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University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
O'Neill, Mark, Claire E. Sears, and David J. Paterson.
Interactive effects of K+,
acid, norepinephrine, and ischemia on the heart: implications for
exercise. J. Appl. Physiol. 82(4):
1046-1052, 1997.
We tested the hypothesis that cardiac ischemia
uncouples the beneficial interaction among hyperkalemia, acidosis, and
raised plasma catecholamines when these chemicals are changed to mimic
their exercise levels. Potassium chloride, lactic acid, and
norepinephrine (NE) were infused intravenously for 2 min into
anesthetized, artificially ventilated, thoracotomized rabbits during
either occlusion of the left circumflex artery (3 min;
n = 10) or after a period of prolonged
ischemia (20 min; n = 7) that led to a
small infarction. NE (1 µg · kg
1 · min1
iv) offset the negative cardiac effects of hyperkalemia (up to 8.7 ± 0.7 mM) and acidosis (arterial pH 7.09 ± 0.03) in normal hearts. Cardiac performance was not significantly depressed by either
acute or chronic ischemia before any infusions. However, the protective
effect of NE during acute ischemia or after prolonged ischemia with
hyperkalemia and acidosis was substantially reduced. These results show
that cardiac ischemia attenuates the protective action of NE and
increases the depressive effects of hyperkalemia and acidosis. Whether
myocardial ischemia amplifies the cardiotoxic effects of hyperkalemia
and acidosis during vigorous exercise by attenuating the beneficial
effect of catecholamines remains to be determined.
rabbit; arrhythmia
INTRODUCTION THE HARMFUL CARDIAC EFFECTS of raised arterial
potassium
([K+]a)
and acid
([H+]a)
and high sympathetic activity are well known (4, 9, 10). However, when
K+, acid, and catecholamines are
increased simultaneously to mimic their exercise concentrations in
whole animals or isolated cardiac tisue, they are tolerated because
they minimize each other's harmful effects (19, 24, 29, 31). Heavy
exercise amplifies the negative cardiac effects of underlying ischemia
by increasing the incidence of ventricular arrhythmias (3), myocardial
infarction (22), and sudden cardiac death (33). Acute myocardial
ischemia facilitates the occurrence of ventricular arrhythmias during
electrical stimulation of cardiac sympathetic nerves or during infusion
of catecholamines (14, 35). It also causes rapid local increases of
extracellular K+ concentration
([K+]o)
and acid (15) and promotes arrhythmias as a consequence of
inhomogeneities in cardiac excitability, conduction velocity, and
refractoriness (11). Thus cardiac ischemia may uncouple the beneficial
interactions among K+, acid, and
catecholamines and depress cardiac performance.
Therefore, the purpose of the study was to investigate the effect of
norepinephrine (NE) on cardiac performance when
[K+]a
and arterial pH (pHa) were
changed to mimic their exercise concentrations
{[K+]o
8.6 mM (20) and pH 6.8 (28)} in the anesthetized rabbit during a
period of acute regional ischemia (3 min) or after a period of
prolonged ischemia (20 min) that led to a small infarction.
METHODS Experiments were performed in accordance with the National Institutes
of Health (NIH) Guide for the Care and Use of
Laboratory Animals [DHHS Publication No. (NIH)
85-23, Revised 1985, Office of Science and Health Reports,
Bethesda, MD 20892] and under a British Home Office Project
Licence (PPL 30/00608).
