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Ion Channels in the cardiovascular system: Function and dysfunction
BOOK
REVIEWS
to discuss the science behind the methodology, with considerable success. There are two audiences for this book. For those who wish to be educated about 3D QSAR, the chapters are organized in a systematic fashion, starting with Peter Andrews’ account of the pharmacological or, more generally, biological processes we are trying to model and what physical processes are involved. The reader is then taken through the process of generating the 3D structures (Pearlman), deciding on the appropriate 3D conformations to use (Garland Marshall) and various methods for defining the pharmacophore involved in a particular system. The next section illustrates how to put numbers to the physical processes involved, with descriptions of key receptor systems. These latter chapters are, in some senses, inappropriate in this book. Marcel Hibert’s chapter, for example, on G proteincoupled receptors, contains no quantitative biological data at all, let alone a quantitative 3D description of a ligand molecule. However, this chapter and related ones do form
Separate meals or a shared plate Ion Channels in the Cardiovascular System: Function and Dysfunction
Futura Publishing Company, 1994. $85.00 (xxix + 580 pages) 1SBN 0 87993 591 X
‘In pursuit of detail, a specialist ends up knowing everything about nothing. Conversely, a generalist knows nothing about everything. In consequence neither has anything to say to the other.’ (An adage.) Over the past forty years, the electrical activity of the heart has been
a link for biologists who may be interested in the techniques of ligand design described by Hans-Joachim Bahm. The second half of the book is a testament to Kubinyi’s persuasive powers in getting many of the leading exponents of these techniques to write accounts of their experiences, and to make available to the rest of us the values and, perhaps more importantly, the limitations of various methods. The second audience and the major market for this book will comprise the rapidly growing number of people in life sciences who now have access to some of these techniques via a variety of work-stations and personal computers. The major method in current use, comparative molecular field analysis (CoMFA), is heavily described both in concept and practice. The separate chapter by Svante Wold on partial least squares VLSI is a reminder that the statistical technique to relate the quantitative description of the molecule to a quantitative desciiption of the biology is an independent process and can be used to relate
other descriptors. This is indicated in Don Abraham’s chapter on the use of hydrophobic fields and Rebecca Wade’s chapter on the application of GRID and GRIN programs. It is possible that the most used part of the book will be the two appendices. The first, on recommendations for CoMFA, should be required reading for all who use the technique and all who referee papers for journals on the subject. The second, on the practical problems of PLS, again keeps us on the ‘straight and narrow’ of valid science. Overall this is an excellent book, which should be accessible to all who work in the area of 3D molecular design. It is extremely well indexed and printed, with much of it in colour. The high price may prevent it from being on the desk of practitioners as a key reference source. It should, however, be available in the libraries of the organizations in which they work.
described in considerable detail. Patch-clamp technology and the cloning of ion channels has recently prompted an explosive increase in the volume of knowledge. Basicscientists can now be so specialized as to spend a whole career investigating isolated aspects of a single channel protein, but clinicians are confronted with ever different and changing clinical problems, and are forced to remain generalists. Examination of patient outcome in randomized empirical surveys still seems to be the most useful approach to developing new therapies. The massive cardiac arrhythmia suppression trial (CAST) showed that Type I antiarrhythmics, which block Na * channels and suppress ventricular arrhythmias, are actually harmful to patients. The pre dictions of basic scientists, that these agents would heip patients experiencing post-infarction arrhythmias, turned out to be incorrect. Such experiences could lead basic science
into
J. Bradshaw Giomolecular Structure Department, Glaxo Research and Development, Park Road, Ware, Hertfordshire, UK SG12 ODP.
ever narrower study of channels for their own sake, and clinicians to ignore the predictions of basic scientists, leaving the two tracks of research diverging yet further. This book begins by outlining the widening gap between ion channel study at the molecular level and the practice of clinical cardiology. The question of whether we can gain molecular insight and use it to obtain better treatment of cardiac problems is implicitly posed. The first part deals with cardiac diseases involving ion channels, and discusses the clinical trials of channel-modulating drugs in the treatment of arrhythmias. This section, which is written by experts in cardiology, points out the paucity of useful predictions coming from biophysical studies and, when compared with the following sections, clearly demonstrates the difference between the mechanistic biophysicists’ approach and the empirical approach of clinicians.
