Linked Life Data

8495233

Source:http://linkedlifedata.com/resource/pubmed/id/8495233

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1993-6-21
pubmed:abstractText
1. The present experiments were undertaken in order to characterize further the apparently irreversible inhibition of the contraction of depolarized rat aorta caused by lacidipine, a 1,4-dihydropyridine calcium antagonist. 2. We studied the effect of lacidipine on contraction evoked by 100 mM KCl solution in rat aorta, treated by N omega-nitro-L-arginine (0.1 mM), an inhibitor of nitric oxide (NO) synthesis. We compared the effect of prolonged depolarization on lacidipine and (+)-isradipine inhibition and the reversal of this inhibition after washout in the absence of dihydropyridines. Assuming that the onset of lacidipine-evoked inhibition was a pseudo-first order association kinetics, we estimated the dissociation rate constant (k-1 = 0.031 min-1), the association rate constant (k1 = 2.70 x 10(8) M-1 min-1) and the dissociation constant (KD = k-1/k1 = 115 pM) which was close to the IC50 value in steady-state conditions (160 pM). 3. The inhibitory effects of lacidipine and (+)-isradipine on rat aorta contraction were reversibly enhanced after preincubation with the drug in a 40 mM KCl-solution. Washout with drug-free 40 mM K(+)-depolarizing solution reversed inhibition in the (+)-isradipine-treated preparations, but not in the lacidipine-treated ones. 4. Radioligand binding studies were performed with [3H]-lacidipine and [3H]-isradipine in microsomes from rat aorta and rat ileum. Both ligands bound to a homogeneous population of binding sites (for[3H]-lacidipine: KD = 23 +/- 2.6 pM, Bmax = 380 +/- 21 fmol mg-1 protein in membranes from aorta; KD =23 +/- 3.1 pM, Bmax = 790 +/- 60 fmol mg-1 protein in membranes from ileum; for [3H]-isradipine:KD = 140 +/- 46 pM, Bmax = 350 +/- 64 fmol mg-1 protein in membrane from aorta; KD = 68 +/- 14 pM,Bmax = 760 +/- 75 fmol mg-1 protein in membranes from ileum). After isotopic dilution, [3H]-lacidipine and [3H]-isradipine dissociated according to a monoexponential kinetics. In membranes from ileum, the calculated dissociation rate constants (kappa_ 1) were 0.0257 min-1 and 0.0595 min-1, for [3H]-lacidipine and[3H]-isradipine, respectively.5. The non specific binding of [3H]-lacidipine and [3H]-isradipine, was measured in intact rat aorta preparations incubated under the conditions of the functional experiments, in the presence of nifedipine(1 microM). After incubation with [3H]-lacidipine 77.6 +/- 1.9 pM for 2 h the concentration of drug in the tissue was 15.15 +/- 1.18 fmol mg-1 w.wt. and still amounted to 7.24 +/- 0.61 fmol mg-1 w.wt. after 3.5 h washout in drug-free solution. After incubation with [3H]-isradipine 47.2 +/- 0.4 pM for 2 h it was 2.26 +/-0.07 fmol mg-1 w.wt. and was undetectable after 3.5 h washout in a drug-free solution.6. It is concluded that lacidipine interacts reversibly with dihydropyridine binding sites and that the apparent irreversible inhibition of contraction in depolarized preparations could be related to a nonspecific binding in a tissue compartment different from the plasma membrane.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1313732, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-14907713, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1531693, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1656465, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1658191, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1691398, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1725443, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1826619, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-1837846, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2152924, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2174553, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2328404, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2420337, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2427250, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2432624, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2446799, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2582076, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2824756, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2851351, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-2987659, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-6034324, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-6088117, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-6093156, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-6116136, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-6455156, http://linkedlifedata.com/resource/pubmed/commentcorrection/8495233-7449765
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0007-1188
pubmed:author
pubmed:issnType
Print
pubmed:volume
109
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
100-6
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
Radioligand and functional estimates of the interaction of the 1,4-dihydropyridines, isradipine and lacidipine, with calcium channels in smooth muscle.
pubmed:affiliation
Laboratoire de Pharmacologie, Université Catholique de Louvain, Bruxelles, Belgium.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't