1154
if diving animals are devoid of the KATPchannel. At the end of a dive, blood Po? is known to fall to close to zero and it may be a positive disadvantage to have hypoxia induced activation of the KATPchannel causing electrical arrest every time you dive! Maybe diving animals have selected out the KATPchannel over the millennia? The advice of Dr Richard Dawkins and the help and suggestions of Michael Hempstead are gratefully acknowledged. MICHAEL J SHATTOCK
Cardiovascular Research, The Rayne Institute, St Thomas’ Hospital, London SEl 7EH, United Kingdom Noma A. ATP-regulated K channels in cardiac muscle. Nature 1983:305: 147-8. Dawkins R. The selfish gene. Oxford: Oxford University Press, 1976. Jiang C, Xia Y, Haddad GG. The role of ATP-sensitive K’ channels during anoxia: major differences between rat (newborn and adult) and turtle neurons. J Physiol (Lond) 1992; 448:599-6 12.
Editor’s Comment The views expressed in this article are those of the author, not those of an associate editor of the Journal. Readers’ comments and letters on this interesting subject are welcome. DAVID J HEARSE
Editor-in-Chief
Invited letters to the Editor Glibenclamide and cardiac function during ischaemia Sir, - The interesting study by Bril er all (this issue, p 1069) reported that preischaemic administration of the ATP sensitive potassium (KATP)channel blocker glibenclamide attenuated contractile failure during I5 minutes of regional ischaemia and shortened the duration of reperfusion induced ventricular fibrillation, but did not alter the incidence of the ventricular fibrillation. The finding of the “defibrillatory effect” of glibenclamide has added some useful information to our understanding of the possible mechanism of reperfusion induced arrhythmias. However, I feel that the authors’ interpretation of the data with respect to the effect of glibenclamide on cardiac function might provoke some controversy. Assuming that these effects of glibenclamide are attributed to a direct effect of the drug on the cardiac KATPchannel, the basic hypothesis may be that glibenclamide blocks ischaemia induced activation of KATP channels in the ischaemic myocardium and subsequently the possible shortening of action potential duration.’ This putative preservation of action potential duration during ischaemia may decrease the difference in refractoriness between the ischaemic and nonischaemic myocardium and subsequently reduce the probability of the occurrence of re-entry. On the other hand, a preserved action potential duration may allow increased calcium influx because the calcium channel would favour its opening state and the Na-Ca exchange would have rather limited chance for calcium extrusion. This putative increase in Cai may explain the maintained contractile function during the short period of ischaemia. Thus the authors have suggested that the contractile failure during ischaemia was
restored by an “improved” glibenclamide induced calcium influx. However, I feel that it is very difficult to call the extra calcium load during ischaemia an “improved” calcium influx for the restoration of contractile function. From the view of myocardial protection, I believe that every effort should be made to prevent extra calcium load during myocardial ischaemia because calcium overload has been suggested to be a major cause of myocardial ischaemic injurya3 In addition, the rapid induction of contractile failure is one of the basic principles of the use of cardioplegia for myocardial protection during cardiac surgery. I would therefore imagine that opening of the KATPchannel and subsequent shortening of the action potential duration with limited calcium influx and rapid contractile failure may be one of the self defence mechanisms of myocardium against the ischaemic injury. In this regard, it has been suggested that KATPopeners have salutary effects against ischaemic myocardial injury and that glibenclamide accelerates ischaemic i n j ~ r y . ~ The authors hypothesised that block of the KATPchannel would decrease contractile function during regional ischaemia because KATP channel blocking should be hazardous for the myocardium according to the previous report^.^ They concluded thus that the “restoration” of contractile function by glibenclamide is a finding contrary to these reports. However, the basic mechanism responsible for the glibenclamide induced restoration of cardiac function during ischaemia reported in this paper and for the previously reported deterioration of ischaemic injury caused by glibenclamide should be same as long as both effects are mediated by direct effects of the KATPchannel blocker on
Downloaded from by guest on June 9, 2016
