Carbon monoxide: endogenous production, physiological functions, and pharmacological applications

Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.     

Melatonin and its physiological and therapeutic properties

Melatonin is a hormone produced mainly by the pineal gland in most vertebrate species, including humans. Recent metabolic, receptor and functional studies created a picture of the melatoninergic system(s) in living organisms, its organization, physiology and a role in some pathologic conditions. The melatoningenerating system is characterized by three basic features: (1) photosensitivity, (2) diurnal (or circadian) rhythmicity (with highest levels of melatonin production occurring at night in darkness), and (3) agerelated decline in its activity. Cyclic nocturnal increases of melatonin levels are proportional to the length of nights (or dark periods of an imposed lightdark cycle); the hormone thus conveys a photoperiodic message, and functions in an organism as an internal biochemical clock and calendar. Biological actions of melatonin are mediated via specific melatonin receptors, whose distribution in the body is uneven, yet with decisively highest density in the suprachiasmatic nuclei of the hypothalamus, pars tuberalis of the pituitary, and the retina (particularly in birds and lower vertebrates). Such a distribution of melatonin receptors suggests that the principal physiological role of the hormone is related to both chronobiology and modulation of the body hormonal milieu. This review surveys recent developments in the melatonin field, and summarizes current knowledge on the melatoninergic mechanisms, including the therapeutic aspect related to the hormone.     

Reactive oxygen species in the cerebral circulation: physiological roles and therapeutic implications for hypertension and stroke

It is now clear that reactive oxygen species (ROS) can act as signalling molecules in the cerebral circulation under both physiological and pathological conditions. Some major products of superoxide (O(2)(.)(-)) metabolism, such as hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH(.)), appear to be particularly good cerebral vasodilators and may, surprisingly, represent important molecules for increasing local cerebral blood flow. A major determinant of overall ROS levels in the cerebral circulation is the rate of generation of the parent molecule, O(2)(.)(-). Although the major enzymatic source of O(2)(.)(-) in cerebral arteries is yet to be conclusively established, the two most likely candidates are cyclo-oxygenase and nicotinamide adenine dinucleotide phosphate (reduced form) [NADPH] oxidase. The activity of endogenous superoxide dismutases (SODs) play a vital role in determining levels and effects of all individual ROS derived from metabolism of O(2)(.)(-). The term 'oxidative stress' may be an over-simplification that hides the complexity and diversity of the ROS family in cerebrovascular health and disease. Although a generalised increase in ROS levels seems to occur during several vascular disease states, the consequences of this for cerebrovascular function are still unclear.Because enhanced breakdown of O(2)(.)(-) by SOD will increase the generation of the powerful cerebral vasodilator H(2)O(2), this latter molecule could conceivably act as a compensatory vasodilator mechanism in the cerebral circulation under conditions of elevated O(2)(.)(-) production. Some recent clinical data support the concept of a protective role for cerebrovascular NADPH oxidase activity. Although it is quite speculative at present, if NADPH oxidase were to emerge as a major source of beneficial vasodilator ROS in the cerebral circulation, this may represent a significant dilemma for treatment of ischaemic cerebrovascular conditions, as excessive NADPH oxidase activity is associated with the progression of several systemic vascular disease states, including hypertension and atherosclerosis. Despite data suggesting that antioxidant vitamins can have beneficial effects on vascular function and that their plasma levels are inversely correlated with risk of cardiovascular disease and stroke, the results of several recent large-scale clinical trials of antioxidant supplementation have been disappointing. Future work must establish whether or not increased ROS generation is necessarily detrimental to cerebral vascular function, as has been generally assumed, or whether localised increases in ROS in the vicinity of the arterial wall could be beneficial in disease states for the maintenance of cerebral blood flow.     

