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1Manuscript: Explicit Constructivism: a missing link in ineffective lectures? Author: E.S.Prakash Supplement 1: Typical LectureNote - Copyrighted images have been removed and replaced with a URL link to those images.This is an open access article distributed under the terms of the Creative Commons Attribution License
2Chemical and neural regulation of respiration E.S.Prakash, School of Medicine, AIMST University, Malaysia
3How much do we already know How much do we already know? Just write the answers with the question number on a sheet of paperAt sea level, barometric pressure is: mmHgBarometric pressure is the same as atmospheric pressure. T/FIn the upright position, ventilation-perfusion ratio is highest in the upper lung zones. T/FThe maximum volume of air that you can expel after a maximal inspiration is called:The amount of air that remains in the lungs after a tidal expiration is called:
4If you breathe 500 ml per breath 12 times a minute and your dead space is 150 ml, then, what is the amount of fresh gas supplied to your alveoli per minute?
5Organization of content in these lectures: Neural control of breathingNeural control systems: functional organizationChemoreceptors: functional organizationClassification of chemoreceptorsVentilatory responses:to changes in acid-base balanceTo CO2 excessTo oxygen lackInteraction of hypoxia and CO2
6Content outline continued: Nonchemical influences on respirationResponses mediated by airway receptorsResponses mediated by receptors in the lung parenchymaCoughing & sneezingRegulation of respiration during sleepAbnormal respiratory patterns
7Neural control of breathing There are 2 systems:One for voluntary controlOne for spontaneous breathing
8System for voluntary control of breathing: Regulator neurons located in cerebral cortexWhen does this system work?When we control our breathing voluntarilyExample: when you hold your breathExample: when you hyperventilatePathway: From cerebral cortex to motor neurons in the spinal cord which supply muscles of respiration (diaphragm & intercostal muscles)
9System for spontaneous control of breathing: Breathing is mostly spontaneousBreathing is rhythmic (rate as well as depth)We are not aware that we are breathingLocation of respiratory center: medullaPlease see schematic on next slide
10Mechanism of spontaneous breathing Afferents from carotid bodies terminate herePonsMedullary chemoreceptorsPre-Botzinger complex; pre-BOTC (Pacemaker)MedullaI neuronsSpinal cordDiaphragm & intercostal musclesPhrenic neurons
11ComponentDetailsCentral chemoreceptor neurons (sensory)Project to Pre-Botzinger complex of neuronsPre-BOTCDischarge spontaneously; pacemaker neurons for breathing (like SA node in heart); entrained by input from chemoreceptorsI neuronsFire during inspiration; thus the name; project to lower motor neurons (e.g. phrenic n.) that drive muscles of inspiration
12Feedback to the respiratory center from lungs: During inspiration,lungs expand, and lung parenchyma is stretched;stretch receptors are present here;these are activated and convey information to the brain via sensory branches of vagus nerve
13Role of pons in respiration: There is an area called pneumotaxic center in the pons;If this area is damaged, then, depth of inspiration is increased (see next slide)So, this center may serve to switch breathing from inspiration to expirationThis switch works to inhibit I neurons during expiration
14Effect of vagotomy on breathing rate and depth; note the increase in depth NormalAfter vagotomy
15Effect of damage to the pneumotaxic center in vagotomized animals: normalAfter vagotomyapneusis
16Functional organization of chemoreceptors: A rise in PCO2, a fall in pH or PO2 of arterial blood increases respiratory neuron activity in the medulla.Stimulus: a change in blood chemistry …Sensed by: receptors called chemoreceptorsResponse: change in minute ventilation
17Functional organization of chemoreceptors (contd.) Location of chemoreceptors:Central chemoreceptors (in medulla); also called medullary chemoreceptorsArterial chemoreceptors (in carotid & aortic bodies); sometimes called peripheral chemoreceptors
18Functional organization of chemoreceptors (contd.) Innervation of peripheral (systemic arterial chemoreceptors);Figure at Link:Note carotid body is supplied by branch of IX nerve and aortic bodies are supplied by branch of X nerve.