BOOK
REVIEWS
K- channel blockers. Disappointingly, it is not clear from reading these chapters that there is even a bridge between molecular study of channel biophysics and the development of drugs, let alone between biophysics and clinical practice. A panel of expert clinicians and scientists was convened by the National Heart, Lung and Blood Institute in September 1992 to identify programmatic areas that should be pursued to improve clinical therapies. The committee defined several specific areas that should be concentrated on by basic science, but from pharmacological and clinical viewpoints it is not clear what is recommended. it was noted that, despite the negative findings of CAST, chan-
Subsequent parts of this book describe the major current systems contributing to the cardiac action potential, their physiological and pharmacological regulation, and molecular structure. These chapters provide comprehensive and up-to-date reviews of these fields, and will provide useful reference material to interested researchers. However, there is no chapter on the regulation or pharmacology of ATP-sensitive K* channels, which is surprising given the enormous literature on the role of these channels in ischaemic
action.-potential shortening, K+ loss and preconditioning, and their potential manipulation in the treatment of hypertension. There is a discussion of the development of novel Ca*+and
nel-directed therapies may still ultimately provide the best approach to treatment of arrhythmias. A meaningful dialogue between clinicians, basic scientists and pharmacologists is probably the most pressing need. Those wishing to engage in one could do worse than to start by reading, and heeding, this book. The end result could be communal profit from different approaches. ‘Jack Sprat could eat no fat, His wife could eat no lean, And so between them both, you see, They iicked the platter clean.’ (Nursery rhyme). Colin6. Nichols Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
C. A. Reinhardt fed.) Alferrrstiws
Books Received
Anirnni
C. Benichou (ed.) Adverse Drug Rmctiom: A Prncticd Guide to Dingrzosis nrzd Mnrlngelnerlt Wiley, 1994. E25.00 (xviii + 302 pages) ISBN 0 471942111
P. R. Brown and E. Grushka teds) ill Clzror~mtp~rnpl~~Dekker, 1994. $165.00 (xvi + 435 pages) ISBN 0 8247 9087 1
Adzw~c~s
M. F. Scully,V. V. Kakkar and J. Deadman teds) 7%~ Des@ of Sjyrzthetic Iflhibi~ors of Throrrrbirl Plenum, 1993. $75.00 (x + 246 pages) ISBN 0 306 44593 X
Srhcellrrlnr
Biochmistr!y
Vol.
to
1994. f60.00
22
Plenum, 1994. $95.00 (xviii + 413 pages) ISBN 0 306 44554 9
N. J. Rothwell
and F. Berkenbosch (eds) Brnirz Coutrol of Rrspoorrst~s fo Trnrtam Cambridge University Press,
of the Sicilian
A~ztinrrlnytkrnic
Thcrnpy:
Gambit A
Pntho-
Avpronclz Futura, 1994. $65.00 (xii + 337 pages) ISBN 0 87993 596 0
1994. f50.00 (ix + 342 pages) ISBN 0 52141939 5
physiologic
L. E. Samelson (ed.) Z_yrrrphocyte Actizwtiorf Karger, 1994. $168.00 (xii +
220
pages) ISBN 3 8055 5976 3 B. W. Metcalf, B.J. Dalton and G. Paste (eds) Celllrlnr Adzrsiorr:Molrdsr Dejirritiorl to Thrmpwtic Pohrtid Plenum, 1994. $79.50 (xxi + 318 pages) ISBN 0
J. A. Hickman and T. R. T&ton (eds) Cmccr Chtwotkernpy Blackwell, 1993. f59.50 (xiii + 369 pages) ISBN 0 632 03441 6
VCH,
(xviii + 180 pages) ISBN 3 527 30043 0 R. Iyengar ted.1 Metlzoh irtE~~!yrnolo~y A. Rolland (ed.) P/wmcezrticnl PnrficVol. 238 Academic Press, 1994. $80.00 (xxix e 456 pages) ISBN 0 12 182139 0 ulntc Carriers: Thernprtic Applicntiorls Dekker, 1993. $155.00 (448 pages) ISBN 0 8247 9016 2 A. H. Maddy and J. R. Harris (eds)
Members G.Claeson,
Test@
M. R. Trimble ted.) smts: Epilqxy
Advnrzccs
Nczu
in t/u
AuficowulTrmfmwf
of
Wiley, 1994. f25.00 (xi + 170
pages) ISBN 0 471 95122 6
306 44685 5
Book Reviews If you are interested cation
in reviewing
to TiPS Book Reviews, Elsevier Trends
Please note that proceedings under
a recently
published
write with details
Journals, 68 Hills Road, Cambridge,
and new editions
Books Received are not available
book, please
are not reviewed
of the publi-
UK CB2 ILA.
in TiPS. Books previously
listed
for review.
TiPS - December
1994 (Vol.