ubiquitous nature of this protein that has only late in evolutionary time found a role - that is, the channel is expressed in the heart by coincidence rather than by design. If this is indeed the case then it follows that there may be no teleological reason to expect the activation of this channel in ischaemia or hypoxia to be protective - it could equally be damaging. In fact, considerable evidence suggests that although KATPchannel openers may be anti-ischaemic, they may also be proarrhythmic. Thus, protection against infarction may be to no avail if the associated arrhythmias are fatal. Another possible explanation for the existence of this channel is that although the evolutionary advantage derived from it may be very small, it is finite. It is clear that a small evolutionary advantage conferred by a protective protein may still have some evolutionary significance. A number of arguments can be advanced in favour of this idea. As pointed out by Richard Dawkins,? selection pressures can have great evolutionary significance even if they are, to human perception, exceedingly slight. Human (eg, actuarial) estimates of risk and those of natural selection do not match up. A gene that has a minute influence of the probability of survival is very unlikely to save the life of any particular individual - yet that gene, since it is duplicated over thousands of generations, is statistictlly more likely to survive in the gene pool than its allele.Finally, a recent study has shown that although a number of species contain glibenclamide binding sites in neural tissue, the turtle brain shows little or no binding.3 In an unsubstantiated flight of fancy, it would be interesting to see
1155
ATSUO MITANI
Department of Cardiothoracic Surgery St Thomas’ Hospital, London SEl 7EH Bril A, Laville M-P, Gout B. Effect of glibenclamide on ventricular arrhythmias and cardiac function is ischaemia and reperfusion in isolated rat heart. Curdiovasc Res 1992; 26: 1069-76. Nichols CG, Ripoll C, Lederer WJ. The regulation of ATPsensitive K’ channel modulation of the guinea pig ventricular action potential and contraction. Circ Res 1991;68:280-7. Cheung JY, Bonventre JV, Malis CD, Leaf A. Calcium and ischemic injury. N Engl J Med 1986;314:1670-6. Steenbergen C, Murphy E, Watts JA, London RE. Correlation between cytosolic free calcium, contracture, and irreversible ischemic injury in perfused rat heart. Circ Res 1990;66:135-46. Cole WC, McPherson CD, Sontag D. ATP-regulated K’ channels protect the myocardium against ischemidreperfusion damage. Circ Res 1991;69:57 1-8 1. Mitani A, Kinoshita K, Fukamachi K, et al. The effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in the isolated perfused rat heart. Am J Physiol I991 :261:H 1864-7 1.
Glibenclamide and cardiac function during ischaemia the authors’ response We thank Dr Mitani for his interest in our experiments and for his comments. The objective of our study was not to try to be controversial since the model of regional ischaemia we used is different from that of previous studies (global ischaemia).’
Dr Mitani noted that glibenclamide would reduce the probability of the occurrence of re-entry, but by prolonging the pressure development during ischaemia would be deleterious for the myocardium. It is now widely accepted that re-entries may be suppressed by agents which prolong the cardiac potential, namely class 111 antiarrhythmic agents. These agents, which also induce a positive inotropic action, exhibit less cardiac depressive action than class I antiarrhythmic drugs. However, recent studies suggest that class 111 antiarrhythmic agents lose their ability to prolong action potential duration and could further impair cardiac function during i~chaemia.~-’In our study, glibenclamide, which reduces the occurrence of re-entry, was shown to increase left ventricular pressure during ischaemia. In that sense, the effect observed during ischaemia on cardiac function may suggest that blockade of ATP sensitive potassium current could represent an antiarrhythmic mechanism devoid of cardiodepressive activity. In his second comment Dr Mitani suggested that based on the experiments reported previously’ glibenclamide should cause deterioration in the function of the reperfused heart, and potassium channel activators should have a cardioprotective effect. Indeed, by inducing a rapid mechanical arrest potassium channel activators allow better recovery of cardiac function during reperfusion.’ Whereas during global ischaemia the active suppression of the contractile activity is an important component of the protection process, during regional ischaemia the maintenance of pump function is essentiaL6 The results of our study show that glibenclamide did not delay the occurrence of the reduction in left ventricular developed pressure, as observed during global ischaemia, but that it increased left ventricular developed pressure after a few minutes of ischaemia. In that sense the results of our study suggest that glibenclamide could allow a restoration of the pump function of the heart during regional ischaemia. Whether this effect is of ultimate benefit or harm to the heart is not clear and remains to be determined. Finally, the potential clinical use of glibenclamide for heart disease treatment would be limited because the concentrations used in our own and previous studies’ (from 1 to 50 FM) would induce pronounced hypoglycaemia. Obviously considerable further work is required to establish both the risks and the benefits of using potassium channel modulators for ischaemic heart disease, bearing in mind that “data on reperfusion injury from models utilising cardioplegia and total ischaemia in vitro should be applied with caution to regional ischaemia in vivo”.’
