BLOODSTREAM GAS

TRANSPORTATION
The hemoglobin (Hb) bound form
Due to the presence of Hb, the blood's transport
capacity increases by 70 times compared to plasma
Oxygen (O2) binds to ferrous Fe, the reaction being
oxidation!
OXYGEN BOUND TO Hb
• One molecule of Hb binds 4 molecules of O2. Hb has 4 heme
subunits in which Fe2+ is present.
• Oxygen-carrying capacity or oxygenation capacity is the
maximum volume of O2 that can be bound by 1g of Hb.
• Pure Hb binds 1.39 mL O2/g.
• In plasma, there are 15g of Hb/100mL of blood, which means
20.8 mL O2%.
• In smokers, this oxygen-carrying capacity decreases due to
the blocking of a part of Hb with CO.
• And in non-smokers, the oxygen-carrying capacity is 1.30 mL
O2/g because there is a very small amount of metHb and
atmospheric pollution with CO.
• If pure O2 is breathed, the oxygen-carrying capacity will
increase to 1.39 mL O2/g.
The O2Hb dissociation curve.
The binding of O2 to Hb was experimentally performed with
varying partial pressures of O2, and there is no linear
relationship between the proportion of O2Hb and the partial
pressure of the gas. The curve has a sigmoidal graphical
representation. Low partial pressure means low affinity, but
the affinity increases under the influence of O2 itself. At a
partial pressure greater than or equal to 30 mmHg, the
curve becomes hyperbolic, and between 50-100 mmHg,
the partial pressure of O2 becomes a horizontal curve. At a
partial pressure of 50 mmHg, the saturation of Hb with O2
is 85%. At a partial pressure below 40 mmHg (saturation of
40% O2Hb), the curve becomes vertical, and O2 is
released to tissues.
The O2Hb dissociation curve.
• At a partial pressure above 50 mmHg, the dissociation
curve becomes horizontal, so the saturation of Hb
decreases very little even if the partial pressure of O2
decreases significantly.
• At altitude, or in pulmonary diffusion disorders, the partial
pressure of O2 can decrease significantly, even up to 60
mmHg, but the arterial blood Hb saturation remains
around 90%. The saturation of myoglobin, which is similar
to Hb monomers, has the shape of an equilateral
hyperbola. The sigmoid shape of the dissociation curve
results from the successive binding of O2 to the 4 Fe²+
atoms.
The dissociation curve of Hb.
The dissociation curve of Hb.
• The Hb dissociation curve is shifted to the right when
there are increased concentrations of 2,3 DPG, H+, CO2,
and temperature.
• The attachment of the first heme group causes a
conformational change in the polypeptide chain to which
the heme is bound and its neighboring chain, thereby
facilitating attachment to the next heme group. O2 acts as
its own catalyst for attachment.
• At a partial pressure of O2 above 30 mmHg, all
polypeptide chains are engaged.
2,3-diphosphoglycerate (DPG)
• The polypeptide chains in reduced Hb are linked by salt
bridges as follows: there are 4 bridges between the α
chains, one between each α and β chain, and two
between the β chains, linked by a molecule of 2,3-DPG.
• O2 first binds to the heme in α1 chain, then to that in α2
chain. At the same time, the four salt bridges between the
α chains break, releasing H+.
• Then, the bridges between the α and β chains break,
resulting in changes in the position of the chains, and the
β chains release 2,3-DPG.
• Following these changes, O2 binds to the heme on the β
chain.
The dissociation curve of Hb.
• It is shifted to the left when the concentrations of
2,3-DPG, H+, CO2, or temperature are decreased. In the
state of alkalosis or when there are increased levels of
fetal hemoglobin (HbF), the curve is shifted to the left, and
O2 is released with difficulty.
• If CO2 accumulates, pH decreases, and the curve is
shifted to the right.
• The concentration of CO2 fluctuates both at the
pulmonary and tissue levels, which determines the
modification of Hb affinity for O2.
