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Anti-arrhythmic effects of selective inhibition of myocardial phosphodiesterase II
760
However, because gene carriers may have no symptoms, a family
history is not always available and investigation will remain imponant.8 Department of Cardiology, Guy’s Hospital, London SE1 9RT, UK
clinical
suspicion
and
C. A. O’CALLAGHAN D. TRUMP
Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and unifying hypothesis. Prog Cardiovas Dis 1988; 31: 115-72. 2. Singer PA, Crampton RS, Bass NH. Familial QT prolongation syndrome. Convulsive seizures and paroxysmal ventricular fibrillation. Arch Neurol 1974; 31: 64-66. 3. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109: 399-411. 4. Schwartz PJ. The long QT syndrome. In: Kulbertus HE, Wellens HJJ, eds. Sudden death. The Hague: Nijhoff, 1980: 358-78. 5. Schwartz PJ, Periti M, Mullioni A. The long Q-T syndrome. Am Heart J 1975; 89: 1.
378-90. 6. Hoep HW, Eggeling TVH. Pharmacologic blockade of the left stellate ganglion using a drug reservoir pump system. Chest 1990; 97: 250-51. 7. Keating M, Atkinson D, Dunn C, Timothy KW, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome and the Harvey ras-1 gene. Science 1991; 252: 704-06. 8. Vincent GM, Timothy KW, Leppert M, Keating M. Spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327: 846-52.
Anti-arrhythmic effects of selective inhibition of myocardial phosphodiesterase II SIR,-We have proposedl that excess accumulation of myocardial cAMP in response to 0-adrenergic stimulation or ischaemia is arrhythmogenic, and could explain the development of ventricular fibrillation and sudden death in patients with ischaemic heart disease. Decreased formation of myocardial cAMP may explain at least part of the clinically relevant anti-arrhythmic effect of 0-adrenergic blocking agents.2 Myocardial cAMP can also be increased by inhibition of the phosphodiesterases that hydroylse cAMP, with a pro-arrhythmic effect.2,3 Chronic therapy of congestive heart failure by the phosphodiesterase III inhibitor milrinone was accompanied by an increased frequency of ventricular arrhythmias and of death from cardiovascular causes 4 These adverse side-effects of milrinone were as predicted by the "cyclic AMP hypothesis".5 Phosphodiesterase inhibition might therefore be accompanied by a pro-arrhythmic effect, and phosphodiesterase inhibitors might as a class be avoided clinically when there is risk of serious ventricular arrhythmias, such as in ventricular fibrillation. Such arguments, however, ignore the potential anti-arrhythmic effects of another cyclic nucleotide (cGMP). Whereas cAMP is likely to exert its pro-arrhythmic effect at least in part by promotion of the slow inward L-type calcium current, cGMP inhibits this current in chick myocytes 6 cGMP is formed by the activity of the enzyme complex guanylyl cyclase, and, like cAMP, is broken down by the activity of phosphodiesterases with, however, different isoenzymes being maximally effective on the two cyclic nucleotides. While sympathetic activity is one of the causes of formation of cAMP, likely causes of the formation of cGMP are vagal activity, liberation of endothelial-derived relaxing factor (EDRF), or release of atrial natriuretic factor (ANF). EDRF and ANF act especially on blood vessels to stimulate the soluble and particulate forms of
guanylyl cyclase, respectively. Until recently, it has not been possible to inhibit the phosphodiesterases that hydrolyse cGMP without also inhibiting those that act on cAMP. The results of such non-selective inhibition of phosphodiesterases by, for example, theophylline, would be those of a mixture of the increased tissue levels of both cyclic nucleotides. To achieve a specific anti-arrhythmic effect would require a highly selective inhibitor of the myocardial phosphodiesterase that is responsible for the degradation of cGMP-namely phosphodiesterase II. Such an inhibitor has now been described.7 Phosphodiesterase II is found in the human myocardium (figure) and can be selectively inhibited by the new compound, MEP(IC;o=88x 10 -mol/L), which does not affect the activities of the isoenzymes III and IV, which hydrolise cAMP
(IC>
10-4mol/L).
Such selective inhibition of
phosphodiesterase
II in the
and effects of Anti-arrhythmic pro-arrhythmic phosphodiesterase (PDE) inhibitors. PDE I to IV represent different phosodiesterase isoenzymes in human myocardium. Anti-arrhythmic effects of inhibition of PDE II (and possibly of PDE I) can be explained by increased myocardial cGMP, and pro-arrhythmic effects of inhibition of PDE III and/or IV by increased cAMP, as for example when PDE III is inhibited by
milrinone.’.5 PDE I=cGMP hydrolysing (selectively inhibited by Ca2+calmodulin antagonists as well as by M & B 22948), PDE lI=cGMP hydrolysing (selectively inhibited by MEP 1), PDE III=cAMP hydrolysing (selectively inhibited by milrinone), and PDE IV=cAMP hydrolysing (selectively inhibited by rolipram).
