T. Godfraind - Böcker

Although the importance of calcium (Ca2+) in the maintenance of cardiac contractility was recognized as early as 1880, the critical role of the ion in the contractile process in skeletal, cardiac, and smooth muscle has only been established within the last three decades. As the complexity of the pharmacological actions of the Ca2+ channel inhibitors grows, there is a continued need to further clarify the inhibitors, both chemically and functionally. This volume provides an update of the field based on the work presented at the 5th International Symposium on Calcium Antagonists: Pharmacology and Clinical Research. It reviews the current state of the growing area of molecular biology of Ca2+ channels in the cardiovascular area, in addition to the well-established clinical uses of Ca2+ channel inhibitors, recent work pointing to an application in atherosclerosis is described. The text also includes important uses of Ca2+ antagonists in novel areas of interest such as the gastrointestinal tract, renal protection and multi-drug resistance.

As the number of drugs acting on calcium and potassium channels grows, there is a need for a continuous reappraisal of the cellular machinery controlling them. The present volume provides an update on the basic knowledge, the molecular targets of the two channels, and the importance the drugs that bind them have as pharmacological tools and therapeutic agents. This work was presented at the 6th International Symposium on PHARMACOLOGICAL CONTROL OF CALCIUM AND POTASSIUM HOMEOSTASIS: BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS, in Florence (Italy) on October 4-6, 1994. Because of the recent advances in the field, discussions on potassium channels were included for the first time. At least six classes of voltage-dependent calcium channels have been defined based on their physiological and pharmacological properties. Among them, L-type channels, mediating long lasting currents, are better characterized. Calcium homeostasis within the cell is not only regulated by calcium channels; intracellular calcium stores, in particular a pool contained in the lumen of specialized areas of the endoplasmic reticulum, are rapidly exchanged with the cytoplasm and playa key role in the control of calcium homeostasis. This area, however, has not yet been exploited from a therapeutic point of view. Potassium channels are present in virtually every cell type, excitable and nonexcitable, and are distinguished by structural, biophysical, and pharmacological criteria. Different classes including voltage-gated, ligand-gated, AP-sensitive, and G-protein coupled among others, have been defined by their primary regulatory and gating mechanisms.

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).

As the number of drugs acting on calcium and potassium channels grows, there is a need for a continuous reappraisal of the cellular machinery controlling them. The present volume provides an update on the basic knowledge, the molecular targets of the two channels, and the importance the drugs that bind them have as pharmacological tools and therapeutic agents. This work was presented at the 6th International Symposium on PHARMACOLOGICAL CONTROL OF CALCIUM AND POTASSIUM HOMEOSTASIS: BIOLOGICAL, THERAPEUTICAL, AND CLINICAL ASPECTS, in Florence (Italy) on October 4-6, 1994. Because of the recent advances in the field, discussions on potassium channels were included for the first time. At least six classes of voltage-dependent calcium channels have been defined based on their physiological and pharmacological properties. Among them, L-type channels, mediating long lasting currents, are better characterized. Calcium homeostasis within the cell is not only regulated by calcium channels; intracellular calcium stores, in particular a pool contained in the lumen of specialized areas of the endoplasmic reticulum, are rapidly exchanged with the cytoplasm and playa key role in the control of calcium homeostasis. This area, however, has not yet been exploited from a therapeutic point of view. Potassium channels are present in virtually every cell type, excitable and nonexcitable, and are distinguished by structural, biophysical, and pharmacological criteria. Different classes including voltage-gated, ligand-gated, AP-sensitive, and G-protein coupled among others, have been defined by their primary regulatory and gating mechanisms.