Discovery Of Endothelium-derived Relaxing Factor Research Articles

Involvement of endothelial-derived relaxing factors in the regulation of cerebral blood flow

Despite numerous researches and advances in the present times, delayed cerebral vasospasm remains a severe complication leading to a high mortality and morbidity in patients with subarachnoid hemorrhage (SAH). Since the discovery of endothelium-derived relaxing factor (EDRF) in 1980, its role in delayed cerebral vasospasm after SAH has been widely investigated as well as in regulation of basic cerebral blood flow, pathophysiology of vasoconstriction and application on prevention and treatment of cerebral vasospasm. Among all the EDRFs, nitric oxide has caught the most attention, and the other substances which display similar properties with characteristics of EDRF such as carbon monoxide (CO), hydrogen sulfide (H(2)S), hydrogen peroxide (H(2)O(2)), potassium ion (K(+)) and methane (CH(4)) have also evoked great interest in the research field. This review provides an overview of recent advances in investigations on the involvement of EDRFs in the regulation of cerebral blood flow, especially in cerebral vasospasm after SAH. Possible therapeutic measures and potential clinical implications for cerebral vasospasm are also summarized.

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See related article, pp 802–808 Vascular endothelial cells importantly contribute to the regulation of vascular smooth muscle tone through the production of a variety of vasoactive substances and by direct electric communication through myoendothelial gap junctions.1,2 Moncada et al3 discovered the first endothelium-derived vasoactive substance, prostacyclin, in the mid 1970s and rapidly identified its structure and chemical composition.4 This was followed by the landmark observations of Furchgott and Zawadzki.5 and the discovery of endothelium-derived relaxing factor in 1980. Seven years later, the endothelium-derived relaxing factor of Furchgott and Zawadzki was positively identified as NO.6 The existence of a nonprostaglandin, non-NO endothelium-derived hyperpolarizing factor (EDHF) was postulated by Komori et al7 in 1988. Twenty-three years later, we know that there is no one EDHF, but rather multiple pathways by which endothelial cells can produce hyperpolarization-induced relaxation of overlying vascular smooth muscle cells, independent from prostacyclin and NO (Figure).1,2 Figure. Pathways for nonprostacyclin-, non-NO–mediated, endothelium-dependent hyperpolarization of vascular smooth muscle in resistance arteries. Schematic diagram of a longitudinal section through a resistance artery showing smooth muscle and endothelial cell cross-sections and depicting several potential pathways by which ACh can produce endothelium-dependent smooth cell hyperpolarization and vasodilatation independent from prostaglandins and NO. On the left, ACh-induced increases in intracellular Ca2+ activate endothelial small conductance (sKCa) and intermediate conductance (IKCa) Ca2+-activated K+ channels. The released K+ ions can then act as an EDHF through activation of smooth muscle inward rectifier K+ channels (KIR) or Na+/K+ ATPase. Smooth muscle hyperpolarization then closes voltage-gated Ca2+ channels (VGCC), leading to …

Hormonal modulation of endothelial NO production

Since the discovery of endothelium-derived relaxing factor and the subsequent identification of nitric oxide (NO) as the primary mediator of endothelium-dependent relaxations, research has focused on chemical and physical stimuli that modulate NO levels. Hormones represent a class of soluble, widely circulating chemical factors that impact production of NO both by rapid effects on the activity of endothelial nitric oxide synthase (eNOS) through phosphorylation of the enzyme and longer term modulation through changes in amount of eNOS protein. Hormones that increase NO production including estrogen, progesterone, insulin, and growth hormone do so through both of these common mechanisms. In contrast, some hormones, including glucocorticoids, progesterone, and prolactin, decrease NO bioavailability. Mechanisms involved include binding to repressor response elements on the eNOS gene, competing for co-regulators common to hormones with positive genomic actions, regulating eNOS co-factors, decreasing substrate for eNOS, and increasing production of oxygen-derived free radicals. Feedback regulation by the hormones themselves as well as the ability of NO to regulate hormonal release provides a second level of complexity that can also contribute to changes in NO levels. These effects on eNOS and changes in NO production may contribute to variability in risk factors, presentation of and treatment for cardiovascular disease associated with aging, pregnancy, stress, and metabolic disorders in men and women.

Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?

Twenty-five years ago, the discovery of endothelium-derived relaxing factor opened a door that revealed a new and exciting role for the endothelium in the regulation of blood flow and led to the discovery that nitric oxide (NO) multi-tasked as a novel cell-signalling molecule. During the next 25 years, our understanding of both the importance of the endothelium as well as NO has greatly expanded. No longer simply a barrier between the blood and vascular smooth muscle, the endothelium is now recognized as a complex tissue with heterogeneous properties. The endothelium is the source of not only NO but also numerous vasoactive molecules and signalling pathways, some of which are still not fully characterized such as the putative endothelium-derived relaxing factor. Dysfunction of the endothelium is a key risk factor for the development of macro- and microvascular disease and, by coincidence, the discovery that NO was generated in the endothelium corresponds approximately in time with the increased incidence of type 2 diabetes. Primarily linked to dietary and lifestyle changes, we are now facing a global pandemic of type 2 diabetes. Characterized by insulin resistance and hyperglycaemia, type 2 diabetes is increasingly being diagnosed in adolescents as well as children. Is there a link between dietary-related hyperglycaemic insults to the endothelium, blood flow changes, and the development of insulin resistance? This review explores the evidence for and against this hypothesis.

