"Those who choose to increase their knowledge still further by reading ... will discover an exciting new world. " NOEL WHITTAKER, in "Making Money Made Simple" 1989. The development of calcium antagonists has recently been described as representing "one of the major advances in cardiovascular thera peutics of the latter half of the twentieth century" (Braunwald, 1990). However, although the development of these drugs started in the mid nineteen sixties it is only recently that their real potential has begun to be appreciated. Even now the calcium antagonist saga is not complete, since new compounds continue to appear and new therapeutic applica tions emerge. Based on the experience gained in the clinics in which these drugs have been used recognition is being given now to the need to improve upon the prototypes of the group. Such improvement is resulting in the development and production not only of long-acting formulations of the prototypes (nifedipine, verapamil and diltiazem) but also of new calcium antagonists with improved tissue selectivity, potency and duration of action. To those of us who are interested in this field such a development is both exciting and rewarding. As far as the clinicians who prescribe these drugs are concerned the long-acting nature of some of the newer calcium antagonists should make the satisfactory management of their patients an achievable goal.

"What we call the beginning is often the end, and to make an end is to make a beginning. The end is where we start from." T. S. ELIOT, "Geroniton" The discovery of endothelin-l was both an end and a beginning. It is an end because this discovery has started a plethora of investigations as to endothe1in's sites of production, mode of action, it's normal and abnormal physiological role and its involvement in a variety of pathological conditions ranging from renal failure to myocardial infarction, cardiac hypertrophy, hyperten sion, cyclosporine induced toxicity, mental depression, renal failure, stress related illness, and even stroke and sudden death. It is a beginning because no one can foresee where the investigations will ultimately lead, or how they will end. The discovery of the endothelins was a very recent event and soon specialist books will start to appear dealing in detail with different aspects of their chemistry, physiological role and pathological importance. The present book is intended to act as a guide and primer for those who are becoming intrigued by the many endothelin related articles which are now appearing in the journals but who as yet have not had the time or opportunity to be caught up in the web of enthusiasm and excitement which is motivating those more directly involved in the field of research.

This is the first book to summarize experimental results from the new, rapidly expanding field of research into the calcium channel in cell membrane. Calcium is an ubiquitous messenger of various cellular functions. Its fundamental role in the regulation of cardiac contractions has long been recognized. Drugs counteracting some actions of calcium ions, namely calcium antagonists, have since become essential to research. In the last decade it has been established that calcium ions reach their target intracellular system by passing through specialized calcium channels in the membrane. Recently improved experimental techniques combined with the discovery of highly specific Ca channel ligands have dramatically enlarged our knowledge of the molecular structure and function of such channels. The contributions by leading world specialists shed new light on both basic science and possible clinical implications for cardiovascular pharmacology, endocrinology and neuropharmacology.

2 The free internal Ca+ concentration in human red cells is set according to the leak 2 and-pump principle: There is a finite passive Ca+ influx at the physiological 2 2 Ca+ -gradient across the membrane which is compensated by Ca+ pumping in the outward direction with a rate given by the degree of saturation of the A TP-fuelled Ca 2 pump at the steady-state internal Ca+ concentration. Simons (1982) recently devised a method allowing the measurement of the steady 2 2 state internal Ca+ concentration. Cells are suspended in media of different Ca+ con 2 2 tent whose Ca+ concentration is monitored by a Ca+ -selective electrode. When the cells are lysed (by digitonin) there is an upward or downward deflection of the elec 2 trode signal. At the point of zero deflection, the cellular Ca+ concentration equals that 2 of the medium. The result is, that in fresh human red blood cells the Ca+ concentra tion is ;;;; O.4,uM (this is an upper estimate; the true value may be considerably lower).