This volume represents the proceedings ofthe invited lectures ofthe first International Symposium on "Serotonin from Cell Biology to Pharmacology and Therapeutics" which was held in Florence on March 29 -Aprill, 1989. This meeting, held under the co-sponsorship of the Serotonin Club and the Fondazione Giovanni Lorenzini, represents the first attempt to bring together scientists fascinated by the complexity of the action of 5-hydroxytryptamine throughout the body and in various species. Hence this volume provides the reader with the unique overview of the sources, effects, receptors, physiological actions and pathological role of Serotonin. As such it will be of interest not only to the person devoting herorhis research efforts to the study of 5-hydroxytryptamine but also to all scholars and even clinicians wanting to know how the powerful monoamine can modulate cellular functions. To accelerate the publication of these proceedings the Editors and the publishers have selected the camera ready format and have avoided a lengthy refereeing process. Hence the scientific content of, and the opinions expressed in the chapters are the sole responsibility of the authors. The Editors Milan and Houston The Editors want to thank Mrs. H. Liepman and her staff at Kluwer for the prompt and efficient handling of the manuscripts.

It is an exciting task to be the editor of the first monograph covering a new area of the biomedical sciences. Since the first report in 1980 by Robert Furchgott and colleagues (see Chapter 1) of the evidence of endothelium-dependent relaxation in isolated arteries, there are ever increasing numbers of vascular physiologists and pharmacologists who are scraping away the endothelium to look into its role in cardiovascular con trol. And the more one looks, the more one discovers. Not only is the list of substances that can induce endothelium-dependent relaxations im pressively long, but these intriguing cells can also secrete vasoconstrictor substances. The ability of the endothelium to modulate the degree of con traction of the underlying smooth muscle is an ancestral property of the blood vessel wall, illustrating the logic of nature, since the endothelial cells are located in the best possible strategic location to continuously monitor the properties (chemical or physical) of the blood. And more and more data emerge suggesting that in several cardiovascular diseases per turbations in endothelium-dependent responses are one of the early signs of the abnormal process. Thus, the importance of endothelium-dependent responses, triggered by the intellectual curiosity of one of the pioneers of vascular physiology and pharmacology, is now recognized not only by basic scientists, but also by all concerned with the cardiovascular diseases. The purpose of this monograph is to provide them with a reference work, so that they know where to start."

This volume contains the Proceedings of the invited lectures of the Second International Sym posium on SEROTONIN from Cell Biology to Pharmacology and Therapeutics held in Houston, Texas September 15-18, 1992. The meeting was held under the co-sponsorship of the Serotonin Club, the Giovanni Lorenzini Medical Foundation, and the Fondazione Giovanni Lorenzini. This volume discusses the major exploration in knowledge that has occurred recently of the complex role that 5- hydroxytryptamine (serotonin) plays in health and disease. In par ticular, these Proceedings highlight major breakthroughs in molecular biology and classification of receptor subtypes that are responsible for the many actions of the monoamine. The ever increasing importance of serotonin in central regulation, whether autonomic or behavioral is represented by a large number of chapters prepared by world experts. Additionally, the role of serotonin in peripheral organs is also discussed. Hence, this volume provides the reader with a unique, up-to-date review of this exciting and novel area of science. These Proceedings obviously are of great interest, not only to the researchers directly engaged in the quest for the understanding and unraveling of the actions of the interactions with serotonin as a major neurohumoral mediator, but also to all scholars and clinicians who wish to acquire a better understanding of the functioning of the brain and of peripheral organs. Since this volume was constructed as a compilation of invited lectures, the scientific content and the opinions expressed in the chapters are the sole responsibility of the authors."