myocardium is likely to result in accumulation of cGMP but not of cAMP, with a potent anti-arrhythmic effect. A new classification of anti-arrhythmic compounds, based on their mechanism of action, ignores the potential benefits of increased cGMP. 8 Thus, instead of attempting to control ischaemic ventricular arrhythmias by inhibiting formation of the pro-arrhythmic cAMP by 0-adrenergic blockade, it now becomes possible to increase selectively the tissue concentrations of the anti-arrhythmic second messenger, cGMP, thereby defining a new pharmacodynamic profile. Theoretically, an even greater anti-arrhythmic effect should be achieved by combination of this formation. Max Planck Institute, D-6350 Bad Nauheim,
new
mechanism with inhibition of cAMP T. PODZUWEIT
Germany
MRC Heart Research Unit, Medical School, University of Cape Town, South Africa
A. MÜLLER
L. H. OPIE
T, Lubbe WF, Opie LH. Cyclic adenosine monophosphate, ventricular fibrillation, and antiarrhythmic drugs. Lancet 1976; i: 341-42. 2. Lubbe WF, Podzuweit T, Daries P, Opie LH. The role of cyclic adenosine monophosphate in adrenergic effects on vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest 1978; 61: 1260-90. 3. Opie LH, Muller CA, Lubbe WF. Cyclic AMP and arrhythmias revisited. Lancet 1978; ii: 921-23. 4. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl Med 1991; 325: 1468-75 J 5. Lubbe WF, Podzuweit T, Opie LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic Coll Cardiol 1992; 19: 1622-33. effects of phosphodiesterase inhibitors. Am J 6. Tohse N, Sperelakis N. cGMP inhibits the activity of single calcium channels in embryonic chick heart cells. Circ Res 1991; 69: 325-31. 7. Podzuweit T, Muller A, Nennstiel P. Selective inhibition of the cGMP-stimulated cyclic nucleotide phosphodiesterase from pig and human myocardium. J Mol Cell Cardiol 1992; 24 (suppl V): 102. 8. Bigger Jr JT, Breithardt G, Brown AM, et al. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991; 84: 1831-51. 1. Podzuweit
Laterality of hip pain SIR,-Dr Newton and Ms Seagroatt (Jan 16, p 179) report that
replacements were commoner for the right hip than the left, in two Oxford series; they had no clear explanation. We two old medical friends have independently noted in ourselves disabling right hip pain for which we think we have found the cause, which explains the laterality, and which has led to recovery. Walking was restricted by pain for over a year (M. K., bom 1919, from any walking, and J. S., born 1925, after 1 mile); we both
However, because gene carriers may have no symptoms, a family
history is not always available and investigation will remain imponant.8 Department of Cardiology, Guy’s Hospital, London SE1 9RT, UK
clinical
suspicion
and
C. A. O’CALLAGHAN D. TRUMP
Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and unifying hypothesis. Prog Cardiovas Dis 1988; 31: 115-72. 2. Singer PA, Crampton RS, Bass NH. Familial QT prolongation syndrome. Convulsive seizures and paroxysmal ventricular fibrillation. Arch Neurol 1974; 31: 64-66. 3. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109: 399-411. 4. Schwartz PJ. The long QT syndrome. In: Kulbertus HE, Wellens HJJ, eds. Sudden death. The Hague: Nijhoff, 1980: 358-78. 5. Schwartz PJ, Periti M, Mullioni A. The long Q-T syndrome. Am Heart J 1975; 89: 1.
378-90. 6. Hoep HW, Eggeling TVH. Pharmacologic blockade of the left stellate ganglion using a drug reservoir pump system. Chest 1990; 97: 250-51. 7. Keating M, Atkinson D, Dunn C, Timothy KW, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome and the Harvey ras-1 gene. Science 1991; 252: 704-06. 8. Vincent GM, Timothy KW, Leppert M, Keating M. Spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992; 327: 846-52.
