J. Phy8iot. (1984), 353, pp.

393-403 393
With 4 text-ftgures
Printed in Great Britain

DIFFERENTIAL EFFECTS OF ISCHAEMIA AND

HYPERKALAEMIA ON MYOCARDIAL REPOLARIZATION AND
CONDUCTION TIMES IN THE DOG
BY R. M. DONALDSON, F. S. NASHAT, D. NOBLE* AND P. TAGGART
From the Department of Physiology, Middlesex Hospital Medical School,
Cleveland Street, London WIP 6DB

(Received 11 November 1983)

SUMMARY
1. The role of increased extracellular K+ concentration ([K+]O) in the production
of the early electrophysiological changes induced by myocardial ischaemia, was
evaluated by recordings of monophasic action potentials and the paced endocardial
evoked response.
2. Changes in the duration of local repolarization and conduction time were
evaluated during ischaemia, K+ infusion and hypoxia.
3. Raising [K+]o levels in systemic arterial blood from 3 4 + 0-5 mmol 1-1 to
5-9 + 1P5 mmol 1-1 produced a similar shortening of repolarization as was seen during
ischaemia.
4. Prolongation of conduction time occurred only when the [K+]o levels rose to
8-8 ± 1-3 mmol l-1.
5. The conduction time slowing during acute ischaemia was always greater and
occurred at lower [K+]o levels than that produced by K+ infusion at rates equivalent
to the post-ischaemic myocardial venous effluent.
6. Monophasic action potential amplitude and upstroke velocity were reduced in
ischaemia but not markedly affected by the increase in [K+]O.
7. Absolute reduction in repolarization time during K+ infusion was more marked
at the apex than at the base in the epicardial recordings.
8. The superimposition of hypoxia on hyperkalaemia resulted in marked slowing
of repolarization and conduction time.
9. Many but not all of the early electrophysiological abnormalities of acute
ischaemia in the intact heart can be related to raised [K+]O.

INTRODUCTION

The accumulation of extracellular K+ has been implicated in the production

of the early electrophysiological changes induced by acute myocardial ischaemia
(Harris, Bisteni, Russel, Brigham & Firestone, 1954; Soloff, De los Santos &
Oppenheimer, 1960; Ettinger, Regan, Oldewurtel & Khan, 1973; Kaplinsky, Ogawa,
Balke & Dreifus, 1979). Studies employing K+-sensitive electrodes have shown
* University Laboratory of Physiology, Oxford.
394 R. M. DONALDSON AND OTHERS
increases in extracellular K+ concentration ([K+]O) of up to 12 mmol in the
ischaemic myocardium during the early stages of coronary artery occlusion (Wiegand,
Guggi, Meesman, Kessler & Greitschus, 1979; Hill & Gettes, 1980; Hirche, Franz &
Schramm, 1980).
Intracavitary recordings of the paced endocardial evoked response and monophasic
action potentials are sensitive indices of the electrophysiological changes produced
by regional myocardial ischaemia (Donaldson, Taggart, Nashat, Abed, Rickards &
Noble, 1983). Using this technique we have evaluated the differential effects of
ischaemia and hyperkalaemia on ventricular repolarization and conduction times in
open-chested dogs. The combined effects of hyperkalaemia and hypoxia were also
studied.