’
ANTOINE BRIL BERNARD GOUT
SmithKline Beecham Laboratoires Pharmaceutiques Unirt de Recherches, 35760 Saint Grtgoire, France 1 Mitani A, Kinoshita K, Fukamachi K, et al. The effects of
2 3 4
5
glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in the isolated perfused rat heart. Am-J Physiol 1991;261:HI 864-71. Cole WC. McPherson CD. Sontae D. ATP-regulated Kt channels protect the myocardium ‘againsr kchemidreperfusion damage. Circ Res 1991;69:571-81. Cobbe SM. Modification of class I11 antiarrhythmic activity in abnormal myocardium. Curcfiovasc Res 1988;22:847-54. Hoffmeister HM, Miiller S, Seipel L. Effects of the class 111 antiarrhythmic drug D-sotalol on contractile function of postischemic myocardium. J Cardiovusc Pharmacol 199I ; 17581-6. Gout B, Jean J, Bril A. Comparative effects of a potassium channel bldcking drug, UK-68,798, and a specific bradycardic agent, ULFS 49, on exercise-induced ischemia in the dog: significance of
Downloaded from by guest on June 9, 2016
cardiac KATPchannels. In arterially perfused ventricular strips, Cole et a15 have reported that glibenclamide slowed the attenuation of tension development and increased the rise in resting tension during ischaemia. In our previous study6 in perfused rat hearts, glibenclamide accelerated the development of ischaemic contracture during global ischaemia and hastened the depletion of myocardial ATP after reperfusion. This deleterious effect of glibenclamide was accompanied by prolonged pressure development during ischaemia. It is hypothesised that this prolonged pressure development during ischaemia (possibly the result of preserved action potential duration and increased calcium influx by glibenclamide) increases energy demands at a time when energy supply is absent, thus accelerating irreversible myocardial injury. Although the authors’ study was camed out in regionally ischaemic hearts, as far as the myocardium in the region of ischaemia is concerned, a similar effect of glibenclamide would be expected. From the clinical point of view, a similar dilemma may be the administration of catecholamines to patients who suffered from heart failure due to acute myocardial ischaemia. Adrenaline may restore contactile function of the ischaemic myocardium temporarily by increasing the calcium influx into the myocyte, but at the expense of possible deterioration of myocardial ischaemic damage due to the increased energy consumption. In contrast, p adrenoceptor blocking agents are the drugs of choice for patients with coronary artery disease without heart failure because they decrease cardiac contractility and thereby reduce myocardial energy demands on stress. As far as the ischaemic myocardium is concerned, the only expected beneficial effect of the use of catecholamines may be that they would maintain coronary perfusion pressure and dilate the coronary arteries so that the ischaemic myocardium can receive more blood. However, coronary vasodilatation, which is expected with p adrenergic agents, does not occur with glibenclamide because the drug should reduce the coronary flow, as the authors observed in this study.