Anti-arrhythmic effects of selective inhibition of myocardial phosphodiesterase II SIR,-We have proposedl that excess accumulation of myocardial cAMP in response to 0-adrenergic stimulation or ischaemia is arrhythmogenic, and could explain the development of ventricular fibrillation and sudden death in patients with ischaemic heart disease. Decreased formation of myocardial cAMP may explain at least part of the clinically relevant anti-arrhythmic effect of 0-adrenergic blocking agents.2 Myocardial cAMP can also be increased by inhibition of the phosphodiesterases that hydroylse cAMP, with a pro-arrhythmic effect.2,3 Chronic therapy of congestive heart failure by the phosphodiesterase III inhibitor milrinone was accompanied by an increased frequency of ventricular arrhythmias and of death from cardiovascular causes 4 These adverse side-effects of milrinone were as predicted by the "cyclic AMP hypothesis".5 Phosphodiesterase inhibition might therefore be accompanied by a pro-arrhythmic effect, and phosphodiesterase inhibitors might as a class be avoided clinically when there is risk of serious ventricular arrhythmias, such as in ventricular fibrillation. Such arguments, however, ignore the potential anti-arrhythmic effects of another cyclic nucleotide (cGMP). Whereas cAMP is likely to exert its pro-arrhythmic effect at least in part by promotion of the slow inward L-type calcium current, cGMP inhibits this current in chick myocytes 6 cGMP is formed by the activity of the enzyme complex guanylyl cyclase, and, like cAMP, is broken down by the activity of phosphodiesterases with, however, different isoenzymes being maximally effective on the two cyclic nucleotides. While sympathetic activity is one of the causes of formation of cAMP, likely causes of the formation of cGMP are vagal activity, liberation of endothelial-derived relaxing factor (EDRF), or release of atrial natriuretic factor (ANF). EDRF and ANF act especially on blood vessels to stimulate the soluble and particulate forms of
guanylyl cyclase, respectively. Until recently, it has not been possible to inhibit the phosphodiesterases that hydrolyse cGMP without also inhibiting those that act on cAMP. The results of such non-selective inhibition of phosphodiesterases by, for example, theophylline, would be those of a mixture of the increased tissue levels of both cyclic nucleotides. To achieve a specific anti-arrhythmic effect would require a highly selective inhibitor of the myocardial phosphodiesterase that is responsible for the degradation of cGMP-namely phosphodiesterase II. Such an inhibitor has now been described.7 Phosphodiesterase II is found in the human myocardium (figure) and can be selectively inhibited by the new compound, MEP(IC;o=88x 10 -mol/L), which does not affect the activities of the isoenzymes III and IV, which hydrolise cAMP
(IC>
10-4mol/L).
Such selective inhibition of
phosphodiesterase
II in the
and effects of Anti-arrhythmic pro-arrhythmic phosphodiesterase (PDE) inhibitors. PDE I to IV represent different phosodiesterase isoenzymes in human myocardium. Anti-arrhythmic effects of inhibition of PDE II (and possibly of PDE I) can be explained by increased myocardial cGMP, and pro-arrhythmic effects of inhibition of PDE III and/or IV by increased cAMP, as for example when PDE III is inhibited by
milrinone.’.5 PDE I=cGMP hydrolysing (selectively inhibited by Ca2+calmodulin antagonists as well as by M & B 22948), PDE lI=cGMP hydrolysing (selectively inhibited by MEP 1), PDE III=cAMP hydrolysing (selectively inhibited by milrinone), and PDE IV=cAMP hydrolysing (selectively inhibited by rolipram).
myocardium is likely to result in accumulation of cGMP but not of cAMP, with a potent anti-arrhythmic effect. A new classification of anti-arrhythmic compounds, based on their mechanism of action, ignores the potential benefits of increased cGMP. 8 Thus, instead of attempting to control ischaemic ventricular arrhythmias by inhibiting formation of the pro-arrhythmic cAMP by 0-adrenergic blockade, it now becomes possible to increase selectively the tissue concentrations of the anti-arrhythmic second messenger, cGMP, thereby defining a new pharmacodynamic profile. Theoretically, an even greater anti-arrhythmic effect should be achieved by combination of this formation. Max Planck Institute, D-6350 Bad Nauheim,
new
mechanism with inhibition of cAMP T. PODZUWEIT
Germany
MRC Heart Research Unit, Medical School, University of Cape Town, South Africa
A. MÜLLER
L. H. OPIE
T, Lubbe WF, Opie LH. Cyclic adenosine monophosphate, ventricular fibrillation, and antiarrhythmic drugs. Lancet 1976; i: 341-42. 2. Lubbe WF, Podzuweit T, Daries P, Opie LH. The role of cyclic adenosine monophosphate in adrenergic effects on vulnerability to fibrillation in the isolated perfused rat heart. J Clin Invest 1978; 61: 1260-90. 3. Opie LH, Muller CA, Lubbe WF. Cyclic AMP and arrhythmias revisited. Lancet 1978; ii: 921-23. 4. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl Med 1991; 325: 1468-75 J 5. Lubbe WF, Podzuweit T, Opie LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic Coll Cardiol 1992; 19: 1622-33. effects of phosphodiesterase inhibitors. Am J 6. Tohse N, Sperelakis N. cGMP inhibits the activity of single calcium channels in embryonic chick heart cells. Circ Res 1991; 69: 325-31. 7. Podzuweit T, Muller A, Nennstiel P. Selective inhibition of the cGMP-stimulated cyclic nucleotide phosphodiesterase from pig and human myocardium. J Mol Cell Cardiol 1992; 24 (suppl V): 102. 8. Bigger Jr JT, Breithardt G, Brown AM, et al. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991; 84: 1831-51. 1. Podzuweit
Laterality of hip pain SIR,-Dr Newton and Ms Seagroatt (Jan 16, p 179) report that
replacements were commoner for the right hip than the left, in two Oxford series; they had no clear explanation. We two old medical friends have independently noted in ourselves disabling right hip pain for which we think we have found the cause, which explains the laterality, and which has led to recovery. Walking was restricted by pain for over a year (M. K., bom 1919, from any walking, and J. S., born 1925, after 1 mile); we both