19Some facts about systemic arterial chemoreceptors: There are 2 types of cells in the carotid body;Type I glomus cells contain oxygen sensitive K channels (these are the chemoreceptors)Type II cells are supporting cellsThey have a very high blood flowIn carotid bodies, blood flow rate: 2000 ml/100 g tissue/minFor example, the brain gets 50 ml/100 g/min
20Stimuli that activate peripheral chemoreceptors: Low PaO2 (hypoxemia)Drop in arterial pH (acidosis)Rise in PaCO2 (hypercapnia)Low blood flow through the receptors; i.e., when cardiac output and BP are lowNote: these receptors are very sensitive to drop in PaO2 (hypoxemia) compared to rise in PaCO2 (hypercapnia)
21So what are the normal values of each? Arterial Blood Gases & pHNormal rangeArterial pH7.35 – 7.45Arterial PO281 – 100 mm HgArterial PCO235 – 45 mm Hg
22Central chemoreceptors (medullary chemoreceptors) Location: brain stem, ventral surface of medullaThey are located near I neuronsThey project to respiratory neuronsCentral chemoreceptors and respiratory neurons are distinctThey are mainly sensitive to changes in PaCO2A rise in PaCO2 effectively stimulates central chemoreceptors
23CO2 crosses the blood brain barrier (BBB) A rise in PaCO2 lowers CSF pH which is sensed by medullary chemoreceptorsCO2 crosses the blood brain barrier (BBB)CO2bloodbrain ISFH+ + HCO3CO2 + H2O H2CO3Carbonic anhydraseDrop in CSF pH
24Central chemoreceptor neurons monitor the H+ ion concentration of brain ISF; Greater the PaCO2, > the minute ventilation;If you lower PaCO2, minute ventilation is lowered
25Effect of addition of metabolic acid (e. g Effect of addition of metabolic acid (e.g., lactic acid, on ventilation)Example: lactic acidosis (metabolic acidosis)Arterial pH is low (< 7.35);Breathing is rapid and deep (Kussmaul’s respiration) and CO2 is blown offThis response is mediated by carotid bodies (peripheral chemoreceptors) and is lost if they are removed.
26Effect of a rise in blood pH on minute ventilation Example: metabolic alkalosis due to vomiting; i.e., loss of HCl;Arterial pH is high (> 7.45)Respiration is slowed; i.e., decrease in minute ventilation)As a result PaCO2 gradually rises
27What happens if more CO2 is produced as a result of metabolism? More CO2 in blood as a result of ↑metabolismTransient rise in PaCO2Fall in CSF pHRespiration is stimulated effectivelySteady state PaCO2 is normal
28Ventilatory response to CO2 lack or excess 200Minute ventilation (l/min)100Alveolar PCO2 (mm Hg)
29Ventilatory response to oxygen lack: 200Minute ventilation (l/min)100PO2 (mm Hg)
30Ventilatory response to hypoxia, hypercapnia, severe exercise and maximal voluntary ventilation (MVV) compared200Minute ventilation (l/min)MVV: l/minMax. ventilation during exercise100Response to hypercapniaResponse to hypoxiaAlveolar PO2 or PCO2 (mm Hg)
31Comments: Normally, minute ventilation is about 5 l/min MVV = l/min (higher in males cf. females)Thus, there is a great ventilatory reserve;But MVV can be sustained only for a short timeHypoxia and hypercapnia alone are not as potent as severe exercise in stimulating ventilationSo, other factors also drive ventilation during exercise.
32Interaction of ventilatory responses to CO2 and O2 (all partial pressures in mm Hg) PAO2 = 40100PAO2 = 5575PAO2 = 100Ventilation (l/min)502540PACO250
33Conclusion:Conclusion: Hypoxia makes an individual more sensitive to CO2 excess
34Ventilation at high altitudes: Barometric (atmospheric) pressure is lower;When PaO2 is < 60 mm Hg, min. ventilation ↑What happens to PaCO2?It is lowered as a result of hyperventilationWhat happens to pH of arterial blood?pH increases slightly say from 7.4 to 7.45Arterial blood gases: Hypoxemia (low PaO2); hypocapnia (PaCO2 < 35 mm Hg); respiratory alkalosis (pH > 7.45 because of hypocapnia)
35Some working definitions for you: Normocapnia: PaCO2 between 35 and 45 mm HgHypocapnia: PaCO2 < 35 mm HgHypercapnia: PaCO2 > 45 mm HgHypoxemia: PaO2 < 80 mm HgNote: significant activation of carotid bodies occurs only when PaO2 < 60 mm Hg
36Effects of breath holding: Respiration can be voluntarily inhibited for some timeEventually, voluntary control is overridden (breaking point)What is breaking due to?Rise in PaCO2 (acute hypercapnia)Fall in PaO2Individuals can hold their breath longer after removal of carotid bodies;Psychologic factors also contribute
37Effects of hyperventilation: Overbreathing to exhaustion;Eventually there is a “breaking point”Note a period of apnea following hyperventilation;What is breaking here due to?CO2 lackapneaOverbreathing
38Effects of chronic hypercapnia: When does chronic hypercapnia occur?What is the basic cause of chronic hypercapnia?Failure to eliminate CO2; (respiratory failure)Reason: reduction in alveolar ventilationNote:acute hypercapnia stimulates breathingchronic hypercapnia depresses the respiratory center
39Nonchemical influences on respiration: StimulusResponseName of reflexReceptorExcessive lung inflationInhibition of inflation; lung deflationHering Breuer inflation reflexVagal afferents from airwaysExcessive lung deflationInhibition of deflation; lung inflationHering Breuer deflation reflexLung inflationFurther inflationHead’s paradoxical reflex?