The dissociation curve of Hb.
• At the pulmonary level, CO2 diffuses from the blood into
the alveoli, the partial pressure of CO2 in the blood
decreases, and the pH increases, causing the curve to
shift to the left. This makes it easier for O2 to bind to Hb.
• At the tissue level, CO2 diffuses from the tissues into the
blood, causing the curve of O2Hb dissociation to shift to
the right. This reduces the affinity of Hb for O2, leading to
faster release of O2 into the tissues (from the blood to the
tissues).
• Low temperature impedes the release of O2 from O2Hb.
Energetic metabolism
• 2,3 DPG is derived from intracellular glycolysis and is absent in
other cells.
• In erythrocytes, there is 2,3 DPG mutase, with an optimal pH
of 7.5, which catalyzes the synthesis of 2,3 DPG.
• Erythrocytes contain high concentrations of 2,3 DPG, which
are 4 times higher than ATP concentrations and equimolar to
Hb concentrations.
• 2,3 DPG binds equimolarly to the beta chains of deoxygenated
Hb, is a non-diffusible anion, and does not bind to those of
O2Hb.
• Therefore, under the influence of 2,3 DPG, the affinity of Hb for
O2 decreases because the intraerythrocytic pH decreases and
because 2,3 DPG binds to the positive beta chains of Hb.
2, 3 DPG
• Synthesis increases under the influence of thyroid
hormones, androgens, and STH, as well as in alkalosis.
• In acidosis, intracellular glycolysis is blocked, resulting in
a decrease in 2,3-DPG.
• At high altitudes, compensatory hyperventilation occurs,
leading to respiratory alkalosis and increased
concentration of 2,3-DPG.
• There is also an increase in the number of red blood cells
with increased Hb formation.
• These reactions ensure better adaptation to high altitudes.
2, 3 DPG
• After 48 hours of exposure to 4500m, the concentration of
2,3 DPG reaches its maximum level. It returns to normal
after 48 hours of staying at sea level.
• Intense physical exercise increases 2,3 DPG within 60
minutes in untrained individuals.
• In athletes and trained individuals, there is a higher
concentration of 2,3 DPG.
• Patients with chronic hypoxia and anemia have
erythrocytes that are richer in 2,3 DPG, which facilitates
oxygen release in tissues.
• The increase in intraerythrocyte concentration of 2,3
DPG represents an intrinsic mechanism of adaptation
to hypoxia.
2, 3 DPG
• Long-term perfusion with hypertonic glucose leads to a
decrease in the concentration of 2,3-DPG, which impedes
the release of O2 from Hb.
• HbF has a higher affinity for O2 because 2,3-DPG binds
more weakly to the γ chains compared to the β chains.
The polypeptide chains of Hb
2, 3 DPG
2, 3 DPG
Co2 Transport
• In plasma, CO2 exists in 3 forms:
• 1. Dissolved freely in plasma, the concentration of which is
directly proportional to the partial pressure of CO2,
representing approximately 7% of the total amount of CO2.
• 2. In venous blood, the partial pressure of CO2 is 46 mmHg,
which is equivalent to approximately 2.75 ml CO2%.
• 3. In arterial blood, the partial pressure of CO2 is 40 mmHg,
which is equivalent to approximately 2.4 ml CO2%.
• CO2 is also present in the form of sodium bicarbonate
(NaHCO3), which is formed in the capillaries of tissues through
the Hamburger membrane phenomenon. This represents
70-80% of the total amount of CO2.
Co2 Transport
• Combined with Hb, in the form of carbaminoHb or Hb
carbamate, and with proteins, in the form of protein
carbamate. The total amount of CO2 bound to blood
depends on the partial pressure of CO2. As the partial
pressure of CO2 increases, the amount of bound CO2
also increases.
Nervous regulation of respiration
• The autonomic nervous system regulates pulmonary
ventilation based on metabolic needs so that the gas
composition in arterial blood remains constant.
• Sectioning the upper cervical region of the spinal cord leads to
the cessation of respiration.
• There are two mechanisms:

• 1. VOLUNTARY: located in the cerebral cortex, the motor

neuron extensions reach the respiratory muscles (these are
the corticospinal fibers).

• 2. AUTOMATIC: the nerve centers are in the medulla and

pons, and the efferent pathways are in the lateral and ventral
columns of the spinal cord. The automatic centers are in the
reticular formation.
Nervous regulation of respiration
• In the bulb, there are inspiratory and expiratory neurons.
The inspiratory neurons are located in two distinct areas
bilaterally. The smaller one is median and dorsal, adjacent
to the solitary tract nucleus.
• The larger one is located laterally, coinciding with the
rostral portion of the ambiguus nucleus.
• The inspiratory neural centers in the median area have
two categories of neurons, α and β. The α neurons are
more active during inspiration, while the β neurons are
active during both inspiration and expiration.
Nervous regulation of respiration
• When the lungs are maximally stretched, β neurons accelerate
their activity, thus inhibiting the activity of α neurons.

• Vagal afferent impulses limit inspiration through β neurons.

• Expiratory neurons, which discharge mainly during forced

expiration, are located in the caudal and ventral region of the
medulla, along with the retroambiguus nucleus.

• Inspiratory neurons have alternating activity with expiratory

neurons.

• Inspiratory neurons have a low excitability threshold, slow

depolarization, and rhythmic, automatic activity.
Nervous regulation of respiration
• The rhythmic activity of inspiratory neurons determines the rhythmic
contractions and relaxations of the inspiratory muscles, resulting in a
respiratory frequency of 12-16 breaths per minute. The activity of
these neurons gradually intensifies (in a ramp-like pattern) for
approximately 2 seconds, then abruptly stops for 3 seconds
(expiration). This pattern leads to a progressive increase in lung
volume, without inducing inspiratory spasms.

• In the pons, specifically in the upper and dorsal region, lies the
pneumotaxic center, a nervous center that regulates the inspiratory
phase of breathing by limiting its duration or amplitude. When the
activity of inspiratory neurons reaches a certain threshold or
maximum, the pneumotaxic center inhibits their activity and
terminates the inspiratory phase. The pneumotaxic center also plays
a role in coordinating the activity of inspiratory and expiratory
neurons, contributing to the regulation of respiratory rhythm and
depth.
Nervous regulation of respiration
• Apneusis is a form of breathing that occurs in case of a
mediopontine section.
• This type of breathing is characterized by prolonged inspiration
due to tonic discharges from neurons located in the lower
portion of the pons.
• The discovery of the apneustic center in the mediopontine
region was based on experiments that showed its influence on
the inspiratory centers.
• The tonic activity of the apneustic center is decreased by the
pneumotaxic center and by vagal afferents.
• The neurons in the pneumotaxic center, located in the medial
parabrachial nucleus, do not have spontaneous activity but are
influenced by suprajacent nervous zones, namely the cerebral
cortex and the neurons in the bulb.
Regulation
• The activity of neurons in the pneumotaxic CN is inhibitory
on inspiratory CN and excitatory on expiratory CN, thus
preventing apneusis.
• They have a role in the transition phenomenon from
inspiration to expiration.
• The section between the bulb and the pons determines
uneven breathing amplitudes, gasping, which means that
bulbar CNs cannot sustain calm, equal breathing.
Regulation
• The respiratory CNs in the bulb are influenced by other
nervous centers. Near them are the centers for
swallowing and vomiting, and breathing is stopped during
swallowing, vomiting, or belching.
• The CNs in the hypothalamus are involved in
thermoregulation, causing thermal hyperpnea.
• The cerebral cortex acts directly on the striated muscles
of the thoracic cage, without involving the CNs in the bulb,
for voluntary breath-holding, singing, and speaking.
• Emotional states are influenced by the involvement of the
hypothalamus, limbic system, and cerebral cortex. For
example, pleasurable reactions cause hyperventilation,
while fear/stress reactions can cause hypoventilation.
 Reflexes with a role in regulating
respiration.
• All receptive surfaces of the body are connected to respiratory
CNs and can modify respiration. Sensory pathways send
collaterals to the reticular formation where respiratory CNs are
located.
• For example, afferents from cutaneous thermoreceptors
stimulated by cold can inhibit or decrease respiration, while
increased temperature can accelerate respiration. Alternating
cold and hot stimulation can activate or stimulate respiration.
• Afferents through the trigeminal nerve: stimulation of the
supraglottic region leads to inhibition of respiration (e.g. a
cotton swab with ammonia placed in the nose can stop
respiration).
• This explains sudden deaths caused by small amounts of ether
or chloroform, without prior administration of atropine.
Respiratory reflexes.

• Impulses from the subglottic zone stimulate breathing and

increase frequency.
• For example, passive mobilization of the limbs of a resting
person leads to an increase in respiratory rate.
• Afferents from the lungs activate the Hering Breuer reflex.
• There are nerve endings in the bronchioles' musculature that
act as stretch receptors.
• During inhalation, the lung expands, and impulses are
transmitted via the vagus nerve to the bulb, without reaching
the pneumotaxic CN, followed by exhalation.
• This reflex prevents lung overinflation.
• The reflex only occurs when VC (vital capacity) is over 1-1.5 L.
.
• When the alveoli are flattened, inhalation occurs via the
vagus nerve.
• The reflex caused by flattening of the alveoli is not as
strong as the one caused by distension, and it occurs for
example in pneumothorax.
• In humans, this Hering Breuer reflex is minimal. Impulses
from the cardiovascular system receptors.
• The cardiovascular reflexogenic zones have
chemoreceptors and baroreceptors.
• For example, a decrease in blood O2 concentration in the
chemoreceptor territory of the carotid body stimulates
respiration. This reaction is very important for adapting to
altitude.
Respiratory reflexes
• At high altitude, the partial pressure of O2 decreases,
leading to hypoxia, hyperventilation, and increased
elimination of CO2. Stimulation of the carotid and aortic
bodies in hypoxia helps maintain the respiratory rhythm.
• The carotid body contains mainly type I cells, which
represent 60% of the total cells, and can be either clear or
dark. These cells have a well-developed Golgi apparatus
and endoplasmic reticulum, and the dark cells also
contain dopamine-containing dense granules.
• Type I cells are surrounded by type II cells, which are glial
or supporting cells.
Respiratory reflexes