Anesthesia
Surgery
A tracheostomy was performed, and an endotracheal tube (3.5 or 4 mm ID, Portex) was inserted 4 cm into the trachea and secured. Catheters (Portex) were inserted into a femoral artery and vein and into the left carotid artery for sampling of arterial blood, intravenous infusion of test solutions and anesthetic, and monitoring of arterial blood pressure (ABP), respectively. Animals were artificially ventilated (Oxford, Mark II ventilator, Penlon) on 100% oxygen, with tidal volume and frequency adjusted to maintain arterial PCO2 between 35 and 45 Torr. A midline thoracotomy was performed, and the chest was retracted laterally. The pericardium was removed, and a catheter (Y-can, 23 gauge, Wallace) was inserted into the left ventricle via the apical dimple. The heart was covered with warm moist gauze, and the thoracic cavity was covered by plastic film to reduce fluid loss and cooling. The cranial projections of the sympathovagal trunk were located in the neck, ligated, and cut.Ischemia
Regional myocardial ischemia was induced by proximal occlusion of the left circumflex artery, which supplies most of the free surface of the left ventricle in the rabbit (7). A 3.5-mm silk suture (Ethicon) ligature was placed around the artery without dissecting the vessel. A snare was formed by threading the suture through a length of polyethylene tubing. Traction on the ligature occluded the artery.Measurements
Systemic ABP and left ventricular pressure (LVP) were measured by saline-filled pressure transducers (SensoNor 840, Norway) calibrated in the midaxillary line. The rate of rise of LVP (±LVdP/dt) was calculated by using a differentiator (unit 5270, time interval 33 or 100 ms according to the magnitude of the signal, Lectromed, UK). Heart rate was triggered from the R wave of lead II of the electrocardiogram or from the ABP and digitally displayed. In some rabbits, aortic flow was measured by an electromagnetic flow probe (MDL 1401, Skalar) attached to the ascending aorta. All signals were recorded onto a penwriter (MT8P, Lectromed). The analog inputs were passed to a real time data-acquisition system (MP 100, Biopac Systems) employing Acqknowledge 3.1 software for the Macintosh (Macintosh Quadra 950). Heart rate and LVdP/dt were also calculated by computer, and all data were stored on an optical disk (Panasonic 840).Intensive Care
Body temperature was measured by a rectal thermistor and maintained at 38 ± 1°C by heating lamps above and beneath the operating table. A catheter was passed into the bladder via the urethra. Fluid was replaced by an intravenous sterile saline drip (~10-15 ml/h). Arterial blood samples were regularly withdrawn (90 µl) into preheparinized capillary tubes and analyzed for pH, blood gases, and electrolytes (Na+, K+, Ca2+) (Radiometer ABL505, Copenhagen, Denmark). Respiratory acidosis was corrected by adjusting the ventilator. Metabolic acidosis was corrected by infusion of 4.2% sodium bicarbonate solution intravenously as required.Protocols
Intravenous infusion rates for the solutions were as follows: 300 mM KCl at 1 ml · kg1 · min1,
500 mM L-lactic acid at 1 ml · kg1 · min1,
and NE at 1 µg · kg1 · min1.
On the basis of previous work from our laboratory (19, 24, 25, 29, 31),
these concentrations were chosen to mimic some changes in arterial
blood composition seen during exercise
([K+]o)
up to 8.6 mM (20); pH 6.8 (28); local cardiac concentrations of NE
estimated at ~1 µM (5). In all protocols, arterial blood samples
were taken immediately before the infusion, at 30-s intervals during
the infusions, and 1 and 3 min, respectively, after the infusions were
stopped. For the purposes of this study, "acute" ischemia has
been defined as ischemia lasting 3 min, whereas coronary ligation
lasting 20 min is defined as "chronic" ischemia.
Acute ischemia.
STEP 1.
KCl and lactic acid were infused together for 2 min
(n = 10).
STEP 2.
KCl and lactic acid were infused in combination with NE for 2 min
(n = 10).
STEP 3.
The left coronary artery was occluded, and an infusion of KCl, lactic
acid, and NE was begun within 5 s. The infusion lasted for 2 min, and
the snare was released 1 min after the infusion was stopped
(n = 10). Before test solutions were
infused, a control coronary arterial occlusion (3 min) was performed
(n = 7).
STEP 4.
In three animals, the left coronary artery was occluded, and a control
infusion of NE was performed as described in step
3 above.
Chronic ischemia.
STEP 1.
KCl and lactic acid were infused together for 2 min in a fresh set of
animals (n = 7).
STEP 2.
KCl and lactic acid were infused in combination with NE for 2 min
(n = 7).
STEP 3.
The left coronary artery was occluded, and the occlusion was maintained
for 20 min (n = 7). This time was
chosen because it causes subendocardial necrosis in a small part of the
left ventricle (8-15%) (8) without causing a significant
reduction in resting hemodynamics. After release of the ligature and a
return to stable hemodynamic values, steps
1 and 2 were repeated.
Under conditions of both acute and chronic ischemia, the
sequence of infusions was randomized. Repeat infusions were made when
hemodynamics, pHa, arterial blood
gases, and
[K+]a
had returned to baseline (~10 min).
