Physiological Grounds of Breathing Regulation
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S.G. Krivoshchekov
Ph.D. in medical sciences, Professor at the Institute for Physiology at the Siberian Branch of the Russian Academy of Medical Sciences
Key role in the regulation of gas transportation system functioning is performed by respiratory system, consisting of the system of peripheral afferent sensors (chemoreceptors, medullar receptors), the central chain (respiratory neurons in medulla oblongata) and efferent chains in the pulmonary and vascular system.
Regulation of breathing is effected by way of the respiratory center (RC), situated in medulla oblongata and functioning under uninterrupted influence of signals informing on the chemical composition of the internal medium; these signals come from chemoreceptors of arterial vessels and truncus cerebri proper, as well as from mechanoreceptors in lungs and respiratory tracts. This feedback system determines the correspondence of pulmonary ventilation and body's requirements for gas exchange, along with an optimal, the most economical breathing regimen. Influences from the higher situated supratruncal and cortical centers determine alterations in respiratory movements in response to certain conditions - muscular activity, outer temperature, relevant environmental signals, emotional state.
Respiratory center by the warm-blooded consists of a bundle of expiratory and inspiratory respiratory neurons, inspiratory axones of which are connected to the cervical part of the spinal cord, where they switch over to respiratory motoneurons and the diaphragm. Others, situated in the ventral nucleus (expiratory and inspiratory), for their part, switch over to intercostal muscles. Respiratory neurons can regulate their rhythmic activity by way of reciprocal relations between inspiratory aand expiratory neurons, functioning of which is regulated by reticular formation tone (thus creating the RC vigilance level). Rhythmic RC functioning requires an influx of specific information from chemoreceptors, interpreting gas composition of blood and cerebrospinal fluid, as well as from mechanoreceptors, which respond to extension of lungs and air flow in the respiratory tracts.
Arterial chemoreceptors are situated in the cephalic artery and aortic arch and alter their impulse activity with blood oxygen saturation reduction. Arterial chemoreceptors principally function in an emergency situation (acute hypoxia).
Medullar chemoreceptors are situated in medulla oblongata and respond to Í-ions (and since their concentration increases with carbonic dioxide solution in a fluid - therefore to CO2). Afferent impulses coming from arterial chemoreceptors and medullar chemosensitive structures keep up the RC (respiratory center) rhythmic activity. Besides, there are receptors in lungs and respiratory tracts walls (from the nose to the pulmonary tissue bronchi).
Thus, the prime breathing regulator is the chemoreceptor stimulation of the respiratory center. An American Grodins in 1966 worked out the respiratory chemostat theory, at the basis of which lies control by deviation:
CO2 alteration --- ventilation increase --- CO2 reduction.
Yet under physical load ventilation increase occurs before the blood chemical composition alteration. Studies conducted in the recent years revealed that the "working hyperpnea" secret is in activating of somewhat sensors (mechanorecetors of the muscles) that are excited by muscular contraction.
An important point in studying this issue is that the humoral regulation theory discloses but one facet of the phenomenon. Humoral theory does not agree with the most significant regulations of breathing control when under load: rapid increase in ventilation, its accurate adjustment, i.å. an apt adaptation of breathing.
Progress in research towards this end has revealed (in works by the school of M.V. Sergievsky and V.À. Safonov) that an important part in breathing regulation is played by higher parts of cerebrum. Besides the aforesaid breathing is influenced by a variety of specific and non-specific factors: thermoreceptors of skin, mucous membranes, thermoregulation, algesic, luminous, olfactory, tactile, gustatory, vestibular impacts, as well as psychic processes. Through the RC they influence the respiratory muscles. According to the authors' diagram arterial and medullar chemoreceptors provide central nervous system with information on gas composition of blood and acid-basic equilibrium of internal medium of the body, first thing of cerebrospinal fluid and blood supplying the brain. At that, the structural-functional diagram of the RC includes two regulation circuits: the chemoreceptor and the mechanoreceptor one. Signals from the RC govern the functioning of the ventilatory apparatus, which is at the same time the executive link in the prime chemoreceptor circuit of RC control. The aim of the mechanoreceptor circuit is to control the extent of respiratory muscles' contraction at every point of time and with that to keep up the external respiration parameters in concord with directions coming from the RC, these being determined by the required amount of ventilation.