• Type II cells surround the nerve endings without Schwann

sheath when they enter the corpuscle. The principal cells are
separated from the fenestrated capillaries by the type II cells,
interstitial tissue, and pericytes.
• The principal cells of the glomus are in direct contact with
afferent and efferent nerve endings.
• Stimulation of the Hering nerve decreases the response of the
carotid body to hypoxia or CO2 accumulation. Efferent
impulses through the nerve release dopamine from the
granules, which reacts with the sensory nerve endings coiled
around the principal cells. Injection of CA (A, NA, dopamine)
into the carotid body decreases the frequency of discharges in
the Hering nerve.
Respiratory reflexes
• The release of dopamine from efferent nerve endings,
decreasing the sensitivity of sensory fibers, determines central
control over sinus carotid responses.
• The corpuscles have a huge blood flow, and the cells' O2
needs can be exclusively met by dissolved O2.
• For example, anemic patients have normal limits of dissolved
O2, even though O2Hb is reduced, and for this reason,
chemoreceptors are not stimulated.
• Stimulation of baroreceptors in the sinocarotid or cardioaortic
zone, by increasing blood pressure, determines inhibitory
respiratory reflexes, up to cessation of breathing.
• Decreased blood pressure stimulates breathing (e.g. in
hemorrhages or the administration of vasodilator drugs).
Respiratory reflexes
• The efferent pathways from the autonomic nervous
system reach the musculature of the nasal wings through
the facial nerve, the musculature of the larynx through the
laryngeal nerve, the bronchial musculature through the
vagus nerves, the accessory inspiratory muscles
(scalene, longus colli), intercostal inspiratory muscles,
abdominal muscles through the spinal nerves in the
cervical and dorsal region, and the diaphragm through the
phrenic nerve.
• Interrupting this pathway results in "Ondine's curse",
tumors with bulbar compression, or bulbar poliomyelitis.
The only solution is mechanical respiration.
Humoral regulation of respiration