15)
4
7
1
REVIEWS
to discuss the science behind the methodology, with considerable success. There are two audiences for this book. For those who wish to be educated about 3D QSAR, the chapters are organized in a systematic fashion, starting with Peter Andrews’ account of the pharmacological or, more generally, biological processes we are trying to model and what physical processes are involved. The reader is then taken through the process of generating the 3D structures (Pearlman), deciding on the appropriate 3D conformations to use (Garland Marshall) and various methods for defining the pharmacophore involved in a particular system. The next section illustrates how to put numbers to the physical processes involved, with descriptions of key receptor systems. These latter chapters are, in some senses, inappropriate in this book. Marcel Hibert’s chapter, for example, on G proteincoupled receptors, contains no quantitative biological data at all, let alone a quantitative 3D description of a ligand molecule. However, this chapter and related ones do form
Separate meals or a shared plate Ion Channels in the Cardiovascular System: Function and Dysfunction
Futura Publishing Company, 1994. $85.00 (xxix + 580 pages) 1SBN 0 87993 591 X
‘In pursuit of detail, a specialist ends up knowing everything about nothing. Conversely, a generalist knows nothing about everything. In consequence neither has anything to say to the other.’ (An adage.) Over the past forty years, the electrical activity of the heart has been
a link for biologists who may be interested in the techniques of ligand design described by Hans-Joachim Bahm. The second half of the book is a testament to Kubinyi’s persuasive powers in getting many of the leading exponents of these techniques to write accounts of their experiences, and to make available to the rest of us the values and, perhaps more importantly, the limitations of various methods. The second audience and the major market for this book will comprise the rapidly growing number of people in life sciences who now have access to some of these techniques via a variety of work-stations and personal computers. The major method in current use, comparative molecular field analysis (CoMFA), is heavily described both in concept and practice. The separate chapter by Svante Wold on partial least squares VLSI is a reminder that the statistical technique to relate the quantitative description of the molecule to a quantitative desciiption of the biology is an independent process and can be used to relate
other descriptors. This is indicated in Don Abraham’s chapter on the use of hydrophobic fields and Rebecca Wade’s chapter on the application of GRID and GRIN programs. It is possible that the most used part of the book will be the two appendices. The first, on recommendations for CoMFA, should be required reading for all who use the technique and all who referee papers for journals on the subject. The second, on the practical problems of PLS, again keeps us on the ‘straight and narrow’ of valid science. Overall this is an excellent book, which should be accessible to all who work in the area of 3D molecular design. It is extremely well indexed and printed, with much of it in colour. The high price may prevent it from being on the desk of practitioners as a key reference source. It should, however, be available in the libraries of the organizations in which they work.
described in considerable detail. Patch-clamp technology and the cloning of ion channels has recently prompted an explosive increase in the volume of knowledge. Basicscientists can now be so specialized as to spend a whole career investigating isolated aspects of a single channel protein, but clinicians are confronted with ever different and changing clinical problems, and are forced to remain generalists. Examination of patient outcome in randomized empirical surveys still seems to be the most useful approach to developing new therapies. The massive cardiac arrhythmia suppression trial (CAST) showed that Type I antiarrhythmics, which block Na * channels and suppress ventricular arrhythmias, are actually harmful to patients. The pre dictions of basic scientists, that these agents would heip patients experiencing post-infarction arrhythmias, turned out to be incorrect. Such experiences could lead basic science
into
J. Bradshaw Giomolecular Structure Department, Glaxo Research and Development, Park Road, Ware, Hertfordshire, UK SG12 ODP.
ever narrower study of channels for their own sake, and clinicians to ignore the predictions of basic scientists, leaving the two tracks of research diverging yet further. This book begins by outlining the widening gap between ion channel study at the molecular level and the practice of clinical cardiology. The question of whether we can gain molecular insight and use it to obtain better treatment of cardiac problems is implicitly posed. The first part deals with cardiac diseases involving ion channels, and discusses the clinical trials of channel-modulating drugs in the treatment of arrhythmias. This section, which is written by experts in cardiology, points out the paucity of useful predictions coming from biophysical studies and, when compared with the following sections, clearly demonstrates the difference between the mechanistic biophysicists’ approach and the empirical approach of clinicians.