Statistical Analysis
All data are expressed as means ± SE. A one-way analysis of variance for repeated measurements and a post hoc comparison by using Scheffé's test compared the effects of each intervention. A paired t-test was performed between measurements before and during ischemia for the same perfusion condition. P < 0.05 was accepted as being statistically significant.RESULTS
Acute Ischemia
Hyperkalemia and acidosis. Figure 1 shows that simultaneous intravenous infusion of 300 mM KCl (1 ml · kg1 · min1)
and 500 mM lactic acid (1 ml · kg1 · min1)
for 2 min elevated
[K+]a
from 3.4 ± 0.1 to 10.0 ± 0.8 mM
(P < 0.01) and decreased
pHa from 7.38 ± 0.02 to 7.10 ± 0.03 pH units (n = 10;
P < 0.01). This was accompanied by
hemodynamic depression (Figs. 2 and
3). Mean arterial pressure was reduced from 64 ± 5 to
55 ± 7 mmHg; the maximum rate of pressure development in the left
ventricle
(+LVdP/dtmax) was reduced from 3,814 ± 96 to 2,764 ± 520 mmHg/s, whereas
heart rate did not change significantly. All hemodynamics returned to above control values by time (t) = 180 s except for heart rate, which remained below preinfusion values.
);
KCl, lactic acid, and norepinephrine (NE; 
); and KCl, lactic acid
and NE during a 3-min period of coronary arterial ligation (
; shown
as occlusion bar) on arterial pH
(pHa;
A) and arterial
K+ concentration
([K+]a;
B) levels. All values for
pHa and
[K+]a
were statistically different from control [analysis of variance (ANOVA), P < 0.05].
);
KCl, lactic acid, and NE (); and KCl, lactic acid, and NE during a
3-min period of coronary arterial ligation () on mean arterial
pressure (MAP; A) and left
ventricular pressure (LVP; B). Note
that occlusion offset protective effect of NE during hyperkalemia and
acidosis. Significantly different:
* P < 0.05;
** P < 0.01 (ANOVA);
§ P < 0.05 between KCl, lactic acid, and NE and KCl, lactic acid, NE, and
ischemia (t-test).
Hyperkalemia, acidosis, and NE. Simultaneous infusion of NE for 2 min (1 µg · kg
1 · min1
iv) offset the negative cardiac effects of KCl and lactic acid (Figs. 2
and 3). All values up to t = 120 s
were significantly different from those measured during infusion of KCl
and lactic acid alone (paired t-test).
At t = 120 s, mean arterial pressure
was 76 ± 8 mmHg with KCl, lactic acid, and NE compared with 55 ± 7 mmHg with KCl and lactic acid alone;
+LVdP/dtmax was
3,752 ± 773 mmHg/s with KCl, lactic acid, and NE compared with
2,764 ± 520 mmHg/s with KCl and lactic acid alone. An overshoot
occurred in all parameters measured at
t = 180 s, and hemodynamics
returned to control by t = 300 s.
Acute coronary arterial ligation.
Three-minute occlusion of the left circumflex coronary artery did not
produce any significant change in hemodynamics. Mean arterial pressure
fell from 75 ± 9 to 66 ± 9 mmHg;
+LVdP/dtmax decreased from 3,605 ± 507 to 3,365 ± 471 mmHg/s, and heart
rate increased from 234 ± 12 to 248 ± 17 beats/min.
NE and acute ischemia.
The effect of a 2-min infusion of NE (1 µg · kg1 · min1
iv) during a 3-min period of coronary occlusion was examined in three animals. Hemodynamics were not significantly altered during the infusion (mean arterial pressure rose from 67 ± 9 to 77 ± 9 mmHg; +LVdP/dtmax
was elevated from 4,225 ± 716 to 5,572 ± 182 mmHg/s).
Hyperkalemia, acidosis, and NE and acute ischemia.
The effect of simultaneous infusion of KCl, lactic acid, and NE during
a period of coronary arterial occlusion was examined in 10 animals.
Infusion and occlusion were begun at the same time, but the infusion
was stopped after 120 s and the occlusion after 180 s (Fig. 2). The
infusion elevated
[K+]a
from 4.0 ± 0.2 to 9.9 ± 0.6 mM and decreased
pHa from 7.40 ± 0.01 to 7.05 ± 0.04 pH units (P < 0.01).
Accompanying these changes were a decrease in mean arterial pressure
(66 ± 7 to 48 ± 8 mmHg), LVP (87 ± 5 to 62 ± 10 mmHg, P < 0.05),
+LVdP/dtmax (3,644 ± 297 to 2,814 ± 707 mmHg/s), and heart rate (234 ± 9 to 202 ± 7 beats/min). This is in contrast to the elevated values seen for the same parameters during a combined infusion without coronary occlusion (Fig. 2). Coronary occlusion maintained for 1 min
after the infusions prevented the hemodynamic recovery seen after
control infusions without coronary occlusion (Fig. 2). In addition, the
incidence of arrhythmias was greatly elevated by the combined infusion
during coronary occlusion compared with coronary occlusion alone (e.g.,
Fig. 3C).