METHODS
Recordings of the monophasic action potential
Extracellular potential changes during ischaemia were assessed from recordings of monophasic
action potentials (m.a.p.; Fig. 1). Endocardial monophasic action potentials were obtained using
a small (0 3 mm2) non-polarizing electrode placed in contact with the ventricular endocardium and
referred to a local indifferent electrode. The distal electrode located at the tip of the catheter was
buffed off so that it was just recessed within the catheter tip; the indifferent electrode was brought
through a side hole drilled in the catheter 3 mm from the tip, flush with the wall. When the tip
of the catheter impinged on the ventricular endocardium, monophasic potentials of 20-35 mV
amplitude could be recorded. Suction was not used for these recordings. During K+ infusion,
additional suction and wick electrodes, described previously by Lab & Wollard (1978), were
positioned in the epicardial apical and basal regions of the left ventricle.
The arrangement of the various electrodes are shown in Fig. 1. The monophasic signals were
pre-amplified with a high impedance purpose-built d.c. amplifier (Watco Limited). The criteria for
accepting monophasic action potential recordings were the uniformity of the shape in ten or more
consecutive beats, their resemblance to the accepted configuration for transmembrane action
potentials, a smooth repolarization course and a horizontal base line. Duration of the monophasic
action potential was measured at 90 % repolarization time (Fig. 1) (Olsson, Varnauskas & Korsgren,
1971). The measurements were always made at the constant paced cycle length of 300+20 ms.
Changes in the interval between the ventricular stimulus and the upstroke in the monophasic action
potential wereof considered to represent changes in the local conduction time and were expressed
as a fraction the initial control value.
Recording the paced endocardial evoked response
The method of sensing and recording the paced endocardial evoked response has been described
in detail by Donaldson & Rickards (1982). Basically the technique employs a conventional unipolar
pacing catheter which delivers a pacing stimulus of approximately 2-5 mA for 0-5applied. ms to the
ventricular endocardium, care being taken to ensure that only the cathodal current is The
paced endocardial evoked response is seen as a negative QRS wave reaching a nadir in approximately
35 ms after the pacing pulse; this is followed by a clearly defined positive T wave (Fig. 1). By using
the same electrode for pacing and sensing, the system can record local repolarization following a
controlled depolarization. The incorporation of a peak detector with an adjustable sensing window
into the pace maker permits measurement of the interval between the applied stimulus and the
peak of the evoked T wave automatically on a beat-to-beat basis.
The time interval between the pacing stimulus and peak of the T wave provides a measurement
of local repolarization time (Donaldson & Rickards, 1982).
Acute coronary occlusion experiments
Nine coronary occlusion and re-perfusion experiments were scarred out in seven Beagle dogs of
either sex pre-medicated with morphine sulphate 4 mg kg-' and anaesthetized with chloralose and
urethane (80-250 mg kg-'). Additional injections were given as needed to maintain anaesthesia.
 CARDIAC REPOLARIZATION AND CONDUCTION 395
In two dogs pentobarbitone (30 mg kg-') was used. The trachea was intubated with a cuffed
endotracheal tube (McGill) and the animals were artificially ventilated throughout the experiment
with a Starling pump. Ventilation was adjusted to keep the Pa,co, at less than 5-7 kPa and Pa,O2
more than 11 kPa. Ventilation was set at the onset of the experiment and was not altered
afterwards, except during the combined hypoxia and hyperkalaemia studies. The chest was opened
at the level of the fifth left intercostal space. A lobe of the left lung was excised to give a clear