Introduction

This issue of Kidney International contains a series of reviews and articles on current research presented at the International Society of Nephrology Forefronts in Nephrology meeting on “Nitric Oxide and Renal Inflammation,” which took place at St. John's College, Cambridge, United Kingdom, on August 2–5, 2001. This international symposium was held approximately 20 years after the groundbreaking discovery of endothelium-derived relaxing factor (EDRF) by Robert Furchgott. The opening keynote lecture was by Salvador Moncada, who first demonstrated that EDRF is nitric oxide (NO), and the talk focused on the fundamental biology of NO. He emphasized how identifying the degree and duration of target exposure to NO, which arises due to differing activities of the NO synthase isoforms, is essential for understanding the pathophysiological effects of in vivo NO production. In the following four sessions the biology of endothelial NO synthase, inducible NO synthase, and diverse aspects of NO and renal diseases were highlighted by the leading experts in the field. Two major roles for NO were discussed in detail, cell-cell communication and cytotoxicity, and data from in vivo work were presented supporting the hypothesis that pathology arises due to imbalance between constitutive and induced NO production. The therapeutic challenge of how and when to manipulate these NO pathways, however, is still open and will require additional intense research efforts. About 50 scientists from 10 countries participated in the symposium. The meeting provided a forum for established investigators as well as young researchers in the field to participate openly in discussions, exchange views and have their work critically analyzed by experts. The relaxed atmosphere of one of the most traditional colleges in the U.K. opened the way for new contacts and collaborations among the participants. We believe that the articles compiled in this issue of the journal provide the current status of research in the field of NO biology in renal inflammatory diseases and will point to new directions for future studies. We are grateful to the many scientists who contributed their papers for this issue. We thank the International Society of Nephrology for generously supporting this event in Cambridge and the editors of Kidney International for the opportunity to publish this work.

Inducible NO synthase: role in cellular signalling.

The discovery of endothelium-derived relaxing factor and its identification as nitric oxide (NO) was one of the most exciting discoveries of biomedical research in the 1980s. Besides its potent vasodilatory effects, NO was found under certain circumstances to be responsible for the killing of microorganisms and tumour cells by activated macrophages and to act as a novel, unconventional type of neurotransmitter. In 1992, Science picked NO as the 'Molecule of the Year', and over the past years NO has become established as a universal intercellular messenger that acutely affects important signalling pathways and, on a more long-term scale, modulates gene expression in target cells. These actions will form the focus of the present review.

The Discovery of Endothelium-Derived Relaxing Factor and Its Importance in the Identification of Nitric Oxide

The discovery of endothelium-derived relaxing factor (EDRF) and its importance in the identification of nitric oxide (NO) originated with studies using rabbit aorta to examine drug-receptor interactions in vascular smooth muscle. Smooth muscle relaxation by acetylcholine and a number of other agonists was found to be dependent on the presence of endothelial cells, which, when stimulated by the agonist, released a diffusable, very labile, nonprostanoid substance, termed EDRF, that acted on vascular smooth muscle cells to activate relaxation. The characteristics of EDRF, when released from endothelial cells, were similar to the characteristics of NO. It is now established that EDRF, either as NO or some related nitrosyl substance, has a major role in a variety of important biological processes, including the regulation of vascular tone, local blood flow, and blood pressure, inhibition of platelet aggregation and adhesion, and involvement in postischemic reperfusion, memory function, and central nervous system degenerative diseases.

The 1996 Albert Lasker Medical Research Awards. The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide

The discovery of endothelium-derived relaxing factor (EDRF) and its importance in the identification of nitric oxide (NO) originated with studies using rabbit aorta to examine drug-receptor interactions in vascular smooth muscle. Smooth muscle relaxation by acetylcholine and a number of other agonists was found to be dependent on the presence of endothelial cells, which, when stimulated by the agonist, released a diffusable, very labile, nonprostanoid substance, termed EDRF, that acted on vascular smooth muscle cells to activate relaxation. The characteristics of EDRF, when released from endothelial cells, were similar to the characteristics of NO. It is now established that EDRF, either as NO or some related nitrosyl substance, has a major role in a variety of important biological processes, including the regulation of vascular tone, local blood flow, and blood pressure, inhibition of platelet aggregation and adhesion, and involvement in postischemic reperfusion, memory function, and central nervous system degenerative diseases.

Significance of endothelium-derived relaxing factor (EDRF) on pulmonary vasoconstriction induced by hypoxia and hypercapnia.