40Nonchemical influences on respiration (contd.): StimulusResponseName of reflexReceptorLung hyperinflation; increase in pulmonary interstitial fluid pressure; or intravenous injection of capsaicinApnea followed by tachypnea; bradycardia; hypotension; skeletal muscle weaknessJ reflexJuxtacapillary receptors (C vagal fiber endings)Injection of histamineCough, bronchoconstriction, mucus secretionCough reflexIrritant receptor; among airway epithelial cells
41Mechanism and significance of cough: Deep inspirationForced expiration against a closed glottisIntrathoracic pressure increases to 100 mm Hg or moreGlottis opened by explosive outflow of airAirways are cleared of irritants
42Ondine’s curse: Spontaneous control of breathing is disrupted; Voluntary control is intact;One could stay alive only by remembering to breathe;Clinical analog:bulbar poliomyelitis affecting respiratory neurons in the brain stem;disease processes compressing the medulla
43Regulation of respiration during sleep: Respiration is less rigorously controlled during sleep;Brief periods of apnea occur even in normal people;Ventilatory response to hypoxia varies;Sensitivity of brain stem mechanisms reduced?
45Cheyne-Stokes respiration: Periods of apnea punctuated by periods of hyperpneaIt occurs in:congestive heart failurebrain stem disease affecting respiratory centersMechanisms postulated to explain this:Prolonged lung-to-brain circulation timeChanges in sensitivity of medullary respiratory neurons
46Following hyperventilation Activity:Hyperventilate to exhaustionThen, note your pattern of breathingExplain your observationsPeriodic breathinghyperventilationnormalFollowing hyperventilation
47Outline of the explanation: Hyperventilation eliminates CO2;Apnea is due to lack of CO2During apnea, PaO2 falls & stimulates breathingFew breaths eliminate hypoxiaNow there is no stimulus for breathingSo there is apnea againNormal breathing resumes only when PaCO2 is 40 mm HgConclusion: normal breathing pattern is entrained by PaCO2 not PaO2
48Some items for self-study: How is breathing regulated during exercise?What is the mechanism of hiccups?What is the mechanism of yawning?What is the mechanism of sneezing?What happens when you sigh?
50You should also be able to answer these questions: Describe with the help of schematic diagram, the neural mechanism of spontaneous breathingDescribe with the help of schematic diagram, the neural mechanism of voluntary control of respirationDescribe with the help of schematic diagram, the role of systemic arterial chemoreceptors in the regulation of alveolar ventilation
51Describe with the help of schematic diagrams the functional organization and functions of medullary chemoreceptors.How does CO2 stimulate breathing?What is the relationship between PaCO2 and minute ventilation?Describe the mechanism responsible for periodic breathing following voluntary hyperventilation
52Explain the factors that affect breath holding time. Briefly explain the effect of damage to the pneumotaxic center on the pattern of breathingBriefly explain the effect of vagotomy on the pattern of breathing in experimental animals.
53What is the difference between the effect of acute hypercapnia and chronic hypercapnia on minute ventilation?What is Kussmaul’s respiration? When does it occur? What is the mechanism involved?What is periodic breathing? When does it occur? What is Cheyne-Stokes respiration?What are the Hering Breuer reflexes?What is Head’s paradoxical reflex?
54Required Reading:Chapter 36. Regulation of respiration. Ganong WF. Review of Medical Physiology, Mc Graw Hill Co, 2005