E.c.g. -1VJ

ms
Epi m.a.p. 100
apexhrn 0

170
Epi m.a.p. St. I10mV
base

165

1 00

mV
Endo
m.a.p.
180

\ P.e.r. -__ | <

St. /190

Fig. 1. Recording technique. The intracardiac electrode positioned in the apex of the left
ventricle recorded the simultaneous endocardial monophasic action potential (m.a.p.) and
the paced endocardial evoked response (p.e.r.). The time interval between the pacing
stimulus (St.) and the peak of the evoked T wave (T) on the p.e.r. provide a measure of
local repolarization time. Suction and wick electrodes positioned in the epicardial apical
and basal regions of the left ventricle recorded the m.a.p. for the surface of the heart.
Changes in the interval between St. and the upstroke of the m.a.p. were considered to
represent changes in local conduction time. The aortic pressure (Ao.p.) and the electro-
cardiogram (e.c.g.) were documented simultaneously.
view of the anterior surface of the heart. The pericardium was slit open and in deep-chested animals
used to 'cradle' the heart. Acute myocardial ischaemia was produced by complete occlusion of the
left anterior descending coronary artery 1-2 cm distal to its origin, using an 'umbilical' tape. The
dogs were subjected to ischaemic episodes of 1-3 min duration each. These occlusions predictably
resulted in a small area of ischaemia which was confirmed in two experiments by continuous
measurement of myocardial Po2 using a 0-65 mm needle tip PO, monitor (module 636, Roche). In
experiments where more than one occlusion was made, a rest period of 60 min or more was allowed
between the coronary ligations.
396 R. M. DONALDSON AND OTHERS
In these experiments, the pacing electrode and the bipolar monophasic action potential catheter
were positioned next to each other on the endocardial surface of the region supplied by the
temporarily occluded coronary artery. They were introduced either by direct puncture of the
ventricle or via the left atrial appendage. One pair of catheters was positioned in the potentially
ischaemic zone and the other pair in a normal zone of the heart not perfused by the left anterior
descending coronary artery. The non-ischaemic zone was usually located at the base of the right
ventricle. The intracardial electrograms from the non-ischaemic zone and the ischaemic zones were
recorded alternately at paper speeds of 100 and 250 mm s-1 along with three selected e.c.g. leads
and the electronic peak detector using either an eight-channel ink-jet recorder (Siemens-Elema
Mingograf 82) or an eight-channel heat-sensitive recorder (Devices Instruments Limited model M19)
at paced cycle lengths of 300 ms (± 20 ms) (Fig. 1). The paced cycle length was kept constant during
the period of occlusion and at short intervals for 15 min thereafter. Femoral artery pressure was
monitored using a Statham 23 BD strain gauge transducer.
K+ infusion
K+ was infused in the same dogs after completing the coronary experiments and allowing at least
60 min for recovery. The extracellular K+ was raised by the infusion of a 26 mM-KCl solution into
the systemic circulation at a rate of 0.5-1 ml min'. The plasma K+ was measured by flame
photometry from samples obtained from the abdominal aorta.
The coronary venous K+ was monitored from the distal part of the great cardiac vein which was
cannulated with an 18G polyethylene catheter. In each experiment an average of three readings
were obtained.
Combined effects of hyperlcaaemia and hypoxia
In five animals hypoxia was induced by ventilating the animal with 10 % 02 in N2. Breathing
this mixture reduced Pao, to 6-7 kPa.
StatistiC8
The data were compared using paired t statistics.

RESULTS

In the control state the duration of local repolarization as measured from the
epicardium was longest at the apex and shortest at the base in all experiments. At
the endocardium, the repolarization time was longer than that of the corresponding
epicardial site (Fig. 1).
Endocardial recordings during acute coronary occlusion experiments
Typical changes in the duration of the local repolarization was evaluated by the
paced endocardial evoked response are illustrated in Fig. 2. Regional subendocardial
ischaemia shortened the duration of the paced endocardial response from the
ischaemic zone within 10 s of the coronary occlusion in three experiments and within
60 s in the other six studies. The shortening progressed with the occlusion up to 3 min.
The mean control values in nine experiments was 175+19 ms (S.D.); 1 min after
occlusion the mean values had decreased significantly to 167 + 16-1 ms (P < 0-001)
(Table 1); at 2 min the repolarization was shortened by a mean of 20 ms to
155+17 ms. The simultaneous paced monophasic action potentials from the
ischaemic zone showed a decrease in amplitude within seconds. This was followed
shortly, within the minute, by a decrease in the slope of the repolarization, and a
delay in the upstroke velocity and conduction time. At 1 min after coronary occlusion
the repolarization time was shortened from an average 180 + 21-2 ms (S.D.) to
 CARDIAC REPOLARIZATION AND CONDUCTION 397
Control
I 10 mV

M.a.p. _

St. 20100 Ms

P.e.r.
St. 210

Ischaemnia (30 s)

M.a.p.
St.
1-j70

P.e.r.
S.180 '

Fig. 2. Effect of ischaemia on the simultaneous paced endocardial monophasic action

potential (m.a.p.) and on the paced endocardial evoked response (p.e.r.) recorded from
the ischaemic zone of the left ventricle. There is decrease in m.a.p. amplitude and a 50 ms
shortening of the m.a.p. 90% repolarization time. A 30 ms decrease in the stimulus
(St.) - peak T wave interval of the paced endocardial evoked response occurs. Paced cycle
length = 310 ms.