Distribution of pulmonary blood flow is physiologically regulated by alveolar PO2 and PCO2 surrounding the microcirculation in the lung (Fishman, 1976; Yamaguchi et al., 1994). Decrease in PO2 and/or increase in PC02 has been considered to evoke a rise in the pulmonary microvascular resistance to blood flow (Sylvester et al., 1986; Rodman and Voelkel, 1991). It has been suggested that hypoxic pulmonary vasoconstriction (HPV) as well as hypercapnic-induced vasoconstriction may divert blood flow away from the poorly ventilated areas (Fishman, 1976). The importance of the endothelial-derived vasoactive agents in modulating blood flow has been increasingly recognized since the discovery of endothelium-derived relaxing factor (EDRF), a noble vasodilator of both the systemic and pulmonary circulation (Palmer et al., 1987; Ignaro et al., 1987; Moncada et al., 1991). Many authors have attempted to clarify a possible role of EDRF in the occurrence of HPV, however definite conclusion has not been attained. Although hypercapnia caused by alveolar hypoventilation is considered as the additionally important factor affecting pulmonary hemodynamics (O’Brodovich et al., 1982; Marshall et al., 1984; Sylvester et al., 1986; Yamaguchi et al., 1994), there have been no systematic studies showing the potential effects of hypercapnic-induced acidosis on EDRF modulation for pulmonary circulation. The first aim of this study is systematically to reinvestigate the effects of EDRF on HPV applying varied inhibitors or inactivators for EDRF acting on different levels of EDRF metabolic pathway. The second aim is to make clear the possible roles of EDRF modulating the pulmonary vascular response to acute hypercapnia.

Highlights on pulmonary hypertension: a commentary

Physiological description of the pulmonary vascular response to hypoxia and to disease has clarified the func­ tion of pulmonary arteries. The understanding of the cellular regulation of vascular tone has proceeded at a rapid pace, with the discovery of endothelium-derived relaxing factor (EDRF) [11], and its identification as the gas nitric oxide (NO) [12]. Also, endothelin-1, a polypep­ tide elaborated by endothelium, has been found to be the most powerful natural vasoconstriction [13]. Production of endothelium-derived nitric oxide (EDNO) and endothelin1 are influenced by hypoxia. EDNO may be reduced in COLD [14], whilst endothelin-1 [15] can be increased by hypoxia. These observations not only provide insight into the possible role of endothelium in pulmonary hyper­ tension but have led to radically new treatments. Inhaled NO is a selective pulmonary vasodilator [16], and may have an important action in improving gas exchange in patients with acute respiratory distress syndrome (ARDS) [17]. Finally, the vascular smooth muscle cells of the pul­ monary arteries may be particularly important in deter­ mining hypoxic vasoconstriction [ 18]. The articles included in the series on Pulmonary Hypertension published in this and future issues of the Journal provide new insights into major areas of growth of knowledge in the pulmonary vasculature. For brevity, much has been omitted, particularly the description of the pulmonary vasculitides or the involvement of the blood vessels in systemic disease. These will, no doubt, be covered by future symposia; by which time, the struc­ tural and functional consequences of chronic hypoxia on pulmonary vas~ulature are likely to have been fully elu­ cidated.

Importance of the Functional Integrity of the Endothelium in Coronary Vasomotion in Humans

Although our understanding of endothelial functon has been substantially expanded by numerous experimental studies since the discovery of endothelium-derived relaxing factor (EDRF), the functional significance of endothelial function in humans, in particular in the coronary circulation, remained elusive. Recently, the application of new interventional catheter technology and accurate quantitative coronary angiogrphy has set the stage for evaluating the potential importance of the endothelium of coronary arteries in humans.

Importance of the Functional Integrity of the Endothelium in Coronary Vasomotion in Humans

Summary: Although our understanding of endothelial function has been substantially expanded by numerous experimental studies since the discovery of endothelium-derived relaxing factor (EDRF), the functional significance of endothelial function in humans, in particular in the coronary circulation, remained elusive. Recently, the application of new interventional catheter technology and accurate quantitative coronary angiography has set the stage for evaluating the potential functional importance of the endothelium of coronary arteries in humans. Intracoronary application of acetylcholine has been shown to provide a useful tool for identifying coronary endothelial dysfunction, i.e., modest coronary vasodilatation in normal subjects but paradoxical vasoconstriction in atherosclerosis. Sympathetic stimulation by cold pressor test exactly mirrors the response to acetylcholine in normal and atherosclerotic coronary arteries but not in hypercholesterolemia. Flow-dependent dilation can be demonstrated in human coronary arteries in vivo and may play a modulatory role in coronary vasomotor tone; however, this dilation in response to increased flow is impaired in angiographically visible atherosclerosis. By measuring the blood flow response to acetylcholine (and papaverine as a nonspecific dilator), the endothelial function of the coronary microvasculature can be assessed, demonstrating that endothelial function of the coronary microvas-culature is substantially depressed in hypercholesterolemia. This may impair coronary perfusion and could facilitate platelet aggregation in the microcirculation. Thus, evaluation of endothelial function provides a useful tool for identification of early functional vascular abnormalities (both of epicardial coronary arteries and the microcirculation) at a stage not detectable by coronary angiography. This should allow the elucidation of therapeutic interventions that are able to prevent the progression of atherosclerosis at an early stage rather than late, when the efficacy of such a treatment appears to be limited.