A Lifetime's Adventure in Extracellular K+ Regulation: The Scottish Connection.

In a career that has spanned 45 years and shows no signs of slowing down, Dr Bruce Ransom has devoted considerable time and energy to studying regulation of interstitial K+. When Bruce commenced his studies in 1969 virtually nothing was known of the functions of glial cells, but Bruce's research contributed to the physiological assignation of function to mammalian astrocytes, namely interstitial K+ buffering. The experiments that I describe in this review concern the response of the membrane potential (Em) of in vivo cat cortical astrocytes to changes in [K+]o, an experimental manoeuvre that was achieved in two different ways. The first involved recording the Em of an astrocyte while the initial aCSF was switched to one with different K+, whereas in the second series of experiments the cortex was stimulated and the response of the astrocyte Em to the K+ released from neighbouring neurons was recorded. The astrocytes responded in a qualitatively predictable manner, but quantitatively the changes were not as predicted by the Nernst equation. Elevations in interstitial K+ are not sustained and K+ returns to baseline rapidly due to the buffering capacity of astrocytes, a phenomenon studied by Bruce, and his son Chris, published 27 years after Bruce's initial publications. Thus, a lifetime spent investigating K+ buffering has seen enormous advances in glial research, from the time cells were identified as 'presumed' glial cells or 'silent cells', to the present day, where glial cells are recognised as contributing to every important physiological brain function.

Collaborating with Alexander Scriabine and the Miles Institute for Preclinical Pharmacology.

This article represents a timely opportunity to express my affection, admiration and gratitude to Professor David Triggle. David was my Ph.D. advisor as well as a key consultant in the 1980s and early 1990s for research programs at Miles Institute for Preclinical Pharmacology in West Haven, CT, the U.S. research operation of Bayer AG, in the areas of Ca(2+) and K(+) channel ligands. The binding methodology developed in his laboratory was used to search for an endogenous ligand for L-type Ca(2+) channels. We did not find the substance that we were searching for, a genetically-determined, competitive inhibitor for the 1,4-dihydropyridine binding site, but instead isolated the endogenous ligand for the brain's own marijuana, anandamide. Devane, Mechoulam and coworkers first discovered that this compound was the endogenous ligand for delta-9-tetrahydrocannabinol, the active substance in cannabis. The endogenous endocannabinoid system is now the target of many exciting new approaches to drug discovery.

Mechanisms of vascular hyporesponsiveness in septic shock.

PURPOSE: To define some of the most common characteristics of vascular hyporesponsiveness to catecholamines during septic shock and outline current therapeutic approaches and future perspectives. METHODS: Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. RESULTS: NO and peroxynitrite are mainly responsible for vasoplegia and vascular hyporeactivity while COX 2 enzyme is responsible for the increase in PGI2, which also contributes to hyporeactivity. Moreover, K+ATP and BKCa channels are over-activated during septic shock and participate in hypotension. Finally, other mechanisms are involved in vascular hyporesponsiveness such as critical illness-related corticosteroid insufficiency, vasopressin depletion, dysfunction and desensitization of adrenoreceptors as well as inactivation of catecholamines by oxidation. CONCLUSION: In animal models, several therapeutic approaches, targeted on one particular compound have proven their efficacy in preventing or reversing vascular hyporesponsiveness to catecholamines. Unfortunately, none have been successfully tested in clinical trials. Nevertheless, very high doses of catecholamines ( > 5 µg/kg/min), hydrocortisone, terlipressin or vasopressin could represent an alternative for the treatment of refractory septic shock.

Potassium channels in Drosophila: historical breakthroughs, significance, and perspectives.

Drosophila has enabled important breakthroughs in K(+) channel research, including identification and fi rst cloning of a voltage-activated K(+) channel, Shaker, a founding member of the K(V)1 family. Drosophila has also helped in discovering other K(+) channels, such as Shab, Shaw, Shal, Eag, Sei, Elk, and also Slo, a Ca(2+) - and voltage-dependent K(+) channel. These findings have contributed significantly to our understanding of ion channels and their role in physiology. Drosophila continues to play an important role in ion channel studies, benefiting from an unparalleled arsenal of genetic tools and availability of tens of thousands of genetically modified strains. These tools allow deletion, expression, or misexpression of almost any gene in question with temporal and spatial control. The combination of these tools and resources with the use of forward genetic approach in Drosophila further enhances its strength as a model system. There are many areas in which Drosophila can further help our understanding of ion channels and their function. These include signaling pathways involved in regulating and modulating ion channels, basic information on channels and currents where very little is currently known, and the role of ion channels in physiology and pathology.

Renal and extrarenal regulation of potassium.

The ISN Forefronts in Nephrology Symposium took place 8-11 September 2005 in Kartause Ittingen, Switzerland. It was dedicated to the memory of Robert W. Berliner, who died at age 86 on 5 February 2002. Dr Berliner contributed in a major way to our understanding of potassium transport in the kidney. Starting in the late 1940s, without knowledge of how potassium was transported across specific nephron segments and depending only on renal clearance methods, he and his able associates provided a still-valid blueprint of the basic transport properties of potassium handling by the kidney. They firmly established that potassium was simultaneously reabsorbed and secreted along the nephron; that variations in secretion in the distal nephron segments play a major role in regulating potassium excretion; and that such secretion is modulated by sodium, acid-base factors, hormones, and diuretics. These conclusions were presented in a memorable Harvey Lecture some forty years ago, and they have remained valid ever since. The concepts have also provided the foundation and stimulation for later work on single nephrons, tubule cells, and transport proteins involved in potassium transport.