TABLE 1. Change in repolarization and conduction times during ischaemia, K+ infusion and
combined hyperkalaemia and hypoxia studies
Ischaemia K+ infusion
Control (2 min) Control K+infusion + hypoxia

Arterial [K+]. 3-6+0-6 5 ±12t 34+05 5-9+15 8-8+1P3 6-0+P12

(mmol 1-1) n= 18 n = 15 n= 18 n= 18 n = 16 n=5
Endocardial 180+21 150+ 17.6* 165+25 148+23* 134+28* 128+20*
m.a.p.
90% repolarization (ms) n=9 n=9 n=9 n=9 n=9 n=5
Paced endocardial 175+19 155+ 17* 160+21 148+ 16* 130+ 18* 120+ 16*
evoked response (ms) n=9 n=9 n=9 n=9 n=9 n=5
C.t./c.t.. 1.72 + 0.4* 1-12+0-2 1.65+0.4* 1.78+0.3*
n=9 n=9 n=9 n=5
The values represent mean + 1 S.D. n = sample size.
t Coronary sinus [K+]. measured after release of the coronary arterial occlusion.
* P < 0-001 compared with control values.
C.0 = Control conduction time.
398 R. M. DONALDSON AND OTHERS
167 + 20-4 ms (P < 0 001) and at 2 min to 150 + 17-6 ms (Table 1). Following release
of the occlusion, the ischaemic changes were reversed rapidly, invariably within 30 s
of reperfusion. The corresponding e.c.g. usually showed no changes; when these
occurred they were subtle and delayed in onset. The monophasic action potential
shortening usually paralleled the decrease of the simultaneous paced endocardial
evoked response obtained from the adjacent myocardium. Provided 30-45 min
recovery periods were allowed beyond the transient coronary ligations, these
electrophysiological changes were reproducible.
The paced evoked response and monophasic action potentials from the non-
ischaemic zones showed no changes throughout the experiments.
Endocardial and epicardial recordings during K+ infusion
Mean arterial [K+]0 was 3-4 + 0 5 mmol 1-1 during control conditions. The values
of [K+] obtained during the infusion were subdivided into either moderately raised
(5-8 + 1-5 mmol 1-1) and high (8-8 + 1-3 mmol 1-1) K+ subgroups (Table 1). Changes in
the endocardial repolarization time are shown in the Table. A significant shortening
of repolarization was noted at both levels of [K+]o. The conduction time was not
significantly prolonged in the lower [K+]0 groups, but increased significantly to
1-65 + 1-4 at the higher values of [K+]o.
The epicardial monophasic action potential tracings obtained during the hyper-
kalaemic experiments showed that the degree of shortening of repolarization was
non-homogeneous. Measurements at the apex always exceeded those obtained from
the base in control conditions (Fig. 1). A preferential shortening of epicardial apical
repolarization occurred during infusion with K+, and resulted in shorter apical than
basal monophasic action potential durations as the [K+]O rose.
Comparison of repolarization and conduction time changes during ischaemia and
hyperkalaemia
Fig. 3 compares endocardial control recordings with those obtained during K+
infusion and ischaemia. Increasing systemic K+ levels to arterial [K+]O of 8 and
7.7 mmol 1-1 respectively delayed the conduction time and shortened endocardial
repolarization. During ischaemia, depression ofmonophasic action potential amplitude
and upstroke velocity were more marked and there was a greater delay in conduction
time. The slowing of conduction time during ischaemia was more marked and
occurred at lower coronary sinus [K+]o than that produced by K+ infusion (Table 1).
Thus coronary sinus [K+]o values of 5 + 1-2 mmol 1-1 were documented after the
release of the 2 min coronary occlusion. Following the coronary occlusion, the
conduction time ratio was 1-72 + 0-4 ms. During K+ infusion the ratio was 1-2 + 0-2
at the lower [K+]. group and significantly greater (1I65+0-4) at the higher levels
(Table 1).
Combined effects of hyperkalaemia and hypoxia
The ischaemic changes in repolarization and conduction were successfully repro-
duced by K+ infusion during hypoxia (Fig. 4). The combination of hyperkalaemia
at [K+]. equivalent to the lower K+ subgroup and hypoxia resulted in marked
shortening of the duration of the monophasic action potentials and of the paced
endocardial evoked response; the epicardium changes were more manifest in the
 CARDIAC REPOLARIZATION AND CONDUCTION 399
Control Ki infusion Ischaemia

M.a.p.

