Presynaptic Purinergic Modulation of the Rat Neuro-Muscular Transmission.

ATP, being a well-known universal high-energy compound, plays an important role as a signaling molecule and together with its metabolite adenosine they both attenuate the release of acetylcholine in the neuro-muscular synapse acting through membrane P2 and P1 receptors, respectively. In this work, using a mechanomyographic method, we analyzed the presynaptic mechanisms by which ATP and adenosine can modulate the transduction in the rat m. soleus and m. extensor digitorum longus. N-ethylmaleimide, a G-protein antagonist, prevents the modulating effects of both ATP and adenosine. The action of ATP is abolished by chelerythrin, a specific phospholipase C inhibitor, while the inhibitory effect of adenosine is slightly increased by Rp-cAMPS, an inhibitor of protein kinase A, and by nitrendipine, a blocker of L-type Ca2+ channels. The addition of DPCPX, an A1 receptor antagonist, fully prevents the inhibitory action of adenosine in both muscles. Our data indicate that the inhibitory action of ATP involves metabotropic P2Y receptors and is mediated by phospholipase C dependent processes in rat motor neuron terminals. We suggest that the presynaptic effect of adenosine consists of negative and positive actions. The negative action occurs by stimulation of adenosine A1 receptors while the positive action is associated with the stimulation of adenosine A2A receptors, activation of protein kinase A and opening of L-type calcium channels. The combined mechanism of the modulating action of ATP and adenosine provides fine tuning of the synapse to fast changing conditions in the skeletal muscles.

P2 Receptor Signaling in Motor Units in Muscular Dystrophy.

The purine signaling system is represented by purine and pyrimidine nucleotides and nucleosides that exert their effects through the adenosine, P2X and P2Y receptor families. It is known that, under physiological conditions, P2 receptors play only a minor role in modulating the functions of cells and systems; however, their role significantly increases under some pathophysiological conditions, such as stress, ischemia or hypothermia, when they can play a dominant role as a signaling molecule. The diversity of P2 receptors and their wide distribution in the body make them very attractive as a target for the pharmacological action of drugs with a new mechanism of action. The review is devoted to the involvement of P2 signaling in the development of pathologies associated with a loss of muscle mass. The contribution of adenosine triphosphate (ATP) as a signal molecule in the pathogenesis of a number of muscular dystrophies (Duchenne, Becker and limb girdle muscular dystrophy 2B) is considered. To understand the processes involving the purinergic system, the role of the ATP and P2 receptors in several models associated with skeletal muscle degradation is also discussed.

Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission.

A review of the data on the modulatory action of adenosine 5'-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission.

The effects of ATP on the contractions of rat and mouse fast skeletal muscle.

INTRODUCTION: The aim of this study was to compare the effects of adenosine-5'-triphosphate (ATP) and adenosine on the contractility of rodent extensor digitorum longus (EDL) muscle at normal and low temperatures. METHODS: Contractions of rat and mouse isolated EDL were induced by either electrical stimulation (ES) or exogenous carbachol and recorded in the presence of ATP or adenosine (both at 100 µM). RESULTS: ATP at all temperatures caused a decrease of the contractions induced by carbachol in rat and mouse EDL and ES-induced contractions in rat EDL, while it potentiated the ES-induced contractions of mouse EDL. Adenosine reduced the contractility of rat and mouse EDL evoked by ES and did not affect the carbachol-induced contractions of rat and mouse EDL at any temperature. DISCUSSION: Under various temperature conditions, ATP inhibits pre- but potentiates postsynaptic processes in the mouse EDL; in the rat EDL ATP causes only inhibition of neuromuscular conduction. Muscle Nerve 59:509-516, 2019.

Developing medical education capacity in Russia: twenty years of experience.

BACKGROUND: The partnership between Yale University (USA) and Kazan State Medical University (KSMU, Russia) was established in 1996 and transitioned to Western Connecticut Health Network (WCHN)/University of Vermont Robert Larner, M.D. College of Medicine (USA) in 2012 with the goal of modernizing medical education at KSMU primarily through introduction of the American medical education structure, role modeling, and educational capacity building. It was centered on the formation of a select group of Russian junior faculty members familiar with American medical education who would then initiate a gradual change in medical education at KSMU. Here we describe the 20 year partnership, rooted in local capacity building, through which a sustainable, mutually rewarding international collaboration was established. In addition, we evaluate the program's outcomes and impact on medical education at Kazan State Medical University, and assess its influence on Russian program participants. METHODS: Senior residents and faculty were sent to KSMU to conduct teaching sessions with local faculty and trainees. Their responsibilities included familiarizing Russian colleagues with specific topics in clinical medicine, importing knowledge about the basics of teaching, clinical epidemiology and evidence based medicine, and creating, in consistency with the American model, a "Clinical Teaching Team Structure" that integrates patient care with clinical education. Furthermore, 44 of selected KSMU members, including 13 junior faculty (29.5%), 14 clinical PhD students (31.8%), 12 interns/residents (27.3%), and five medical students (11.4%), were trained at Yale/WCHN or one of their major affiliated community hospitals for a period of 1 to 12 months for a total of 844 participant-weeks of training. RESULTS: Thirty (68.2%) individuals who were trained in the U.S. are currently working in Kazan primarily as faculty at KSMU. Among them, three trainees (10%) have become heads of their department, eight (26.7%) hold senior faculty positions, and two (6.7%) have clinical and educational administrative leadership positions. Two major clinical departments have adopted the "Clinical Teaching Team Structure." As a result of the collaboration, three teaching courses - Evidence-Based Medicine, Tropical Medicine, and HIV/AIDS Medicine - have been designed and incorporated into the curriculum. CONCLUSION: This partnership has been instrumental in introducing the American medical education model and expanding the medical knowledge of faculty, residents, and students of KSMU on infectious diseases, HIV/AIDS, tropical medicine, renal diseases, and global health topics. Capacity building through the Yale/WCHN-KSMU exchange program has greatly contributed to the quality of medical education at Kazan State Medical University.