Being anchored to the available for the moment materials it can be argued that there are 3 mechanisms functioning on the RC level, responsible for the generation and control of respiratory movements:
The generation mechanism proper, determining an automatic breathing rhythm.
Integration - coordination mechanism, enabling the processing of signals from peripheral and central structures, intensifying and coordinating of the generator's neurons.
Mechanism coordinating the functioning of respiratory and cardiovascular centers.
Homeostasis at the metabolically optimal level is maintained by various body systems, most crucial of these being the external respiration and blood circulation, exhibiting a certain amount of autonomy, as well as peculiar regulations.
Here comes an apt question as to how significant can be the environmental factors' influence on the breathing control mechanism. This is particularly important insofar the concerned issues are: à) the entire gas exchange mechanism of the body, be it at rest or by muscular work; b) alteration of breathing and the regulation mechanisms underlies most pathology and pre-pathology conditions.
It is ascertained that al regulation mechanism links can be susceptible to adaptation-adjustment alterations, each of them being able to alter to a certain extent the entire metabolic and acid-basic equilibrium of the body. The central part (respiratory center) is under the modulation influence on the part of superior parts of cerebrum and can alter its activity degree in response to changes in emotional state or psychotherapeutic manipulations. As an example of psychotherapeutic approach application for the gas transport system control alteration and treatment of non-specific diseases of cardiorespiratory system may serve the volitional deep breathing liquidation methodsÿ [K.P. Buteiko, 1980], the guided gas exchange regulation method [Davidenko and co-authors, 1980], "paradox exercises' system by À.N. Strelnikova", the hypoxic training methods (the Strelkov's training device, IHT - the interval hypoxic training), breathing through application of the Frolov's Respiration Training device (TDI), as well as respiratory exercises of ancient oriental systems (Indian yogi and Chinese tsi-gun).
Each of the said sanative methods is to a certain degree based on alterations aimed at breathing control. There are various means to achieve this: the antihypoxic (physiologic, biochemical etc.) mechanisms' development, heightening of hypercapnic reactiona thresholds through adaptive alterations in the respiratory center, change of cellular structures participating in O2 mass transfer. At that the key role is played by oxygen and body's response to its deficiency.
The gas transport system control undergoes the most significant alterations by subjecting the body to hypoxia. This is quite natural, since hypoxia in a body as a whole takes effect not just thrugh oxygen content reduction in the inspired air, it also accompanies every manifestation of pathology.
It is reveled in the works of many researchers that alterations in a living body are manifested differently, in accord with character, strength and duration of hypoxic effect. For a long time for purposes of cure and prophylaxis exclusively mountainous areas were used (alpine health resorts, 3,000-3,500 m above sea level). It was not long ago that an attempt to use large altitude chambers to curative ends was made (on the base of aerospace industries undergoing conversion), hypoxia having been created by artificial atmospheric pressure reduction. Yet due to a number of reasons (being expensive, handicapped communication to the patient) the method has not enjoyed wide application. In the late years the field of normobaric hypoxia for cure and prophylaxis purposes has witnessed a pronounced success [Kovalenko and others, 1993; Kolchinskaya and others, 1993; Volkov, 1993, Strelkov, 1990, Chizhov, 1997]. The method was called: "The interval hypoxic training". The crux of the method is that a patient inspires a normobaric hypoxic mixture (8-9 volume percent) for 3-5 minutes by an uninterrupted control over oxyhemoglobin content in blood. One session consists of 5 to 8 trials (with intervals of rest long enough to bring oxyhemoglobin content to the initial value). There are 20 sessions in the treatment course.