C.t.
f

P.e.r. 1
145 St
IV St.
14
140I
LI L
(i I/
[K10o (mmol l-l) 3.4'
7.7 56
Fig. 3. Comparison of the changes in conduction time (c.t.) and in the duration of
endocardial repolarization during K+ infusion and ischaemia. The [K+]O in the coronary
venous effluent is shown at the bottom of the illustration. Conduction time slowing during
ischaemic was greater and occurred at lower [K+]. than that produced by K+ infusion.
Hyperkalaemia and ischaemia produced similar changes in m.a.p. and p.e.r. duration.
M.a.p. amplitude was more affected during the coronary occlusion experiment (note
different calibration). Paced cycle length = 295 ms.

Control K+ infusion K+ infusion + hypoxia

[K+] (mmol l-l) 3.6
6-7 6-7
100 ms
10 mV1
Apical m.a.p.f
St.
St. 10 8
C.t. 170 t. v.- 150\
60 60
\10mVI
Basal m.a.p.
145 80
P.er. 160 6
65 65
P.e.r. I
St.

Fig. 4. Recordings of the epicardial apical and basal monophasic action potentials (m.a.p.s)
and ofthe paced endocardial evoked response during hyperkalaemia and during K+ infusion
and hypoxia. The combination of K+ infusion and hypoxia resulted in marked shortening
of m.a.p. and p.e.r. duration; at the epicardium changes were more manifest in the apical
m.a.p. recordings. Marked slowing of conduction time (c.t.) resulted at arterial K+ levels
of 6-7 mmol 1-1 in the presence of hypoxia. This c.t. slowing was much greater than that
produced by the K+ rise alone. Paced cycle length = 320 ms.
400 R. M. DONALDSON AND OTHERS
apical recordings (Fig. 4). Marked slowing of conduction time resulted at serum [K+]o
of 6+ 12 mmol 1-1 during hypoxia. The conduction time ratio at that level of
K+ was 1P78 + 0-3 (Fig. 4 and Table 1).