Contents:
1. What do gap junctions do anyway? 2. Cardiovascular gap junctions: Functional Diversity, complementation and specialization of connexins 3. Endothelium and smooth muscle pathways for conduction along resistance microvessels 4. Membrane potential and calcium responses evoked by acetylcholine in submucosal arterioles of the guinea-pig small intestine 5. The effects of ouabain, 18a-glycyrrhetinic acid and connexin-mimetic peptides on intercellular communication in cells expressing a Cx43-GFP chimeric protein 6. Role of gap junctions in endothelium-dependent hyperpolarizations 7. Heterogeneity of EDHF-type relaxations of rabbit and rat arteries analysed with peptides homologous to the extracelluar loops of connexins 37, 40 and 43 8. Myoendothelial and circumferential spread of endothelium-dependent hyperpolarization in coronary arteries 9. Direct myoendothelial contact in human pulmonary microvessels 10. Role of gap junctional communication in EDHF-mediated responses and mechanisms of K-induced dilatations 11. Comparison of alpha and beta isoforms of glycyrrhetinic acid and carbenoxolone as inhibitors of EDHF-type relaxation 12. Inhibitory effect of 18-beta-glycyrrhetinic acid on the relaxation induced by acetylcholine in the rat aorta 13. A central role for endothelial cell potassium channels in EDHF-mediated responses 14. Could the EDHF be K in porcine coronary arteries? 15. Nitro-L-arginine/indomethacin-resistant relaxations to acetylcholine in small gastric arteries of the rat: Effect of ouabain plus Ba2+ and relation to potassium ions 16. Effects of barium, ouabain and K+ on the resting membrane potential and endothelium-dependent responses in rat arteries 17. EDHF and potassium: Blockade of chloride channels reveals relaxations of rat mesenteric artery to potassium 18. Cytochrome P450 2C is a source of EDHF and reactive oxygen species in the porcine coronary artery 19. Cortisol increases EDHF-mediated relaxations in porcine coronary artery 19. Cortisol increases EDHF-mediated relaxations in porcine coronary arteries and up-regulates the expression of cytochrome P450 2C9 20. An arachidonic acid metabolite(s) produced by the endothelial cytochrome P450 isoform, CYP3A4, relaxes the lingual artery of the monkey via K+ channel opening 21. EDHF-mediated responses induced by bradykinin in the porcine coronary artery 22. Epoxyeicosatrienoic acid release mediates nitric oxide-independent dilatation of rat mesenteric vessels 23. Epoxyeicosatrienoic acid and endothelium-dependent hyperpolarization in porcine coronary arteries 24. Lipoxygenase-derived metabolites of arachidonic acid are not involved in the endothelium-dependent hyperpolarization to acetylcholine in the carotid artery of the guinea-pig 25. Cytochrome P450 isoforms in the brain encode cell specific hyperpolarizing factors with a common mechanism of action 26. Expression of recombinant cytochrome P450 epoxygenase in rat brain 27. Identification of 11, 12, 15-trihydroxyeicosatrienoic acid as the mediator of acetylcholine- and arachidonic acid-induced relaxations in the rabbit aorta 28. Identification of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in mice 29. Components of the potassium currents underlying the actions of endothelium- derived hyperpolarizing factor in arterioles 30. Evidence for relaxation to endothelium-derived hyperpolarizing factor (EDHF) in isolated small mesenteric arteries of the mouse 31. Pharmacological characterization of potassium channels in intact mesenteric arteries and single smooth muscle cells from eNOS-/- and +/+ mice 32. EDHF, which is not NO, is a major endothelium-dependent vasodilator in mice 33. Prostacyclin and iloprost in the isolated carotid artery of the guinea pig 34. Role of charybdotoxin/apamin sensitive K+ Ca channels in pulsatile perfusion- mediated coronary vasodilatation in vivo 35. Essential role of estrogen in the EDHF-mediated responses of mesenteric arteries from middle-aged female rats: Possible contribution of gap junctional protein connexin 43 36. Endothelium-derived hyperpolarizing factor (EDHF) and utero-feto-placental circulation in the rat 37. Endothelium-derived hyperpolarizing factor maintains a normal relaxation to bradykinin despite impairment of the nitric oxide pathway in porcine coronary arteries with regenerated endothelium 38. Mechanisms underlying the vasodilatation caused by bradykinin in essential hypertensive patients 39. Influence of diabetes on endothelium-dependent responses in mesenteric and femoral arteries of rats 40. Folate restores the NO synthase- and cyclooxygenase-resistant renal vasodilator response to acetylcholine in diabetes 41. Resistance of EDHF-mediated relaxations to oxidative stress in human radial arteries 42. Critical limb ischemia results in different types of endothelial dysfunction depending on the vascular bed studied 43. Potentiated EDHF-mediated dilatations in the rat middle cerebral artery following ischemia/reperfusion 44. The EDHF-dependent but not the NO-dependent component of the acetylcholine-induced relaxation of the rabbit aorta is resistant to ionized radiation 45. Inhibition of converting enzyme prevents the age-related decline in endothelium-dependent hyperpolarization 46. Effects of a converting enzyme inhibitor, an AT1-receptor antagonist and their combination on endothelial dysfunction in hypertension 47. EDHF: Gap junction or chemical? And many other questions

