BISC 307L 2nd Edition Lecture 36 Current LectureRegulation of VentilationWithin the erythrocyte, as the CO2 flows into the alveolar air, that creates a gradient for CO2 to leave the erythrocyte, and that shifts the equilibrium for the carbaminohemoglobin as the CO2 is removed by diffusing into the plasma and then the alveolus. So CO2 comes off the Hb, that was about 23%. We start with Oxyhemoglobin (Hb-H). When oxygenated, hemoglobin loses its affinity for protons. They dissociate, and that makes the inside of the red blood cell more positive, and that attracts bicarbonate in across the membrane in exchange for chloride.That is called the reverse chloride shift. So we have protonsand bicarbonate in here, which combines to carbonic acid.There’s a lot of carbonic anhydrase, so it dissociates. Anddriven by the removal of CO2, this whole reaction moves tothe right and bicarbonate in the plasma is taken out andbecomes CO2 in the RBC’s that diffuses out. So its pretty mucheverything running in reverse – to make it all work though, it isimportant that deoxyhemoglobin binds protons andoxyhemoglobin doesn’t. Regulation of VentilationSkeletal muscles control ventilation – diaphragm, intercostal muscles, external cleidomastoids. They are not spontaneously active, but rather they are innervated by alpha motor neurons. And these are brain stem motor neurons (seen to the right). In the brain stem, there are two groups of nerve cells that are functionally defined, called the ventral and dorsal respiratory groups – those are where the AP’s of the respiratory system will originate. There are neurons with unstable membrane potentials that generate rhythmic AP’s in bursts. And that descending excitation from those neurons goes to spinal and brain stem neurons that innervate the respiratory muscles. The control of this outflow of motor information is determined by the level of the respiratory gases. Oxygen does not play a major role in ordinary moment-to-moment, quiet breathing. CO2 is much more important. Hb carries a tremendous reserve of oxygen, so oxygen levels in the blood are not a sensitive indicatory of a need for respiration. On the other hand, CO2 is, because it is a direct waste product of metabolism. So we need gas sensitive nerves/chemoreceptors. These reflexes are going to start with chemoreceptors that will sense the level of respiratory gases in the blood and respond appropriately. There are 2 types of chemoreceptors – central and peripheral. The central chemoreceptors are the ones in the brainstem, they sense the respiratory gases. The central just refers to the central nervous system. These are sensitive to carbon dioxide. Peripheral chemoreceptors are located in the aortic body and the carotid body. These are good places to measure the oxygen level of systemic circulation. Don't confuse the aortic and carotid bodies with the aortic and carotid sinuses – those participate in the baroreceptor reflex. The carotid body is a group of cells that are sensitive to oxygen in the carotid artery and the aortic body is a group of oxygen sensing cells in the wall of the aorta. And these cells are called glomus cells. They sense oxygen, and in response to hypoxia, they release dopamine as an NT. Dopamine excites afferent/sensory nerves. So glomus cells are like hair cells, they don’t have axons, they sense something, and make synapses onto afferent neurons that do go into the CNS. Normally, they are not very active. The extent of hypoxia that is needed to stimulate them is very extreme.Day-to-day, these things do not do much. Under conditions of low ambient oxygen concentration at high altitudes or in respiratory diseases like COPD where hypoxia can occur, then these peripheral chemoreceptors can provide strong excitatory drive to the respiratory control center. The central chemoreceptors are sensing CO2. They are involved in the moment to moment regulation of the rate and depth of breathing. It turns out that the chemoreceptor neurons are not CO2 sensitive, they are hydrogen ion sensitive. They get excited by low pH. So acidification of cerebral spinal fluid is the stimulus for activation of these neurons, which them stimulate respiration.Protons cannot cross the brain-blood barrier. Endothelial cells in the capillaries of the brain are sealed to each other by tight junctions, constituting the blood-brain barrier. And H ions cannot get into or out of the blood through that barrier. CO2 readily diffuses througheverything though, so the way these proton sensitive neurons get their protons is by CO2 diffusing out of the blood when its high. There are other reflexes on top of this, reflexes that trigger coughing and sneezing. So coughing and sneezing are respiratory actions. Vocalization is another one. There is a protective reflex called the Herring Brewer reflex. When one exercises, you tend to breathe more deeply and rapidly – at a point when the tidal volume reaches a level of about 2x normal, one liter, then thisreflex gets activated – it protects the lungs against overinflation. It prevents the lungs from being overstretched during very active breathing. These can be very powerful reflexes – for example, you can’t commit suicide by holding your breath. Clinical conditions – SIDS and hyperventilation.Hyperventilation – very dramatic, when you hyperventilate, you blow off excess CO2. And blowing off excess CO2 is going to cause hypocapnia, which triggers vasoconstriction of brain arterioles. When brain arterioles get constricted the cerebrum gets ischemic. The ischemia is what triggers the dizziness and triggers acidosis in the brain. The low CO2 level in the brain triggers the vasoconstriction of the arterioles, and the brain gets ischemic, and the CO2 accumulates and causes acidosis in the cerebral spinal fluid. Stimulates the central chemoreceptors which respond to acidosis with more breathing. Acidosis will stimulate these neurons, triggering more breathing. The first aid for this is recommended to breath into a paper bag, so you are rebreathing your expired air, which has more CO2. And that relieves the hypocapnia. SIDS – Sudden infant death syndrome – this is one form of sleep apnea. Insomnia, for one thing,can be a problem, and even death. SIDS is the leading cause of death of babies under a year of age, in the US. Starting about 20 years ago, the American academy of pediatrics has been advocating the practice of putting babies to sleep on their