Effects of ATP and adenosine on contraction amplitude of rat soleus muscle at different temperatures.

INTRODUCTION: The aim of this study was to evaluate the effects of adenosine 5'-triphosphate (ATP) and adenosine on the contractility of mammalian skeletal muscle under hypothermic conditions. METHODS: Contractions of isolated rat soleus muscle were induced by either electrical stimulation (ES) or carbachol at physiological temperatures (37°C) and hypothermic conditions (30-14°C) and recorded in the presence of ATP, adenosine, suramin, and 8-(p-sulfophenyl)-theophylline (8-SPT). RESULTS: At 37°C, incubation of the muscles with ATP inhibited ES-induced contractions; the inhibitory effect of ATP disappeared at 14°C. Adenosine inhibited ES-induced contractions at all temperature levels; 8-SPT fully prevented the action of adenosine. ATP and adenosine did not significantly affect carbachol-induced contractions at 37°C, while at lower temperatures ATP potentiated them. Suramin fully prevented effects of ATP. CONCLUSIONS: ATP is involved in both pre- and postsynaptic regulation of rat soleus muscle contractility, and these processes are significantly more pronounced at low temperatures. Muscle Nerve 55: 417-423, 2017.

Training Young Russian Physicians in Uganda: A Unique Program for Introducing Global Health Education in Russia.

BACKGROUND: Global health is a new concept in Russia. There has been an ongoing academic collaboration between the Yale School of Medicine in the United States and Makerere University College of Health Sciences in Uganda since 2010, and the US Western Connecticut Health Network/University of Vermont College of Medicine since 2012, to introduce global health concepts to Kazan State Medical University (KSMU) in Russia. The purpose was to educate Russian physicians and medical trainees about the practice of clinical medicine and medical education, as well as the general practice of global health in culturally diverse, resource-limited settings. OBJECTIVES: The aim of this study was to evaluate the initial outcomes of this multi-institutional partnership and to assess the impact of the global health elective on the participants and on KSMU. METHODS: Participants were selected to attend a 6-week elective in global health at Mulago Hospital in Kampala, Uganda. The elective consisted of clinical experience, education about Uganda's common diseases, and region-specific sociocultural classes. It included a predeparture orientation and, upon return, completion of a standard questionnaire to assess the program's impact. RESULTS: Since 2010, there have been 20 KSMU members (4 medical students, 4 interns, 9 residents, 2 fellows, and 1 faculty member) who have participated in the program. As a result of the elective, the participants reported increased knowledge of tropical medicine (70%) and HIV/AIDS (75%), and 95% reported increased cultural sensitivity and desire to work with the underserved. The majority noted a very positive impact of their careers (90%) and personal life (80%). KSMU established the first successful collaborative program in global health education in Russia, leading to the integration of tropical medicine and global health courses in medical school curriculum. CONCLUSION: This elective has proven highly effective in introducing the concept of global health to faculty, fellows, residents, and medical students at KSMU. It trained these participants to address the challenges faced by physicians in culturally diverse and resource-limited countries.

Dual effects of ATP on isolated arteries of the bovine eye.

Although the presence of purinoreceptors has been shown in many human and animal arteries, there is few data yet about their role in the arteries of the eye. The purpose of the present study was to evaluate the effects of several agonists of purinoreceptors on isolated arteries of the bovine eye. Responses of isolated preparations of bovine ophthalmic (OA) and posterior ciliary arteries (PCA) to agonists of purinoreceptors (ATP, α,ß-methylene-ATP-α,ß-meATP, 2-methylthioATP-2meSATP, uridine-5'-triphosphate-UTP) as well as agonists of adreno-, cholino-, adenosine and histamine receptors were recorded by a standard organ bath method. ATP induced contractions of the intact vessels but caused relaxation of α,ß-meATP-pretreated arteries. Contractile responses of PCA to high concentrations of ATP and α,ß-meATP were significantly stronger than responses of OA, as well as relaxative responses to ATP and adenosine were significantly stronger in PCA than in OA. We suggest that there are several subtypes of functionally active purinoreceptors in both OA and PCA, although the potency of agonists of purinoreceptors to produce mechanical responses is higher in PCA than in OA. Purinoreceptors can be potential targets for new drugs, treating vascular pathology of the eye.