Gases help fuel the vascular debate

Research into local mediators in the blood vessel wall has been an area of great activity ever since the 1960s, when Florey remarked that the endothelium was ‘more than a nucleated cellophane wrapper’ (Florey, 1966). In the 1970s, prostanoids, particularly prostaglandin I2 (PGI2), were the most popular research targets following the report from John Vane’s group of a prostanoid which relaxed vascular smooth muscle (Moncada et al. 1976). In the 1980s, research into nitric oxide (NO) came to the fore after Furchgott and Zawadzki’s report on the requirement of the endothelium for the relaxation of blood vessels in response to acetylcholine (Furchgott & Zawadzki, 1980). It subsequently became apparent, following the use of inhibitors of NO and PGI2 in experimental systems, that there were further pathways within blood vessels which mediated relaxant responses. Debate about the identity of these pathways and how they interact continues. This issue contains papers by two speakers from the symposium entitled Short-lived Mediators in the Blood Vessel Wall, held as part of Life Sciences 2007 in Glasgow on 12th July 2007, that addressed this debate. The symposium was part of a joint meeting of the Biochemical Society, the British Pharmacological Society and The Physiological Society. Opening the symposium, Jane Mitchell (London, UK) gave an overview of the effects of NO and PGI2 within the blood vessel and their signalling. In particular, she focused upon actions of PGI2 mediated by the nuclear receptors, peroxisome proliferatoractivated receptors (PPARs; Mitchell et al. 2007). David Bishop-Bailey (London, UK) reviewed the current understanding of epoxyeicosatrienoic acids (EETs; Wray & Bishop-Bailey, 2007). The EETs are produced through the metabolism of arachidonic acid by cytochrome P450 enzymes. These molecules appear to have wide-ranging effects on the vascular system, including relaxation of vascular smooth muscle and modulation of inflammatory responses; one selected oral communication from this symposium by Mairéad Carroll (New York, USA) outlined her investigation into the role of EETs in renal protection. Currently, there is little evidence regarding the endogenous receptors for EETs and the pathways responsible for their actions. David Bishop-Bailey’s article in this volume (Wray & Bishop-Bailey, 2007) explores the possible role of EETs as endogenous ligands for PPARs, contributing further to the story developed by Jane Mitchell (Mitchell et al. 2007). In addition to the speakers whose papers we see here, the symposium also saw presentations from Giuseppe Cirino (Naples, Italy) and Arthur Weston (Manchester, UK). Giuseppe Cirino presented evidence of hydrogen sulphide (H2S) as a newly discovered short-lived gaseous mediator in the blood vessel wall. Hydrogen sulphide is well known as the toxic gas that smells like rotten eggs; however, recently more attention has been paid to its activities as a messenger in both the cardiovascular and the central nervous systems. Hydrogen sulphide (H2S) is formed by two enzymes, one of which, cystathionine-γ -lyase (CSE), is present in smooth muscle cells (Wang, 2002). Measurable quantities of H2S have been found in both human and rat tissues, including blood vessels, and in serum (Wang, 2002; Fiorucci et al. 2006). Evidence of its physiological role has been provided by in vitro studies, which have shown that H2S relaxes blood vessels, such as the rat aorta and portal vein (Wang, 2002), while in vivo studies show that bolus intravenous injections of H2S to rats causes transient decreases in blood pressure (Wang, 2002). Further investigation of these results in vivo using selective ion channel modulators, such as pinacidil (an ATP-sensitive potassium channel, KATP, opener) and glibenclamide (KATP channel blocker), indicate that the relaxant effects of H2S are dependent upon activation of the KATP channel on smooth muscle cells; a concept that is supported by electrophysiological studies (Fiorucci et al. 2006). There are also interesting interactions between H2S and NO within the vascular system. Nitric oxide enhances endogenous H2S production by increasing CSE activation and expression (Wang, 2002), while H2S markedly increases the relaxation of vascular tissues in response to a NO donor (Fiorucci et al. 2006). Matthew Whiteman (Exeter, UK) also gave a selected oral communication which proposed a role for H2S in the regulation of the availability of NO in the vascular system, suggesting a further interaction between these mediators. Hydrogen sulphide may also act on endothelial cells to increase the release of other vasodilating factors, contributing to its vascular effects (Wang, 2002). Future investigation into the action of H2S would benefit from the development of selective enzyme inhibitors for CSE, which would give us greater insight into this third gaseous signalling molecule, in addition to NO and carbon monoxide, and its particular roles in health and disease. Arthur Weston provided an overview of his current opinions in the more contentious field of research into endothelium-derived hyperpolarization factor (EDHF). Endothelium-derived hyperpolarization factor was identified as a third endothelium-dependent factor responsible for the relaxations of smooth muscle that persisted after inhibition of the endogenous production of NO and PGI2. Since these relaxations were associated with a hyperpolarization of vascular smooth muscle cells, the unknown mediator was named EDHF. ‘Release’ of EDHF is initiated by an increase of intracellular calcium in endothelial cells, and the consequential activation of endothelial cell small conductance calcium-activated K+ (SKCa) and intermediate conductance calciumactivated K+ (IKCa) channels, which elicit a hyperpolarization of endothelial cells (Busse et al. 2002). Blockers of these channels, TRAM-34 (([1-(2-chlorophenyl) diphenyl) methyl]-1H-pyrazole) for IKca and apamin for SKca, prevent EDHFinduced relaxation of blood vessels and are used pharmacologically to investigate EDHF (Feletou & Vanhoutte, 2006). While many proposals have been made over the years regarding the chemical nature of EDHF, Arthur Weston focused upon two main schools of thought. Firstly, one school of thought favours the idea that gap junctions are responsible for transmitting endothelial cell hyperpolarization from endothelial cells to vascular smooth muscle cells. Gap junctions form a low-resistance electrical