if diving animals are devoid of the KATPchannel. At the end of a dive, blood Po? is known to fall to close to zero and it may be a positive disadvantage to have hypoxia induced activation of the KATPchannel causing electrical arrest every time you dive! Maybe diving animals have selected out the KATPchannel over the millennia? The advice of Dr Richard Dawkins and the help and suggestions of Michael Hempstead are gratefully acknowledged. MICHAEL J SHATTOCK
Cardiovascular Research, The Rayne Institute, St Thomas’ Hospital, London SEl 7EH, United Kingdom Noma A. ATP-regulated K channels in cardiac muscle. Nature 1983:305: 147-8. Dawkins R. The selfish gene. Oxford: Oxford University Press, 1976. Jiang C, Xia Y, Haddad GG. The role of ATP-sensitive K’ channels during anoxia: major differences between rat (newborn and adult) and turtle neurons. J Physiol (Lond) 1992; 448:599-6 12.
Editor’s Comment The views expressed in this article are those of the author, not those of an associate editor of the Journal. Readers’ comments and letters on this interesting subject are welcome. DAVID J HEARSE
Editor-in-Chief
Invited letters to the Editor Glibenclamide and cardiac function during ischaemia Sir, - The interesting study by Bril er all (this issue, p 1069) reported that preischaemic administration of the ATP sensitive potassium (KATP)channel blocker glibenclamide attenuated contractile failure during I5 minutes of regional ischaemia and shortened the duration of reperfusion induced ventricular fibrillation, but did not alter the incidence of the ventricular fibrillation. The finding of the “defibrillatory effect” of glibenclamide has added some useful information to our understanding of the possible mechanism of reperfusion induced arrhythmias. However, I feel that the authors’ interpretation of the data with respect to the effect of glibenclamide on cardiac function might provoke some controversy. Assuming that these effects of glibenclamide are attributed to a direct effect of the drug on the cardiac KATPchannel, the basic hypothesis may be that glibenclamide blocks ischaemia induced activation of KATP channels in the ischaemic myocardium and subsequently the possible shortening of action potential duration.’ This putative preservation of action potential duration during ischaemia may decrease the difference in refractoriness between the ischaemic and nonischaemic myocardium and subsequently reduce the probability of the occurrence of re-entry. On the other hand, a preserved action potential duration may allow increased calcium influx because the calcium channel would favour its opening state and the Na-Ca exchange would have rather limited chance for calcium extrusion. This putative increase in Cai may explain the maintained contractile function during the short period of ischaemia. Thus the authors have suggested that the contractile failure during ischaemia was
restored by an “improved” glibenclamide induced calcium influx. However, I feel that it is very difficult to call the extra calcium load during ischaemia an “improved” calcium influx for the restoration of contractile function. From the view of myocardial protection, I believe that every effort should be made to prevent extra calcium load during myocardial ischaemia because calcium overload has been suggested to be a major cause of myocardial ischaemic injurya3 In addition, the rapid induction of contractile failure is one of the basic principles of the use of cardioplegia for myocardial protection during cardiac surgery. I would therefore imagine that opening of the KATPchannel and subsequent shortening of the action potential duration with limited calcium influx and rapid contractile failure may be one of the self defence mechanisms of myocardium against the ischaemic injury. In this regard, it has been suggested that KATPopeners have salutary effects against ischaemic myocardial injury and that glibenclamide accelerates ischaemic i n j ~ r y . ~ The authors hypothesised that block of the KATPchannel would decrease contractile function during regional ischaemia because KATP channel blocking should be hazardous for the myocardium according to the previous report^.^ They concluded thus that the “restoration” of contractile function by glibenclamide is a finding contrary to these reports. However, the basic mechanism responsible for the glibenclamide induced restoration of cardiac function during ischaemia reported in this paper and for the previously reported deterioration of ischaemic injury caused by glibenclamide should be same as long as both effects are mediated by direct effects of the KATPchannel blocker on
Downloaded from by guest on June 9, 2016
