Ferid Murad (1936-2023).

Physician-scientist who discovered NO signaling.

Historical origins of the discovery of mammalian nitric oxide (nitrogen monoxide) production/physiology/pathophysiology.

The award of the 1998 Nobel Prize in Physiology or Medicine to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad "for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system" highlighted the discovery of NO in mammals. This breakthrough also coincided with the discoveries of the role of NO as a cytotoxic effector in the immune system and as an intercellular neurotransmitter in the nervous system. This brief overview describes the chronological development of this trilinear convergence in 1986-1988, including background chemistry and history of human/nitrogen oxide interactions in general.

Synergy between medicinal chemistry and biological research.

Salvador Moncada studied medicine at the University of El Salvador (El Salvador) before coming to the UK in 1971 to work on a PhD with Professor John Vane at the Institute of Basic Medical Sciences, Royal College of Surgeons (UK). After a short period of research at the University of Honduras (Honduras), he joined the Wellcome Research Laboratories (UK) where he became Head of the Department of Prostaglandin Research and later, Director of Research. He returned to academic life in 1996 as founder and director of the Wolfson Institute for Biomedical Research at University College London (UK). Moncada played a role in the discovery of the mechanism of action of aspirin-like drugs and later led the teams which discover prostacyclin and identified nitric oxide as a biological mediator. In his role as a Director of Research of the Wellcome Laboratories, he oversaw the discovery and development of medicines for epilepsy, migraine, malaria and cancer. Currently, he is working on the regulation of cell proliferation as Director of the Institute of Cancer Sciences at the University of Manchester (UK). Moncada has won numerous awards from the international scientific community and in 2010, he received a knighthood from Her Majesty Queen Elizabeth II for his services to science.

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.

Sepsis and septic shock: a history.

Infectious disease has been a leading cause of death in humans since the first recorded tabulations. From Hippocrates and Galen, to Lister, Fleming and Semmelweiss, this article reviews the notable historical figures of sepsis research. The early descriptions and theories about the etiology (microbial pathogens), pathogenesis (toxins and mediators), and treatment of sepsis-associated disease are also discussed.

Hemoglobin research and the origins of molecular medicine.

Much of our understanding of human physiology, and of many aspects of pathology, has its antecedents in laboratory and clinical studies of hemoglobin. Over the last century, knowledge of the genetics, functions, and diseases of the hemoglobin proteins has been refined to the molecular level by analyses of their crystallographic structures and by cloning and sequencing of their genes and surrounding DNA. In the last few decades, research has opened up new paradigms for hemoglobin related to processes such as its role in the transport of nitric oxide and the complex developmental control of the alpha-like and beta-like globin gene clusters. It is noteworthy that this recent work has had implications for understanding and treating the prevalent diseases of hemoglobin, especially the use of hydroxyurea to elevate fetal hemoglobin in sickle cell disease. It is likely that current research will also have significant clinical implications, as well as lessons for other aspects of molecular medicine, the origin of which can be largely traced to this research tradition.

Nitrous or nitric? Same difference. Molecular formulas in the 1840s.

The molecular formulas given by James Y. Simpson for nitrous oxide, diethyl ether, and chloroform are difficult to interpret today. The organic formulas are "incorrect" today because Jean Dumas (the influential chemist who was one of the discoverers of chloroform) used John Dalton's presumption of molecular simplicity. That is, water was long presumed to be HO. The nitrous oxide formula was incorrect owing to confusion with Dalton's nitrous gas, now termed nitric oxide. The Simpson formulas illustrate that inhaled anesthesia arrived at the time of a cusp in the history of chemistry.

Nitric oxide and the endothelium: history and impact on cardiovascular disease.

There are few discoveries with the magnitude of the impact that NO has had on biology during the 25 years since its discovery. There is hardly a disease today not associated with altered NO homeostasis. In fact, despite numerous other endothelial functions, endothelial dysfunction has become synonymous with reduced biological activity of NO. Translating the preclinical discoveries in NO biology to new modalities for disease management has not been as impressive. Beyond the success of drugs for erectile dysfunction, clinical trials of nitric oxide synthase inhibitor have been proven either ineffective or wrought with side effects. NO donors (e.g., nitroglycerine) remain frequently used cardiovascular agents, but were discovered before 1980. Gene therapy studies have yet to become clinically useful. There is no doubt that endothelial- and NO-dysfunction is a hallmark of cardiovascular disease, including diseases which are considered as major current public health concerns: hypertension, obesity, diabetes, malnutrition. In many cases, cardiovascular disease (CVD) can be prevented by identifying and controlling modifiable risk factors. One conceivable approach to the management of multiple risk factors in CVD could be to treat endothelial dysfunction (e.g., by enhancing eNOS expression), since many CVD risk factors are related to endothelial dysfunction. In this regard one goal may include optimizing eNOS function. This can be realized by supplementing co-factors, e.g., BH4, or substrate, L-arginine, by increasing cGMP availability via phosphodiesterase inhibitors or sGC activators or by increasing NO bioavailability via antioxidants. The association of other proteins with the nitric oxide synthase (NOS) isoforms and sGC could also serve as experimental and potentially therapeutic targets to modulate NO bioactivity. There is tremendous promise behind NO itself as well as the numerous other molecules and processes associated with the L-arginine-NO-cGMP pathway. Collaborative efforts among bench scientists, clinical investigators and epidemiologists are the key in realizing this promise.