Still another method to enjoy wide acceptance was breathing to the V.F. Frolov's method under application of respiratory training device of the author's design (Frolov,1997,1999). The prime influence factors are: a moderate hypoxia condition, hypercapnia and an increased resistance to breathing.
Reassuring results have been obtained, which testify to an extensive therapeutic effect and convenience when applying. After application and approbation of the above-mentioned methods the following indications as to their application have been worked out.
- The generation mechanism proper, determining an automatic breathing rhythm.
- Integration - coordination mechanism, enabling the processing of signals from peripheral and central structures, intensifying and coordinating of the generator's neurons.
- Mechanism coordinating the functioning of respiratory and cardiovascular centers.
Homeostasis at the metabolically optimal level is maintained by various body systems, most crucial of these being the external respiration and blood circulation, exhibiting a certain amount of autonomy, as well as peculiar regulations.
Here comes an apt question as to how significant can be the environmental factors' influence on the breathing control mechanism. This is particularly important insofar the concerned issues are: à) the entire gas exchange mechanism of the body, be it at rest or by muscular work; b) alteration of breathing and the regulation mechanisms underlies most pathology and pre-pathology conditions.
It is ascertained that al regulation mechanism links can be susceptible to adaptation-adjustment alterations, each of them being able to alter to a certain extent the entire metabolic and acid-basic equilibrium of the body. The central part (respiratory center) is under the modulation influence on the part of superior parts of cerebrum and can alter its activity degree in response to changes in emotional state or psychotherapeutic manipulations. As an example of psychotherapeutic approach application for the gas transport system control alteration and treatment of non-specific diseases of cardiorespiratory system may serve the volitional deep breathing liquidation methodsÿ [K.P. Buteiko, 1980], the guided gas exchange regulation method [Davidenko and co-authors, 1980], "paradox exercises' system by À.N. Strelnikova", the hypoxic training methods (the Strelkov's training device, IHT - the interval hypoxic training), breathing through application of the Frolov's Respiration Training device (TDI), as well as respiratory exercises of ancient oriental systems (Indian yogi and Chinese tsi-gun).
Each of the said sanative methods is to a certain degree based on alterations aimed at breathing control. There are various means to achieve this: the antihypoxic (physiologic, biochemical etc.) mechanisms' development, heightening of hypercapnic reactiona thresholds through adaptive alterations in the respiratory center, change of cellular structures participating in O2 mass transfer. At that the key role is played by oxygen and body's response to its deficiency.
The gas transport system control undergoes the most significant alterations by subjecting the body to hypoxia. This is quite natural, since hypoxia in a body as a whole takes effect not just thrugh oxygen content reduction in the inspired air, it also accompanies every manifestation of pathology.
It is reveled in the works of many researchers that alterations in a living body are manifested differently, in accord with character, strength and duration of hypoxic effect. For a long time for purposes of cure and prophylaxis exclusively mountainous areas were used (alpine health resorts, 3,000-3,500 m above sea level). It was not long ago that an attempt to use large altitude chambers to curative ends was made (on the base of aerospace industries undergoing conversion), hypoxia having been created by artificial atmospheric pressure reduction. Yet due to a number of reasons (being expensive, handicapped communication to the patient) the method has not enjoyed wide application. In the late years the field of normobaric hypoxia for cure and prophylaxis purposes has witnessed a pronounced success [Kovalenko and others, 1993; Kolchinskaya and others, 1993; Volkov, 1993, Strelkov, 1990, Chizhov, 1997]. The method was called: "The interval hypoxic training". The crux of the method is that a patient inspires a normobaric hypoxic mixture (8-9 volume percent) for 3-5 minutes by an uninterrupted control over oxyhemoglobin content in blood. One session consists of 5 to 8 trials (with intervals of rest long enough to bring oxyhemoglobin content to the initial value). There are 20 sessions in the treatment course.
Still another method to enjoy wide acceptance was breathing to the V.F. Frolov's method under application of respiratory training device of the author's design (Frolov,1997,1999). The prime influence factors are: a moderate hypoxia condition, hypercapnia and an increased resistance to breathing.