ubiquitous nature of this protein that has only late in evolutionary time found a role - that is, the channel is expressed in the heart by coincidence rather than by design. If this is indeed the case then it follows that there may be no teleological reason to expect the activation of this channel in ischaemia or hypoxia to be protective - it could equally be damaging. In fact, considerable evidence suggests that although KATPchannel openers may be anti-ischaemic, they may also be proarrhythmic. Thus, protection against infarction may be to no avail if the associated arrhythmias are fatal. Another possible explanation for the existence of this channel is that although the evolutionary advantage derived from it may be very small, it is finite. It is clear that a small evolutionary advantage conferred by a protective protein may still have some evolutionary significance. A number of arguments can be advanced in favour of this idea. As pointed out by Richard Dawkins,? selection pressures can have great evolutionary significance even if they are, to human perception, exceedingly slight. Human (eg, actuarial) estimates of risk and those of natural selection do not match up. A gene that has a minute influence of the probability of survival is very unlikely to save the life of any particular individual - yet that gene, since it is duplicated over thousands of generations, is statistictlly more likely to survive in the gene pool than its allele.Finally, a recent study has shown that although a number of species contain glibenclamide binding sites in neural tissue, the turtle brain shows little or no binding.3 In an unsubstantiated flight of fancy, it would be interesting to see
1155
ATSUO MITANI
Department of Cardiothoracic Surgery St Thomas’ Hospital, London SEl 7EH Bril A, Laville M-P, Gout B. Effect of glibenclamide on ventricular arrhythmias and cardiac function is ischaemia and reperfusion in isolated rat heart. Curdiovasc Res 1992; 26: 1069-76. Nichols CG, Ripoll C, Lederer WJ. The regulation of ATPsensitive K’ channel modulation of the guinea pig ventricular action potential and contraction. Circ Res 1991;68:280-7. Cheung JY, Bonventre JV, Malis CD, Leaf A. Calcium and ischemic injury. N Engl J Med 1986;314:1670-6. Steenbergen C, Murphy E, Watts JA, London RE. Correlation between cytosolic free calcium, contracture, and irreversible ischemic injury in perfused rat heart. Circ Res 1990;66:135-46. Cole WC, McPherson CD, Sontag D. ATP-regulated K’ channels protect the myocardium against ischemidreperfusion damage. Circ Res 1991;69:57 1-8 1. Mitani A, Kinoshita K, Fukamachi K, et al. The effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in the isolated perfused rat heart. Am J Physiol I991 :261:H 1864-7 1.
Glibenclamide and cardiac function during ischaemia the authors’ response We thank Dr Mitani for his interest in our experiments and for his comments. The objective of our study was not to try to be controversial since the model of regional ischaemia we used is different from that of previous studies (global ischaemia).’
Dr Mitani noted that glibenclamide would reduce the probability of the occurrence of re-entry, but by prolonging the pressure development during ischaemia would be deleterious for the myocardium. It is now widely accepted that re-entries may be suppressed by agents which prolong the cardiac potential, namely class 111 antiarrhythmic agents. These agents, which also induce a positive inotropic action, exhibit less cardiac depressive action than class I antiarrhythmic drugs. However, recent studies suggest that class 111 antiarrhythmic agents lose their ability to prolong action potential duration and could further impair cardiac function during i~chaemia.~-’In our study, glibenclamide, which reduces the occurrence of re-entry, was shown to increase left ventricular pressure during ischaemia. In that sense, the effect observed during ischaemia on cardiac function may suggest that blockade of ATP sensitive potassium current could represent an antiarrhythmic mechanism devoid of cardiodepressive activity. In his second comment Dr Mitani suggested that based on the experiments reported previously’ glibenclamide should cause deterioration in the function of the reperfused heart, and potassium channel activators should have a cardioprotective effect. Indeed, by inducing a rapid mechanical arrest potassium channel activators allow better recovery of cardiac function during reperfusion.’ Whereas during global ischaemia the active suppression of the contractile activity is an important component of the protection process, during regional ischaemia the maintenance of pump function is essentiaL6 The results of our study show that glibenclamide did not delay the occurrence of the reduction in left ventricular developed pressure, as observed during global ischaemia, but that it increased left ventricular developed pressure after a few minutes of ischaemia. In that sense the results of our study suggest that glibenclamide could allow a restoration of the pump function of the heart during regional ischaemia. Whether this effect is of ultimate benefit or harm to the heart is not clear and remains to be determined. Finally, the potential clinical use of glibenclamide for heart disease treatment would be limited because the concentrations used in our own and previous studies’ (from 1 to 50 FM) would induce pronounced hypoglycaemia. Obviously considerable further work is required to establish both the risks and the benefits of using potassium channel modulators for ischaemic heart disease, bearing in mind that “data on reperfusion injury from models utilising cardioplegia and total ischaemia in vitro should be applied with caution to regional ischaemia in vivo”.’
