Linked Life Data

8825880

Source:http://linkedlifedata.com/resource/pubmed/id/8825880

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
1996-12-3
pubmed:abstractText
RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the dual coronary perfusion model to assess pharmacological activity since, even in rat, a species with extremely low collateral flow, there is evidence of cross-flow between the left and right ventricles.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2828
pubmed:author
pubmed:issnType
Print
pubmed:volume
27
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2595-606
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Further investigations into the mechanism of antifibrillatory action of the specific IK1 blocker, RP58866, assessed using the rat dual coronary perfusion model.
pubmed:affiliation
University Laboratory of Physiology, University of Oxford, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't