Reassuring results have been obtained, which testify to an extensive therapeutic effect and convenience when applying. After application and approbation of the above-mentioned methods the following indications as to their application have been worked out.
- Influence on the physical and mental efficiency and immune system condition by practically healthy people, whose professional activity is liable to stressor loads.
- Application of the methods for bronchial asthma and other allergic and autoimmune diseases.
- Application in treatment of neurotic patients (hypo- and hypersthenic conditions), and for the future, possibly, for therapy of some endogenous psychic illnesses.
- Application of the methods for reduction of the cardiac ischemia risk factors' pronouncedness, for treatment of neurocirculatory distonia and hypertension.
A list of indications of this sort manifests that conditioning of the breathing regulation system by way of guided manipulations calls forth a range of alterations taking effect in a human body. Thus, particularly by hypoxic training there are alterations in the oxygen intake and transport system to be observed, this taking effect in the very first days of hypoxia action. There is a process of creating a systemic structural memory trace, which includes RNA and protein synthesis activation in lungs, myocardium, bone marrow, coronary bed vessels, as well as in sympathetic neurons that innervate the heart. The result of such synthesis activation is an unhampered growth of the organs responsible for oxygen transport, namely: respiratory surface and pulmonary alveoae number increse, moderate hypertrophy and cardiac functional capabilities increase, 1,5-2 times' increase in coronary bed capacity, polycythemia and oxygen capacity increase, respiratory center's and respiratory muscles' neurons hypertrophy [Pshennikova, 1973; Meersohn and others, 1972; Kolchinskaya and others, 1993].
Simultaneously the energy supply system power increase takes place on the cellular level of the heart and other organs, which is manifested in mytochondria number increase and glycolysis enzymes activity. These alterations, while increasing the power and economizing the respiratory and circulatory system function, intensify adrenergic mobilization and heighten resistance to hypoxia.
It's been observed that adaptation to hypoxia is accompanied by cardiac protection activity in the post-infarction period, furthering the collaterals' development and ischemia area lessening, as well as reducing the necrotic area due to direct cytiprotective action [Ehrenburg, Gorbatenkov, 1993].
It's been proved that adaptation to a periodical hypoxy factor prevents myocardium glycogen and ATF critical fall, as well as disturbance in myocardium contractile function and cardiac deficiency development at aortic stenosis [Meerson et al., 1971].
The second bunch of alterations taking effect during adapting to periodic hypoxia is characterized by a whole system of shifts at the superior neuroendocrine control level which is manifested in protein and ribonucleic synthesis activation in the brain. As for larger hemispheres, this process is most pronounced in cortex where RNA content is increased by 50%, and protein synthesis estimated by inclusion of marked aminoacids - by 100%. In the lower positioned parts of the brain that are less sensitive to oxygen deficiency the activation is much less pronounced, à and is again considerable in vegetative centers' zone of medulla oblongata.
Simultaneously accumulation of serotonin and dofamin in the brain takes place while norepinepherine content is reduced; in adrenal glands there is a multiple increase in opioid peptid content, primarily beta-endorfin. At that in the blood a regular reduction of serotonin and histamin content is observed. Expectedly, this wide range of stable alterations of neuroendicrine control results in consequences far surpassing the limits of resistance to hypoxia. It follows that through adaptation to hypoxia and hypercapnia it is possible not only to prevent the stressor depression of the contractile function and cardiac defibrillation threshold, but also ischemic arrhythmia, neurogenous nature of which is proved by multiple modern studies.
At the same time rather stable shifts in hydrous-saline metabolism and resistive vessels myogenic tone control are observed. At that, during the adaptation process a partial atrophy of supraoptic nucleus of hypothalamus and zona glomerulosa of adrenal glands , i.å. the systems,which by means of aldosterone and antidiuretic hormone ensure retention of a certain water and sodium chloride reserve in the body. This is accompanied by an adaptive reduction of resistographically estimated vascular tone myogene component, as well as arteries and arteriole rigidity reduction which, according to the existing ideas, should reduce the pressor reflexes' pronouncedness. It is natural that such shifts must lead to to loss of sodium and water excess in the body, reducing hypertension development possibility, other conditions remaining equal. Finally, there are changes in the immune system to be observed. There is Ò- and  - lymphocytes ratio alteration develpment towards Â-lymphocytes prevalence in such lymphoid organs as spleen. An important result of this change is a partial depression of immune reactions, mediated by Ò-cellular mechanisms at simultaneous strengthening of humoral immune response, estimated by the number of antibody-generating cells and antibody content in blood.