Contents:
1. Potassium Channels and Member Potential in Vascular Endothelial and Smooth Muscle Cells 2. Possible Contribution to CLCA1 to Calcium-Activated Chloride Channels in Murine Smooth Muscle Cells 3. Trafficking and Transduction Functions of the NA Pump in Vascular Smooth Muscle Cells 4. Isoforms of NA, K-Atpase 5. Calcium Sparks and Membrane Potential 6. Proteinase-Activated Receptor-2: Release of an Endothelium-Derived Hyperpolarizing Factor Distinct from that Released by Acetylcholine 7. Mechanical Stimulation Increases the Activity and Expression of Cytochrome P450 2C in Porcine Coronary Artery Endothelial Cells 8. Important Role of Hydrogen Peroxide as an Endothelium-Derived Hyperpolarizing Factor in Animals and Humans 9. Altered Calcium Dynamics do not Account for the Attenuation of EDHF-Mediated Dilatations in the Middle Cerebral Artery of Female Rats 10. Connexin-Mimetic Peptides: Influence of Nitric Oxide Synthase and Cyclooxygenase-Independent Renal Vasodilatation, Basal Renal Blood Flow and Blood Pressure in the Rat 11. Urocortin-Induced Relaxations of the Rat Coronary Artery 12. Nitric Oxide is the Only EDHF Released by the Endothelium in Lymphatic Vessels of the Guinea-Pig Mesentery 13. Role of EDHF in Vascular Tone in vivo 15. Improvement of Age-Related Impairment of Endothelium-Derived Hyperpolarization by Renin-Angiotensin System Blockade 16. Characterization of Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxation of Small Mesenteric Arteries from Diabetic (DB/DB -/-) Mice 17. Endothelium-Dependant Responses in Small Arteries Isolated from Normal and Pre-Eclamptic Pregnant Women 18. Free Radical Species and Endothelium Dysfunction During Deoxycorticosterone-Salt Induced Hypertension 19. EDHF Involvement in Skin Pressure-Induced Vasodilation 20. N-Acetylcysteine and Immobilization Stress Attenuate the Dysregulation of Endthelium-Dependent Coronary Vascular Tone Induced by Acute Hemorrhage 21. Red Wine Polyphenolic Compounds Induce EDHF-Mediated Relaxation and Hyperpolarization in the Porcine Coronary Artery: Involvement of Redox-Sensitive Mechanisms 22. Estrogen Substitution Restores the Basal Influence of Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor on Vascular Tone in Isolated Mesenteric Arteries from Ovariectomized Rats 23. Ascorbate Inhibits EDHF in the Bovine Eye but not in the Porcine Coronary artery 24. Gabexate Mesilate Inhibits Endothelium-Dependent Relaxation, But Causes Endothelium-Independent Relaxation of Rat Blood Vessels 25. Mechanisms Underlying Basal Vascular Tone in the Guinea-Pig Mesenteric Aterioles 26. Endothelium-Dependent Depolarization and its Implications for Endothelium-Derived Hyperpolarizing Factor 27. Role of Gap Junctions in EDHF-Mediated Relaxation Response in Human Subcutaneous Resistance Arteries 28. Permissive Role of Camp in the Mediation of Relaxations Initiated by Endothelial Hyperpolarization 29. Myoendethelial Gap Junctions

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, exciting new work pointing to an application in atherosclerosis is described. The book also includes important uses of Ca2+ antagonists in novel areas of interest such as the gastrointestinal tract, renal protection and multi-drug resistance.

