diphenylurea NS1643 represents such a HERG-activator. NS

1643 activated human HERG channels in a heterologous

expression system, whereas Na+ and Ca2+-channels were not

blocked by the agent. Here we describe the effects of NS1643

on force of contraction and action potential parameters in

isolated guinea pig papillary muscles.

NS 1643 (10 AM) affected mainly the late phase of

depolarisation: APD90 was decreased from 156 T 6 to 137 T 13

ms (mean T SEM, n = 5, P < 0.05) whereas APD20 remained

unaffected compared to time-matched controls. Frequency-

dependency of the effect on APD90 was not observed. Resting

membrane potential (-87 T 0.4 mV) and upstroke velocity (229 T21 V/s) were not affected up to concentrations of 30 AM and 100

AM respectively. The shortening of APD with 10 AM NS1643

was accompanied by a small negative inotropic effect. Force of

contraction decreased from 59 T 8 to 33 T 5 AN (n = 5) in the

presence of 10 AMNS1643, for comparison in TMC from 89 T 14to 69 T 14 AN.

Activation of IKr by NS1643 effectively shortens AP in

guinea pig papillary muscle. Excitability and conduction seem

to be unaffected. The small negative inotropic effect could be

related to the shortening of action potentials.

doi:10.1016/j.yjmcc.2006.03.188

174. Basal vagal nerve activity does not predict

susceptibility to dofetilide-induced torsade de pointes in

anaesthetized rabbits

Andras Farkas a, Attila S. Farkas a, Laszlo Rudas b, Istvan

Lepran c, Szabolcs Orosz d, Norbert Csık b, Tamas Forster a,

Miklos Csanady a, Julius Gy. Papp c,e, Andras Varro c. a 2nd.

Dept. of Internal Medicine, University of Szeged, Hungary.b Dept. of Anaesthesiology and Intensive Care, University. of

Szeged, Hungary. c Dept. of Pharmacology and Pharmacother-

apy, University of Szeged, Hungary. d Gedeon Richter LTD,

Budapest, Hungary. e Div. Cardiovasc. Pharm. HAS

Proarrhythmic activity of repolarisation prolonging drugs

can be enhanced by vagal nerve mediated bradycardia. This

study examined whether baseline vagal nerve activity

measured indirectly by baroreflex sensitivity (BRS) and heart

rate variability (HRV) correlates with the subsequent occur-

rence of dofetilide-induced torsade de pointes ventricular

tachycardia in Na-pentobarbital anaesthetized rabbits. After a

10 min baseline interval, which was used to calculate baseline

HRV and BRS values, a1-adrenoceptor agonist phenylephrine

(15 Ag/kg/min, for 35 min) and dofetilide (0.02 mg/kg/h, for

30 min) were infused intravenously to each animal. HRV,

BRS and arrhythmia analysis were performed retrospectively.

Dofetilide infusion induced torsade de pointes in 20 animals

out of 30. The baseline HRV values (428 T 9 ms, mean of RR

interval means T S.E.; 3.6 T 0.3, mean of the standard

deviations of the mean RR intervals T S.E.; 3.2 T 0.3,

RMSSD T S.E.) and the baseline BRS values (1.35 T 0.26

ms/mmHg, mean up BRS T S.E., 1.09 T 0.20 ms/mmHg,

mean down BRS T S.E) of the animals experiencing torsade

de pointes (TdP group, n = 20) did not differ significantly

from those values measured in animals not experiencing

torsade de pointes (non-TdP group, n = 10, data not shown).

Thus, it is concluded that baseline vagal nerve activity did not

predict susceptibility to dofetilide-induced torsade de pointes

in anaesthetized rabbits.

Acknowledgments

Funded by: ETT 203/2003, OTKA F046776, Bolyai BO/

00168/03.

doi:10.1016/j.yjmcc.2006.03.189

175. An inducible cell system to investigate connexin

co-expression and action potential propagation within the

heart

Neil Thomas b, Emmanuel Dupont a, Deborah Halliday a,

Christopher H. Fry b, Nicholas J. Severs b. National Heart and

Lung Institute, Imperial College London. b Institute of Urology

and Nephrology, University College London

Cx43, Cx40 and Cx45 are co-expressed in distinctive

combinations and relative quantities in different, functional-

ly-specialized subsets of cardiomyocytes and are commonly

altered in human heart disease. To evaluate the functional

correlates of these connexin co-expression patterns, we have

developed in vitro models designed to express the same

combinations of connexins in the same relative quantities as

those found in defined cardiac tissues and disease states in

vivo. RLE cells (which endogenously express Cx43) have

been engineered to generate clones inducible for Cx40 and

Cx45. Immunoconfocal microscopy analysis suggests that

the Cx40:Cx43 ratio within a connexon affects compatibility

of heteromeric Cx40/Cx43 connexon docking whereas

connexons made of different ratios of Cx45 and Cx43 are

always fully compatible. At maximal induction, despite

increased total connexin expression (¨50%), the levels of

connexon aggregated into gap junctions is decreased and the

extent of electrical coupling remains unchanged. The

expression levels of endogenous Cx43 are thus influenced

by those of the transfected connexins. Co-expressing cells

appear to use different ratios of Cx40 and Cx43 in

heteromeric connexons and/or regulate the amounts of

connexons aggregated into gap junctions in order to

maintain communication/electrical coupling. To study the

complex interaction between cell/tissue architecture, active

ion channels and gap-junctional communication in action

potential propagation, we have isolated sub-clones of the

HL-1 cardiomyocyte cell line which, unlike RLE cells,

display electrical activity and are amenable to the same type

of genetic engineering. These engineered cell lines will

allow us to relate quantitatively the expression of connexins

to conduction velocities.

doi:10.1016/j.yjmcc.2006.03.190

ABSTRACTS / Journal of Molecular and Cellular Cardiology 40 (2006) 920–1015984