• The concentrations of O2, CO2, and H+ in the body fluids

are maintained constant by mechanisms that regulate
respiration.
• Variations in these concentrations modify respiration. An
increase in CO2 and H+ leads to an intensification of
respiration through their action on peripheral and central
chemoreceptors.
• A decrease in O2 only stimulates peripheral
chemoreceptors.
• A decrease in partial pressure of O2 to 60-80 mmHg has
a negligible effect on respiration, only values below 50
mmHg significantly affect it.
Humoral regulation of respiration
• Regulation of breathing is mainly controlled by partial pressure
of CO2 and pH.
• Inhalation of a gas mixture rich in CO2, above 5%, leads to
hyperventilation, which reaches a maximum value at 9%.
• Further increase in CO2 concentration above 9% causes
depression of the central nervous system, including respiratory
neurons, leading to coma and even death (at 40-50%).
• Respiratory responses to changes in arterial blood CO2
concentration occur at partial pressure differences of 1-2
mmHg. After inhalation of CO2, respiratory response through
peripheral chemoreceptor stimulation appears within 4
seconds.
Humoral regulation of respiration
• Central chemoreceptors are stimulated after 20-40
seconds, the time needed for gas transport from the lungs
to the bulb capillaries.
• If the carotid and aortic bodies are denervated, the
ventilatory response to CO2 action reaches 70% of the
total reaction.
• The central chemoreceptor zone is located between the
emergence site of nerves IX-XI, on the ventrolateral
surface of the bulb.
• Application of HCl to the central chemoreceptor zone or
direct stimulation of it results in hyperventilation, while
cooling the zone results in hypoventilation.
Humoral regulation of respiration
• The cells of the central Rp zone are sensitive to changes in H+
levels in the cerebrospinal fluid and cerebral interstitial fluid.
The blood-brain barrier is very slowly penetrated by H+ and
bicarbonate ions in the blood, but CO2 diffuses very easily
through the membrane.
• CO2 that reaches the cerebrospinal fluid is rapidly hydrated,
forming H2CO3, which instantly dissociates into H+ and CO3-.
The concentration of H+ is in line with the partial pressure of
CO2 in arterial blood.
• The deep bulbar neurons are in contact with the cerebral
interstitial fluid, which is impermeable to H+ and HCO3- but
accessible to CO2.
• After hydration, CO2 releases H+, which directly stimulates the
respiratory neurons.
Humoral regulation of respiration
Blood temperature directly influences respiration.
Increased temperature leads to increased frequency and
amplitude of respirations.
In low doses, adrenaline activates the reticular formation,
which stimulates respiration.
Reflexes triggered by irritation of
AW
• Coughing: an inspiration of approximately 2.5 liters,
followed by an expiration, initially with closed glottis,
increases the intrapulmonary pressure above 100 mmHg,
then the glottis suddenly opens and the air is explosively
expelled.
• The cough receptors are located in the bifurcation of the
trachea, extrapulmonary bronchi, and larynx.
• The stimuli can be chemical or mechanical.
• The cough receptors are connected to the vagal fibers.
• Other receptors are also present in the pleura and
intestines.
The cough
The sneeze
• Rp are terminations of the trigeminal nerve, and the
stimuli are irritative or olfactory.
• It is an expiration with an open glottis, the air is blocked
for a while by the soft palate and uvula, which then open
suddenly and the air is expelled through the nasal
passages.
• Liquid can also be eliminated, which can spread up to 6
meters.
Sneeze
Hiccups
• This is the spasmodic contraction of the diaphragm
accompanied by an inspiration during which the glottis
closes abruptly, with the sudden cessation of the column
of air.
• The respiratory receptors (Rp) are located at the level of
the diaphragm or at the level of central neurons.
Hiccups
Crying
• Psychoemotional reaction with respiratory and autonomic
changes.
• Respiratory changes include jerky inspirations with
prolonged expirations and lacrimation.
Tearing
Effortful breathing
• During physical exertion, oxygen consumption and CO2
formation increase. In venous blood that reaches the
alveoli, the partial pressure of O2 drops from 40 mmHg to
25 mmHg, which results in a greater gradient and
facilitates the diffusion of O2 into the plasma.
• Circulation is intensified, and the circulatory output can
increase from 5L/min to 14000ml/min during exertion.
• The amount of CO2 eliminated increases from 250 ml/min
at rest to 8000ml/min during exertion.
• In exertion, there is a proportional relationship between
the intensity of the effort and the retention of O2 until a
maximum is reached, which cannot be exceeded.
Effortful breathing
• If the effort is maintained, with a higher amplitude, the
oxygen consumption is maintained at a plateau, and the
concentration of lactic acid in the blood increases rapidly.
Lactic acid comes from the muscular metabolism, where
there is a lack of oxygen.
• After the effort, the respiratory rate remains high until the
oxygen debt is repaid, which can take up to 90 minutes.
Ventilation is accelerated during the recovery period due
to H+ formed from lactic acid.
• During intense effort, the lactic acid is neutralized by the
buffer system in the plasma, excess CO2 is eliminated,
and the respiratory quotient increases to 1.5-2.
Effortful breathing
• After exertion, during the period of repaying the O2 debt,
the respiratory quotient decreases to 0.5. Hyperventilation
during exertion occurs through nervous mechanisms:
• - The motor pathways that reach the active muscles emit
collaterals that transmit impulses to the respiratory
centers in the medulla oblongata, stimulating the
respiratory nerves.
• - Proprioceptive afferents, especially those from the limbs.
• - An increase in blood temperature, which increases the
sensitivity of the respiratory centers to the action of CO2.
Pathological breathing
• Cheyne Stokes respiration is characterized by successive
increases and decreases in the amplitude of breathing,
interrupted by apnea.
• One cycle can last from 45 seconds to 3 minutes. It occurs due
to hypoexcitability of the respiratory cranial nerves.
• These nerves are sensitive to high concentrations of CO2 in
the blood. When they are stimulated, hyperpnea occurs,
excess CO2 is eliminated, and the activation of the nerves
stops, leading to apnea.
• As a result, the concentration of CO2 in the blood increases,
and the cycle repeats. Cheyne Stokes respiration is normal in
underdeveloped newborns and can occur in conditions such as
heart failure, uremia, morphine poisoning, and cerebral
hemorrhages.
Cheyne Stokes
Biot
• Normal breathing with periods of apnea, with a cycle
ranging from 10 seconds to minutes. It occurs in nerve
tissue lesions, compressions, brain damage, and agony.
Kussmaul
• Acidotic breathing, in 4 steps, occurs predominantly in
diabetic acidosis, and to a lesser extent in uremic
acidosis.