This volume contains the Proceedings of the invited lectures of the Second International Sym posium on SEROTONIN from Cell Biology to Pharmacology and Therapeutics held in Houston, Texas September 15-18, 1992. The meeting was held under the co-sponsorship of the Serotonin Club, the Giovanni Lorenzini Medical Foundation, and the Fondazione Giovanni Lorenzini. This volume discusses the major exploration in knowledge that has occurred recently of the complex role that 5- hydroxytryptamine (serotonin) plays in health and disease. In par ticular, these Proceedings highlight major breakthroughs in molecular biology and classification of receptor subtypes that are responsible for the many actions of the monoamine. The ever increasing importance of serotonin in central regulation, whether autonomic or behavioral is represented by a large number of chapters prepared by world experts. Additionally, the role of serotonin in peripheral organs is also discussed. Hence, this volume provides the reader with a unique, up-to-date review of this exciting and novel area of science. These Proceedings obviously are of great interest, not only to the researchers directly engaged in the quest for the understanding and unraveling of the actions of the interactions with serotonin as a major neurohumoral mediator, but also to all scholars and clinicians who wish to acquire a better understanding of the functioning of the brain and of peripheral organs. Since this volume was constructed as a compilation of invited lectures, the scientific content and the opinions expressed in the chapters are the sole responsibility of the authors.

It is an exciting task to be the editor of the first monograph covering a new area of the biomedical sciences. Since the first report in 1980 by Robert Furchgott and colleagues (see Chapter 1) of the evidence of endothelium-dependent relaxation in isolated arteries, there are ever increasing numbers of vascular physiologists and pharmacologists who are scraping away the endothelium to look into its role in cardiovascular con trol. And the more one looks, the more one discovers. Not only is the list of substances that can induce endothelium-dependent relaxations im pressively long, but these intriguing cells can also secrete vasoconstrictor substances. The ability of the endothelium to modulate the degree of con traction of the underlying smooth muscle is an ancestral property of the blood vessel wall, illustrating the logic of nature, since the endothelial cells are located in the best possible strategic location to continuously monitor the properties (chemical or physical) of the blood. And more and more data emerge suggesting that in several cardiovascular diseases per turbations in endothelium-dependent responses are one of the early signs of the abnormal process. Thus, the importance of endothelium-dependent responses, triggered by the intellectual curiosity of one of the pioneers of vascular physiology and pharmacology, is now recognized not only by basic scientists, but also by all concerned with the cardiovascular diseases. The purpose of this monograph is to provide them with a reference work, so that they know where to start."

MOTOOMI NAKAMURA As we approach the 21st century, ischemic heart disease is the major cause of death in most of the developed nations of the world. Since the 1970s, much effort and expense have led to designs of coronary thrombolytic therapy, percutaneous coronary angioplasty (PTCA), coronary artery bypass grafting, heart transplantation, automatic defibrillators, as well as to the formation of beta blockers and com pounds which block the calcium channel. Socio-educational programs directed at exercise, diet, instruction in the risk factors of smoking, hyperlipidemia and hypertension have contributed to the decrease in the rate of morbidity and mortality of patients with ischemic heart disease. However, the first clinical event of ischemic heart disease, the so-called "heart attack" and sudden cardiac death continues to present problems, as the mechanisms involved in these events are poorly understood. It has long been thought that ischemic heart disease is the sequence of an organic fixed atherosclerotic obstruction of the epicardial coronary arteries and the role of coronary vasomotion has been given much less attention. Recent clinical and laboratory animal studies revealed that increased tonus and spasm of the large epicardial coronary arteries are the cause of various stages of ischemic heart disease. The role of coronary vasospasm in the development of un stable angina, sudden cardiac death and acute myocardial infarction remains open to debate. Pharmacophysiological studies showed that the epicardial large coronary artery contributes only 5% to regulation of normal coronary flow."

This volume represents the proceedings ofthe invited lectures ofthe first International Symposium on "Serotonin from Cell Biology to Pharmacology and Therapeutics" which was held in Florence on March 29 -Aprill, 1989. This meeting, held under the co-sponsorship of the Serotonin Club and the Fondazione Giovanni Lorenzini, represents the first attempt to bring together scientists fascinated by the complexity of the action of 5-hydroxytryptamine throughout the body and in various species. Hence this volume provides the reader with the unique overview of the sources, effects, receptors, physiological actions and pathological role of Serotonin. As such it will be of interest not only to the person devoting herorhis research efforts to the study of 5-hydroxytryptamine but also to all scholars and even clinicians wanting to know how the powerful monoamine can modulate cellular functions. To accelerate the publication of these proceedings the Editors and the publishers have selected the camera ready format and have avoided a lengthy refereeing process. Hence the scientific content of, and the opinions expressed in the chapters are the sole responsibility of the authors. The Editors Milan and Houston The Editors want to thank Mrs. H. Liepman and her staff at Kluwer for the prompt and efficient handling of the manuscripts.