Neuromedin U and its receptors: structure, function, and physiological roles

Neuromedin U (NmU) is a structurally highly conserved neuropeptide. It is ubiquitously distributed, with highest levels found in the gastrointestinal tract and pituitary. Originally isolated from porcine spinal cord, it has since been isolated and sequenced from several species. Amino acid alignment of NmU from different species reveals a high level of conservation, and particular features within its structure are important for bioactivity. Specifically, the C terminus, including a terminal asparagine-linked amidation, is essential for activity. The conservation of NmU across a wide range of species indicates a strong evolutionary pressure to conserve this peptide and points to its physiological significance. Despite this, the precise physiological and indeed pathophysiological roles of NmU have remained elusive. NmU was first isolated based on its ability to contract rat uterine smooth-muscle (hence the suffix "U") and has since been implicated in the regulation of smooth-muscle contraction, blood pressure and local blood flow, ion transport in the gut, stress responses, cancer, gastric acid secretion, pronociception, and feeding behavior. Two G-protein-coupled receptors for NmU have recently been cloned. These receptors are widespread throughout the body but have differential distributions suggesting diverse but specific roles for the receptor subtypes. Here we detail the isolation and characterization of NmU, describe the discovery, cloning, distribution, and structure of its two receptors, and outline its possible roles in both physiology and pathophysiology. Ultimately the development of receptor-specific ligands and the generation of animals in which the receptors have been selectively knocked out will hopefully reveal the true extent of the biological roles of NmU and suggest novel therapeutic indications for selective activation or blockade of either of its receptors.     

Carbon monoxide and myonecrosis: a prospective study

Myonecrosis has been reported to occur in patients with carbon monoxide (CO) poisoning, and last year we reported a case of non-traumatic rhabdomyolysis in a patient with CO poisoning secondary to smoke inhalation. We prospectively studied the association between CO poisoning and rhabdomyolysis by obtaining serum creatine kinase (CPK) levels on 65 of 81 consecutive patients (range 20-1315 IU/L) who presented to the University of Illinois Hospital Emergency Room during a 3-month period with CO levels greater than 5.0% (range 5.0%-63.9%). Thiocyanate levels were obtained on 45 patients (range 0-3.5 mg/dl). We found no statistically significant correlation by linear regression analysis between CO level and CPK level in these patients. A subjective complaint of weakness was obtained in 4 patients and physical evidence of weakness was found in 1 of these (this was felt to be secondary to a cerebrovascular accident). In none of these 4 patients was an elevated CPK level noted. We did, however, note an association between thiocyanate level and CPK level by linear regression analysis (p less than 0.02). A power curve was a better fit for this data (r2 = 0.7). This data suggests that serum CPK levels should not be routinely obtained on patients with CO poisoning and that cyanide may play a more important role in non-traumatic rhabdomyolysis associated with toxic inhalation than had previously been suspected.     

Carbon monoxide: medicinal chemistry and biological effects

Carbon monoxide (CO), which is classically thought of as a toxic molecule and cellular asphyxiate, has become increasingly recognized as an important molecule in the physiological regulation of multiple organ systems and in the restoration of homeostasis in pathophysiological states. CO has long been utilized as a tool in chemistry and physiology secondary to its ability to bind to heme proteins. Additionally, CO is produced endogenously in the breakdown of heme by heme oxygenase enzymes. Here we review the biological chemistry of CO and highlight some of the anti-inflammatory biological effects of the heme oxygenase/CO system.     

Carbon monoxide and the CNS: challenges and achievements

Haem oxygenase (HO) and its product carbon monoxide (CO) are associated with cytoprotection and maintenance of homeostasis in several different organs and tissues. This review focuses upon the role of exogenous and endogenous CO (via HO activity and expression) in various CNS pathologies, based upon data from experimental models, as well as from some clinical data on human patients. The pathophysiological conditions reviewed are cerebral ischaemia, chronic neurodegenerative diseases (Alzheimer''s and Parkinson''s diseases), multiple sclerosis and pain. Among these pathophysiological conditions, a variety of cellular mechanisms and processes are considered, namely cytoprotection, cell death, inflammation, cell metabolism, cellular redox responses and vasomodulation, as well as the different targeted neural cells. Finally, novel potential methods and strategies for delivering exogenous CO as a drug are discussed, particularly approaches based upon CO-releasing molecules, their limitations and challenges. The diagnostic and prognostic value of HO expression in clinical use for brain pathologies is also addressed.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Adrenomedullin in the kidney-renal physiological and pathophysiological roles

Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. AM and AM gene expression are widely distributed in the cardiovascular system, including the kidney. The co-localization of AM and its receptor components such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the kidney, heart, and vasculature suggests an important role for the peptide as a regulator of renal, cardiac, and vascular function. Indeed, in addition to its cardiovascular effects, AM has renal vasodilatory, natriuretic, and diuretic actions. Consistent with these observations, immunohistochemical studies revealed that AM is stained in the collecting duct, distal convoluted tubules, vessels, and glomerular mesangial cells, endothelial cells and podocytes. Plasma AM levels are increased in patients with renal impairment in proportion to the severity of the disease. Previously we and other investigators showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma. Urine also contains both forms of AM; however, the AM-mature/AM-glycine ratio is higher in urine than in plasma. Interestingly, plasma AM-glycine and AM-mature levels are increased in renal failure, whereas urinary AM-glycine and AM-mature are decreased in this condition. These results indicate that the origin of urinary AM is different from that of plasma AM. Experimental studies showed that the renal tissue AM-mature/AM-glycine ratio is higher than that in plasma and urine. In addition, renal tissue concentrations of AM are increased in severely hypertensive rats. Considering that AM has antiapoptotic, antifibrotic, and antiproliferative effects, the increase of AM in renal disease may be a protective mechanism. In fact, AM gene delivery or long-term AM infusion significantly improved glomerular sclerosis, interstitial fibrosis, and renal arteriosclerosis in several malignant hypertensive models. This review describes the biochemistry, physiology, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in renal disease.     

Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

Hydrogen sulfide (H₂S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H₂S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.     

Cholinesterase inhibitors: new roles and therapeutic alternatives.

An important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in Alzheimer disease (AD) patients. While AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15 fold from 5 to 75nM concentrations with little cholinergic side effects in the animal. Based on these data and on clinical data showing a relation between CSF BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolyzing brain acetylcholine. Based on the changes of ChE activity in the brain of AD patients, a rational indication of selective BuChEI (or of mixed double function inhibitors) is the treatment of advanced cases. A second novel aspect of ChEI therapy is the emerging of new indications which include various forms of dementia such as dementia with Lewy Bodies, Down Syndrome, vascular dementia and Parkinson Dementia. Clinical results demonstrate examples of versatility of cholinergic enhancement.     

Targeting gaseous molecules to protect against cerebral ischaemic injury: mechanisms and prospects

1. Ischaemic brain injury is a leading cause of death and disability in many countries. However, the pathological mechanisms underlying ischaemic brain injury, including oxidative stress, calcium overload, excitotoxicity and neuronal apoptosis, are perplexing and this makes it difficult to find effective novel drugs for the treatment of the condition. 2. Recently, gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), hydrogen sulphide (H(2)S) and hydrogen (H(2)) have attracted considerable interest because of their physiological and pathophysiological roles in various body systems. Emerging evidence indicates that gaseous molecules are involved in the pathological processes of ischaemic brain damage. 3. In the present review, we summarize evidence regarding the involvement of gaseous molecules in ischaemic brain injury and discuss the therapeutic potential of targeting gaseous molecules. 4. Collectively, the available data suggest that the application of these biological gas molecules and their pharmacological regulators may be a potential therapeutic approach for the treatment of ischaemic brain injury.     

Central serotonin receptors: effector systems,physiological roles and regulation

Radioligand binding studies have revealed four distinct serotonin (5HT) binding sites in rat brain that are thought to function as 5HT receptors. These include the 5HT-1a, 5HT-1b, 5HT-1c, and 5HT-2 binding sites. Studies have shown that the 5HT-2 binding site mediates a number of effects of 5HT agonists and serves as a 5HT receptor in neuronal and non-neuronal tissues. The 5HT-2 site employs phosphoinositide hydrolysis for signal transduction. The 5HT-1c binding site is also a functional receptor that is linked to phosphoinositide hydrolysis. However, the physiological role of the 5HT-1c receptor is not yet known. Lack of appropriate pharmacological tools for probing the 5HT-1a and 5HT-1b binding sites has made it difficult to definitively determine whether these binding sites are coupled to biochemical effector systems or mediate any of the physiological responses to 5HT agonists. However, there is some evidence that the 5HT-1a site is coupled to adenylate cyclase, and a number of functional roles for the 5HT-1a and 5HT-1b sites have been proposed.