Research conducted by the laboratory of functional reserves of the organism at the Physiology Institute at the Siberian Branch of the Russian Academy of Medical Sciences (head - S.G. Krivoshekov) has revealed data peculiar nature, concerning the physiologic mechanisms of adaptation to various sorts of hypoxic and hypercapnic influences depending an their intensity and duration, adaptation to breathing with heightened resistance, breathing regulation while adapting to low temperatures and alpine hypoxia, as well as in rehabilitation of patients of cardiovascular and respiratory profile.
In particular, it has been pointed out that adaptation changes concern not only gas exchange and respiration parameters, but along with that most general control mechanisms of the central nervous system, which govern memory, emotions, information processing strategy by the brain, accounted for by prevalent activation of of a particular cerebrum hemisphere [Krivoshchekov, 1998, Leutin and others,1999]. It has been ascertained that respiration pattern change is effected rather fast (for 5 days) and is based on the RC (respiratory center) hypoxic and hypercapnic reactivity alterations. It has been proved that the rapidness of creation of new programs of interrelation with the dramatically altered medium is provided by selection of high significance signals by the emotiogene structures of the brain.
Studies of protracted work in protective garment with increased respiration to breathing have revealed changes in prime breathing parameters, increase in oxygen capacity and reduction of hypercapnic reactivity. It's also been proved that physical work capabilty increases, along with muscular activity. Studies of gas exchange parameters after 2-months' adaptation to a combined effect of moderate doses of hypoxy, hypercapnia and heightened resistance to breathing have displayed the increase in their efficiency.
Profound study of ventilatory responce peculiarities to the hypoxic stimulus showed its dependence on the somatic type of a man, as well as interrelation between muscular and adipose tissue growth and partial CO2 tension in blood at a state of relative composure and under physical load in the anaerobic threshold zone. It is supposed that variations in ventilatory sensitivity to CO2 and CO2 content in blood by different somatic types are effected through gas exchange peculiarities and those of muscular activity energy supply, which account for variations on the CO2-production level.
Data thus obtained allow to define a hypothesis on the prime role of central respiratory mechanism at the early stages of the organism's adaptation to hypoxia, hypercapnia and increased resistance to breathing. At the base is development of a strategy aimed at such control alteration, which ensures forming u of antihypoxic adjustment mechanisms. It is supposed that CO2 plays an important role in regulating the antixypoxic mechanisms, both respiratory and circulation, ensuring an adequate oxygen supply and oxygen regimens optimization.
A question is poised why multiple repetition of hypoxic and hypercapnic stimuli results in a faster forming up of the adaptive (antihypoxic) guard than a stronger and even lengthy, but single effect. There can be several reasons for that. As the most attractive we hold the idea of memory trace formation while adapting to a new medium [Slonim, 1976], which is interpreted as the memory mechanism participation in an accelerated adjustment to a dramatically altered medium due to active selection of biologically relevant emotiogene information. This process includes the development of lateral inhibition, which allows, while being multiply repeated for a long time, the memory trace reproduction and impossibility of its amnesia. Besides that oxygen is intensely consumed by the brain (20% of all the taken-in into the organism) for maintenance the ionic membrane gradient, while memory trace forms up by altering post-synaptic receptors' and mediators' interaction. It is evident that its content protracted reduction in blood (in case of lengthy hypoxia) would be reflected less positively on the memory trace forming up then similarly strong impacts, but interchanged with normoxia periods, needed for the sodium-potassium pump energy maintenance.