Chronic Ischemia
Chronic coronary arterial ligation. Complete occlusion of the left circumflex coronary artery for 20 min provoked arrhythmias in five of the seven animals studied. Two of these animals developed ventricular fibrillation that reverted to normal sinus rhythm either spontaneously or after cardiac massage. Ventricular premature beats (singles, bigeminy, and salvos) were the main arrhythmias seen and were not sustained for the duration of the occlusion but occurred in discreet trains after ~3-5 and 13-18 min of ischemia. Hyperkalemia and acidosis postischemia. Twenty minutes of ischemia did not significantly alter baseline hemodynamics except during sustained arrhythmic activity. Resting heart rate was elevated from 222 ± 8 to 255 ± 20 beats/min. Infusing KCl and lactic acid decreased mean arterial pressure from 67 ± 6 to 43 ± 4 mmHg (P < 0.01). Values for +LVdP/dtmax postischemia closely paralleled the preischemia values, perhaps because of the postischemia tachycardia. Changes in pHa and [K+]a after 20 min of ischemia were not significantly different from preischemia control (Table 1).
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) and KCl, lactic acid and NE ().
A and
B: preocclusion responses.
C and
D: postocclusion responses. Note that
period of occlusion did not result in altered baseline hemodynamics but attenuated protective effect of NE.
LVdP/dtmax,
maximum rate of pressure development in left ventricle. Significantly
different: * P < 0.05, ** P < 0.01 (ANOVA).
§ P < 0.05, §§ P < 0.01 (t-test).
DISCUSSION
This paper reports that both acute regional cardiac ischemia and a period of prolonged ischemia, which led to a small infarction, substantially attenuated the protective effect of raised levels of NE against the negative cardiac effects of hyperkalemia and acidosis in vivo.
K+, Acid, and Catecholamines and Cardiac Performance
NE can offset the negative effects of elevated K+ and H+ in whole animals and in the isolated heart (29), an effect that is mimicked by stimulation of cardiac sympathetic nerves (24) and elevation of plasma calcium (19). This response is virtually abolished by propranolol (24) and verapamil (25). Moreover, the negative cardiac effects of hyperkalemia and acidosis are enhanced by propranolol, but this response is reversed by an intravenous infusion of calcium chloride (19) or raised angiotensin II (non-adrenergic receptor-coupled pathway) in isolated cardiac tissue (31). Conversely, raised [K+]o can offset adrenergic-induced arrhythmias in the pig (24) and in humans (6). Modulation of intracellular calcium, therefore, appears to be crucial in allowing the heart to cope with the large swings in catecholamines, acid, and raised [K+]o as would be seen in vigorous exercise.Does Acute Ischemia Exacerbate the Proarrhythmic Effects of Catecholamines?
Coronary arterial occlusion is associated with high cardiac adrenergic tone as a result of activation of the sympathosympathetic reflex (17) and local release mechanisms (32). Catecholamines are known to be harmful to the ischemic myocardium because they increase myocardial oxygen consumption (27), promote platelet aggregation (12), and increase the incidence of ventricular arrhythmia (26). In this study, it is unlikely that arrhythmias that are dependent on local or reflex release of cardiac catecholamines are responsible for the depression in cardiac performance seen during acute ischemia. Accumulation of K+, acid, and especially adenosine during acute ischemia reduces transmitter release from sympathetic varicosities (23). There is also no significant increase in the catecholamine concentration in coronary venous effluent after 10 min of global ischemia in the isolated rabbit heart (34), and any rapid reflex activation of NE would be abolished in our preparation because the cardiac sympathovagal trunk was cut.In the present study, arrhythmias were seen in six of the ten animals subjected to acute coronary occlusion plus infusion of K+, acid, and NE. There were no arrhythmias during 3 min of occlusion alone, and hemodynamics were essentially unchanged when occlusion was accompanied by infusion of NE alone. Moreover, antiarrhythmic doses of propranolol enhance the negative inotropic effects of hyperkalemia and acidosis in normal rabbits (19) and during acute ischemia (unpublished observations). Therefore, it seems unlikely that our results can be explained by a proarrhythmogenic effect of NE.
Do Acute and Chronic Ischemia Affect the Efficacy of Catecholamines in Restoring Cardiac Function During Raised K+ and Acidosis?