BOOK
REVIEWS
K- channel blockers. Disappointingly, it is not clear from reading these chapters that there is even a bridge between molecular study of channel biophysics and the development of drugs, let alone between biophysics and clinical practice. A panel of expert clinicians and scientists was convened by the National Heart, Lung and Blood Institute in September 1992 to identify programmatic areas that should be pursued to improve clinical therapies. The committee defined several specific areas that should be concentrated on by basic science, but from pharmacological and clinical viewpoints it is not clear what is recommended. it was noted that, despite the negative findings of CAST, chan-
Subsequent parts of this book describe the major current systems contributing to the cardiac action potential, their physiological and pharmacological regulation, and molecular structure. These chapters provide comprehensive and up-to-date reviews of these fields, and will provide useful reference material to interested researchers. However, there is no chapter on the regulation or pharmacology of ATP-sensitive K* channels, which is surprising given the enormous literature on the role of these channels in ischaemic
action.-potential shortening, K+ loss and preconditioning, and their potential manipulation in the treatment of hypertension. There is a discussion of the development of novel Ca*+and
nel-directed therapies may still ultimately provide the best approach to treatment of arrhythmias. A meaningful dialogue between clinicians, basic scientists and pharmacologists is probably the most pressing need. Those wishing to engage in one could do worse than to start by reading, and heeding, this book. The end result could be communal profit from different approaches. ‘Jack Sprat could eat no fat, His wife could eat no lean, And so between them both, you see, They iicked the platter clean.’ (Nursery rhyme). Colin6. Nichols Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
C. A. Reinhardt fed.) Alferrrstiws
Books Received
Anirnni
C. Benichou (ed.) Adverse Drug Rmctiom: A Prncticd Guide to Dingrzosis nrzd Mnrlngelnerlt Wiley, 1994. E25.00 (xviii + 302 pages) ISBN 0 471942111
P. R. Brown and E. Grushka teds) ill Clzror~mtp~rnpl~~Dekker, 1994. $165.00 (xvi + 435 pages) ISBN 0 8247 9087 1
Adzw~c~s
M. F. Scully,V. V. Kakkar and J. Deadman teds) 7%~ Des@ of Sjyrzthetic Iflhibi~ors of Throrrrbirl Plenum, 1993. $75.00 (x + 246 pages) ISBN 0 306 44593 X
Srhcellrrlnr
Biochmistr!y
Vol.
to
1994. f60.00
22
Plenum, 1994. $95.00 (xviii + 413 pages) ISBN 0 306 44554 9
N. J. Rothwell
and F. Berkenbosch (eds) Brnirz Coutrol of Rrspoorrst~s fo Trnrtam Cambridge University Press,
of the Sicilian
A~ztinrrlnytkrnic
Thcrnpy:
Gambit A
Pntho-
Avpronclz Futura, 1994. $65.00 (xii + 337 pages) ISBN 0 87993 596 0
1994. f50.00 (ix + 342 pages) ISBN 0 52141939 5
physiologic
L. E. Samelson (ed.) Z_yrrrphocyte Actizwtiorf Karger, 1994. $168.00 (xii +
220
pages) ISBN 3 8055 5976 3 B. W. Metcalf, B.J. Dalton and G. Paste (eds) Celllrlnr Adzrsiorr:Molrdsr Dejirritiorl to Thrmpwtic Pohrtid Plenum, 1994. $79.50 (xxi + 318 pages) ISBN 0
J. A. Hickman and T. R. T&ton (eds) Cmccr Chtwotkernpy Blackwell, 1993. f59.50 (xiii + 369 pages) ISBN 0 632 03441 6
VCH,
(xviii + 180 pages) ISBN 3 527 30043 0 R. Iyengar ted.1 Metlzoh irtE~~!yrnolo~y A. Rolland (ed.) P/wmcezrticnl PnrficVol. 238 Academic Press, 1994. $80.00 (xxix e 456 pages) ISBN 0 12 182139 0 ulntc Carriers: Thernprtic Applicntiorls Dekker, 1993. $155.00 (448 pages) ISBN 0 8247 9016 2 A. H. Maddy and J. R. Harris (eds)
Members G.Claeson,
Test@
M. R. Trimble ted.) smts: Epilqxy
Advnrzccs
Nczu
in t/u
AuficowulTrmfmwf
of
Wiley, 1994. f25.00 (xi + 170
pages) ISBN 0 471 95122 6
306 44685 5
Book Reviews If you are interested cation
in reviewing
to TiPS Book Reviews, Elsevier Trends
Please note that proceedings under
a recently
published
write with details
Journals, 68 Hills Road, Cambridge,
and new editions
Books Received are not available
book, please
are not reviewed
of the publi-
UK CB2 ILA.
in TiPS. Books previously
listed
for review.
TiPS - December
1994 (Vol.
15)
4
7
1