DISCUSSION
During the early phases of regional ischaemia, ionic and electrical changes take
place in a small area of the myocardium, leading to a decrease in the resting
membrane potential and shortening in the duration of the action potential (producing
disparate repolarization times); there is asynchronous activation due to differential
conduction delay (Lazzara, El-Sherif & Scherlag, 1974; Downar, Janse & Durrer,
1977; Russell, Smith & Oliver, 1979; Janse & Kleber, 1981). The decrease in duration
of the action potential which has been noted by the measurement of transmembrane
potentials (Friedman, Steward, Fenoglio & Wit, 1973; Kleber, Janse, Van Capelle
& Durrer, 1978) is due mainly to shortening of the plateau phase of repolarization
(Janse & Kleber, 1981). The causes of the shortening are still unresolved. Possible
mechanisms include the depression of the fast inward current (Noble, 1979; Vleugels,
Vereecke & Carmeliet, 1980), the suppression of the slow inward current, i81
(Cheneval, Hyde, Blondel & Gurardier, 1972; Nargeot, 1976; Chesnais, Coraboeuf,
Sauviat & Jassas, 1975; Kohlhardt & Kubler, 1975) and changes in the Ca2+-dependent
K+ currents.
Whatever the ionic mechanism, these electrical changes may influence the develop-
ment of the ventricular arrhythmias of the early phase of ischaemia (Boineau & Cox,
1973; Lazzara, El-Sherif, Hope & Scherlag, 1978; Janse & Kleber, 1981); abnormally
enhanced automaticity and diastolic depolarization may also play a role in this
context. The changes in monophasic action potentials duration and conduction time,
although crude estimations of refractoriness and conduction velocity, are relevant
to the assessment of the electrophysiological alterations during ischaemia on the
intact heart. We have shown previously that these clinically applicable intracardiac
recordings can detect and monitor the early electrophysiological changes of ischaemia
(Donaldson et al. 1983). The duration of the paced endocardial evoked response and
monophasic action potentials normally represent a measure of the local refractory
period of the myocardium. Whether this ig true for ischaemic tissue, where post-
repolarization refractoriness may cause a disparity between action potential duration
and refractoriness (Janse & Kleber, 1981) is uncertain.
The electrophysiological changes associated with acute ischaemia are attributable
to various factors, such as the sudden unavailability of oxygen or substrate or the
accumulation of substances such as K+ released by the ischaemic myocardium into
the extracellular space. Increased extracellular K+, has been considered to be a major
factor in the production of electrical changes in ischaemia (Harris et al. 1954; Soloff
et al. 1960; Ettinger et al. 1973; Kaplinsky et al. 1979).
High K+ solutions were perfused into the myocardium to increase [K+]. to approxi-
mate levels previously recorded during early ischaemia in the myocardium with
K+-sensitive electrodes (Wiegand et al. 1979; Hill & Gettes, 1980; Hirche et al. 1980).
Elevation of [K+]o produced a shortened repolarization time comparable to that seen
during ischaemia, but conduction time was only prolonged when the [K+]0 rose to
 CARDIAC REPOLARIZATION AND CONDUCTION 401
8-8 + 1-3 mmol 1-1 (Table 1). The monophasic action potential amplitude and upstroke
velocity were noticeably reduced in ischaemia (Fig. 3) but not markedly affected by
the rise in [K+]O. It ought to be noted that the difficulty in measuring monophasic
action potential amplitude limits the comparison to cases where consecutive mono-
phasic action potential records for a limited number of beats in the same site were
obtained. It may be argued that during myocardial ischaemia the [K+]. at the site
of tissue destruction increases much more than what could be produced in animal
experiments. In this condition the higher concentration of K+ may be the more appro-
priate figure for use when comparing the effects of ischaemia and hyperkalaemia.
This question is unlikely to be resolved by measurement of the concentration of K+
in the coronary sinus. Absolute reduction in repolarization time was more marked
at the apex than it was at the base in the epicardial recordings.
The mechanism for this non-homogeneous effect of hyperkalaemia on the duration
of repolarization is not evident from this study. Differences in the degree of local K+
levels related to differences in regional blood flow, or differences in the sensitivity of
various regions to particular K+ levels (Mendez, Muller, Merideth & Moe, 1969) are
amongst the possible mechanisms. The non-uniform effects of hyperkalaemia on
repolarization have relevance with respect to changes in the electrocardiograph have
relevance with respect to changes in the electrocardiographic T wave (Cohen, Giles
& Noble, 1976) and are of probable significance to the development of ventricular
arrhythmias.
The superimposition of hypoxia and hyperkalaemia resulted in marked slowing of
the conduction time (Fig. 4). The changes were much more marked in the epicardial
records from the apical region.
The effects of hyperkalaemia on the duration of repolarization in the intact heart
of the dog documented from the extracellular recordings are similar to those noted
in isolated tissue experiments (Weidman, 1956; Vasalle, 1965) and those computed
by Noble (1965) and DiFrancesco & Noble (1981). Similar findings have been
demonstrated in the isolated porcine heart (Morena, Janse, Fiolet, Krieger, Crijns &
Durrer, 1980) and in open-chested pigs (Hill & Gettes, 1980). Many of these
electrophysiological features result from the effects of [K+]. on the inward rectifying
background current iK1 present in Purkinje and myocardial cells (Noble, 1979).
In conclusion, it appears that the early electrophysiological abnormalities of acute
ischaemia in the intact heart can be related to raised extracellular K+ concentration.
However, the contribution of other changes in intracellular and extracellular pH,
Pco, and their effects on the extracellular accumulation of metabolic products could
not be excluded.

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