The left circumflex coronary artery is dominant in the rabbit and supplies most of the free left ventricular wall; therefore, the mass of cardiac tissue that is perfused will be decreased during acute ischemia involving this artery. Intravenous infusion of NE, K+, and acid will have little direct influence on the ischemic area because of the poor collateral circulation that has been described for the rabbit. Although this may account, in part, for the decreased tolerance of the heart to K+, acid, and NE during ischemia, occlusion of the artery alone did not significantly alter hemodynamics, whereas the protective effect of NE was attenuated by occlusion.Chronic ischemia, resulting in infarction of a portion of the left ventricular myocardium, clearly plays a role in reducing the effectiveness of NE during hyperkalemia and acidosis. This may be related to a reduction in the sensitivity of the heart to NE, thereby amplifying the negative cardiac effects of hyperkalemia and acidosis. Within the first 15 min of coronary arterial occlusion, the final lateral borders of an infarction are established (8). Reperfusion after 15- or 30-min occlusion of rabbit left circumflex coronary artery consistently produces subendocardial necrosis that results in an infarction size of 8 or 15% of the ventricle, respectively. Even though reperfusion at 20 min rapidly reverses ECG segment depression, this is incomplete and suggests irreversible damage to cells in the ischemic area (7). Our protocol of 20-min ischemia is consistent with the intervention causing irreversible damage to a small area of ventricle.
The restorative action of catecholamines was substantially reduced and essentially ineffective in offsetting the depressive effects of hyperkalemia and acidosis (Fig. 4). This decreased effectiveness of the NE might be explained by a decrease in myofilament sensitivity to calcium, possibly due to activation of proteases by calcium overload during reperfusion (18).
Limitations of Study
Extrapolation of our results to a normal exercising subject is limited by the nature of our anesthetized, open-chest cardiac-denervated preparation. Clearly, there are multiple factors changing during exercise for which we have not controlled. In particular, peripheral and central neural activities as well as other chemical factors associated with exercise that were not simulated might have a bearing on our results. However, to test the hypothesis that myocardial ischemia may affect the efficacy of the protective effect of catecholamines on the heart during hyperkalemia and acidosis, it was necessary to delimit our protocol and study only the individual and collective effects of these factors. Therefore, our results may be related only to aspects of exercise, and thus further experiments are required to show their physiological significance.Implications for Exercise in Ischemic Heart Disease
Most incidences of exercise- or stress-induced sudden cardiac death or myocardial infarction (21, 22) can be explained by an underlying cardiac pathology, where exercise is thought to amplify the negative effects of ischemia and infarction (2, 16). At rest, transient cardiac ischemia produces few arrhythmias (33), but occlusion of a coronary artery in dogs with a healed infarction 1 min before intense exercise was stopped and maintained for 1 min after exercise causes ventricular fibrillation (3). Furthermore, pretreatment with verapamil completely suppresses exercise-induced ventricular fibrillation in the dog, suggesting that the proarrhythmogenic effects of enhanced calcium entry are central to the development of ventricular fibrillation (2). However, unlike
-adrenergic antagonists, there is no compelling epidemiological evidence that shows calcium-channel antagonists have a
protective effect in patients' post-myocardial infarctions (13, 30).
Our results show that acute reversible ischemia, as well as infarction, disrupts the interplay among K+, acid, and catecholamines. The decrease in functioning myocardial mass secondary to acute ischemia or infarction attenuates the protective effects of NE and enhances the negative inotropic effect of hyperkalemia and acidosis. Occasionally, these changes might provide a trigger for arrhythmogenesis and cardiac arrest. However, given the nature of our preparation, we cannot rule out the idea that exercise amplifies the negative cardiac effect of ischemia by enhancing the proarrhythmic nature of catecholamines (1).
In conclusion, our results confirm the protective role of NE in the structurally normal heart during hyperkalemia and acidosis and show that acute ischemia or a small infarction may offset this protection and increases the depressive effects of elevated K+ and acid. Whether this process is relevant to exercise performance in subjects with ischemic heart disease or a healed infarction remains to be determined.
ACKNOWLEDGEMENTS
We are grateful to the British Heart Foundation (RG 95003), which kindly supported this study. M. O'Neill was supported by a Rhodes Scholarship, and C. E. Sears is supported by a Wellcome Prize Research Studentship.
FOOTNOTES
Address for reprint requests: D. J. Paterson, Univ. Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, UK (E-mail: DJP{at}physiol.ox.ac.uk).
Received 4 September 1996; accepted in final form 14 November 1996.
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