Linked Life Data

8750918

Source:http://linkedlifedata.com/resource/pubmed/id/8750918

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1996-11-6
pubmed:abstractText
The inhibition of the pacemaker current (if) in sheep cardiac Purkinje fibers by ZD 7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium++ + chloride] is lost use-dependently. This disinhibition of if was investigated by using the two-microelectrode voltage-clamp technique. The pulse protocol consisted of a rest period (holding potential of about -50 mV, 1-10 micromol/l ZD 7288) followed by a train of test pulses (potential negative to -100 mV, stimulation frequency 0.05 Hz). At the beginning of the first test pulse there was an immediate reduction of if but inhibition was lost during continued stimulation. Activation of if is sigmoidal and the early delay in current activation was prolonged from 33 ms (no ZD 7288) to 424 ms (10 micromol/l ZD 7288). Therefore hardly any disinhibition occurred during short test pulses (0.5s). During longer test pulses (5 s, -120 mV, 10 micromol/l) disinhibition developed with a time constant of about 2 s. The inhibition of if by ZD 7288 was lost voltage-dependently. With 10 micro mol/l ZD 7288 the half-maximal disinhibition occurred at -92 mV and the slope factor of the disinhibition/voltage curve (Boltzmann relation) was 4.8 mV. The voltage-dependent disinhibition could be abolished largely by extracellular application of protease (0.5 mg/ml, 7 min). After prior disinhibition, reinhibition at the holding potential (about -50 mV) followed a bi-exponential time course indicating that inhibition may be produced by a fast (tau=0.7 min) and a slow component (tau=20-30 min). Increasing ZD 7288 concentration from 1 to 10 mu mol/l accelerated reinhibition, mainly by an increase of the amplitude (A) of the fast component. The ratio Afast/Aslow was 0.399 at 1 micromol/l and 2.65 at 10 micromol/l ZD 7288. The reinhibition of if was unchanged by shifting the holding potential from -50 mV to -20 mV. Trials to wash out the effects of 10 micromol/l ZD 7288 gave two results. The inhibition of if was slightly reversed after a wash-out of 1.5 h with drug-free solution. A second effect of the drug, the fast reinhibition, could be completely removed by wash-out. In summary if is inhibited by ZD 7288 at membrane potentials at which the virtual if gate is closed. Disinhibition occurs during long-lasting hyperpolarization but will hardly be operative in unclamped fibres under physiological conditions.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0028-1298
pubmed:author
pubmed:issnType
Print
pubmed:volume
353
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
64-72
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Inhibition of pacemaker current by the bradycardic agent ZD 7288 is lost use-dependently in sheep cardiac Purkinje fibres.
pubmed:affiliation
Institut für Pharmakologie, Heinrich-Heine-Universität Düesseldorf, Germany.
pubmed:publicationType
Journal Article