 4-Dihydropyridines  (1)
  • angiotensin II receptor antagonist  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 355 (1996), S. 119-125 
    Details
    ISSN: 1432-1912
    Keywords: Key words Aranidipine ; Metabolites ; Ca2+ channel antagonist ; 1 ; 4-Dihydropyridines ; Binding study ; Slow kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aranidipine, a novel dihydropyridine derivative, gives rise to two active metabolites, M-1(α) and M-1(β), which exhibit hypotensive activity comparable to that of nifedipine. The aim of this study was to examine the recovery phase of the vasodilating effect of M-1(α) and of M-1(β), to determine their binding characteristics and to compare the results with those for aranidipine and other dihydropyridine derivatives. During intra-arterial infusion into the femoral vascular beds of anesthetized dogs, M-1(α), M-1(β), and nifedipine, produced increases in femoral blood flow at doses three times higher than the dose of aranidipine required to produce a comparable effect. The onset and recovery of the effects of the metabolites on femoral blood flow were significantly slower than the onset and recovery of the effect of nifedipine. The inhibitory activities of M-1(α) and M-1(β) towards stimulated 45Ca uptake in isolated guinea pig aorta were less than that of aranidipine. In binding studies, using porcine heart membrane preparations, [3H]M-1(α) and [3H]M-1(β) had larger Kd values than [3H]aranidipine and [3H]nitrendipine, but the maximal binding number for each of them was almost the same. The association and dissociation rate constants for [3H]M-1(α) and [3H]M-1(β) binding, as well as those for [3H]aranidipine binding, were significantly smaller than those for [3H]nitrendipine, corresponding to the recovery of the in vivo vasodilating effects of the metabolites. The dissociation rate constants of these radiolabeled ligands were highly positively correlated with the elimination rate constants of their in vivo vasodilating effects. From these results, we conclude that M-1(α) and M-1(β), although their binding affinities and Ca2+ antagonistic actions are less potent, possess slower kinetic binding properties than many other dihydropyridines and that the slow kinetic interaction of these metabolites with the dihydropyridine receptor may contribute to the long-lasting in vivo vasodilating effect of aranidipine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00004909
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
    Details
    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011932800729
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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