’
ANTOINE BRIL BERNARD GOUT
SmithKline Beecham Laboratoires Pharmaceutiques Unirt de Recherches, 35760 Saint Grtgoire, France 1 Mitani A, Kinoshita K, Fukamachi K, et al. The effects of
2 3 4
5
glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in the isolated perfused rat heart. Am-J Physiol 1991;261:HI 864-71. Cole WC. McPherson CD. Sontae D. ATP-regulated Kt channels protect the myocardium ‘againsr kchemidreperfusion damage. Circ Res 1991;69:571-81. Cobbe SM. Modification of class I11 antiarrhythmic activity in abnormal myocardium. Curcfiovasc Res 1988;22:847-54. Hoffmeister HM, Miiller S, Seipel L. Effects of the class 111 antiarrhythmic drug D-sotalol on contractile function of postischemic myocardium. J Cardiovusc Pharmacol 199I ; 17581-6. Gout B, Jean J, Bril A. Comparative effects of a potassium channel bldcking drug, UK-68,798, and a specific bradycardic agent, ULFS 49, on exercise-induced ischemia in the dog: significance of
Downloaded from by guest on June 9, 2016
cardiac KATPchannels. In arterially perfused ventricular strips, Cole et a15 have reported that glibenclamide slowed the attenuation of tension development and increased the rise in resting tension during ischaemia. In our previous study6 in perfused rat hearts, glibenclamide accelerated the development of ischaemic contracture during global ischaemia and hastened the depletion of myocardial ATP after reperfusion. This deleterious effect of glibenclamide was accompanied by prolonged pressure development during ischaemia. It is hypothesised that this prolonged pressure development during ischaemia (possibly the result of preserved action potential duration and increased calcium influx by glibenclamide) increases energy demands at a time when energy supply is absent, thus accelerating irreversible myocardial injury. Although the authors’ study was camed out in regionally ischaemic hearts, as far as the myocardium in the region of ischaemia is concerned, a similar effect of glibenclamide would be expected. From the clinical point of view, a similar dilemma may be the administration of catecholamines to patients who suffered from heart failure due to acute myocardial ischaemia. Adrenaline may restore contactile function of the ischaemic myocardium temporarily by increasing the calcium influx into the myocyte, but at the expense of possible deterioration of myocardial ischaemic damage due to the increased energy consumption. In contrast, p adrenoceptor blocking agents are the drugs of choice for patients with coronary artery disease without heart failure because they decrease cardiac contractility and thereby reduce myocardial energy demands on stress. As far as the ischaemic myocardium is concerned, the only expected beneficial effect of the use of catecholamines may be that they would maintain coronary perfusion pressure and dilate the coronary arteries so that the ischaemic myocardium can receive more blood. However, coronary vasodilatation, which is expected with p adrenergic agents, does not occur with glibenclamide because the drug should reduce the coronary flow, as the authors observed in this study.
