Chemical Controls of Respiration

A.    Chemoreceptors (CO2, O2, H+)

1.    central chemoreceptors - located in the medulla
2.    peripheral chemoreceptors - large vessels of neck

B.    Carbon Dioxide Effects

1.    a powerful chemical regulator of breathing by increasing H+ (lowering pH)
    
a. hypercapnia            Carbon Dioxide increases -> 
                        Carbonic Acid increases ->
                        pH of CSF decreases (higher H+)- >
                        
DEPTH & RATE increase (hyperventilation)

b. hypocapnia - abnormally low Carbon Dioxide levels which can be produced by excessive hyperventilation; breathing into paper bag increases blood Carbon Dioxide levels

C.     Oxygen Effects

1.    aortic and carotid bodies - oxygen chemoreceptors

2.    slight Ox decrease - modulate Carb Diox receptors
3.    large Ox decrease - stimulate increase ventilation
4.    hypoxic drive - chronic elevation of Carb Diox (due to disease) causes Oxygen levels to have greater effect on regulation of breathing

D.    pH Effects (H+ ion)

1.    acidosis - acid buildup (H+) in blood, leads to increased RATE and DEPTH (lactic acid)

E.    Overview of Chemical Effects

 Chemical                             Breathing Effect

increased Carbon Dioxide (more H+)     increase
decreased Carbon Dioxide (less H+)     decrease

slight decrease in Oxygen             effect CO2 system
large decrease in Oxygen             increase ventilation

decreased pH (more H+)                 increase
increased pH (less H+)                 decrease

Excitability ( Bathmotropism ) : Excitability means the ability of cardiac muscle to respond to signals. Here we are talking about contractile muscle cells that are excited by the excitatory conductive system and generate an action potential.

Cardiac action potential is similar to action potential in nerve and skeletal muscle tissue , with one difference , which is the presence of plateau phase . Plateau phase is unique for cardiac muscle cells .
The  resting membrane potential for cardiac muscle is about -80 mV.
When the cardiac muscle is stimulated an action potential is generated . The action potential in cardiac muscle is composed of four phases , which are :

1. Depolarization phase (Phase 0 ) :

A result of opening of sodium channels , which increase the permeability to sodium , which will lead to a rapid sodium influx into the cardiac muscle cell.

2. Repolarization : Repolarization in cardiac muscle is slow and triphasic :

a. Phase 1 (early partial repolarization ) : A small fast repolarization , results from potassium eflux and chloride influx.
b. Phase 2 ( Plateau ) : After the early partial depolarization , the membrane remains  depolarized , exhibiting a plateau , which is a unique phase for the cardiac muscle cell. Plateau is due to opening of slow calcium-sodium channels , delay closure of sodium channels , and to decreased potassium eflux.
c. Phase 3  ( Rapid repolarization) :  opening of potassium channels and rapid eflux of potassium.
d. Phase 4 ( Returning to resting level) in other words : The phase of complete repolarization. This due to the work of sodium-potassium pump.

Absolute refractory period:

Coincides wit phase 0,phase1 , and phase 2 . During this period , excitability of the heart is totally abolished . This prevents tetanization of the cardiac muscle and enables the heart to contract and  relax to be filled by blood ..

Relative refractory period : 

Coincides with the rapid repolarization and allows the excitability to be gradually recovered .
Excitation contraction relationship : Contraction of cardiac muscle starts after depolarization and continues about 1.5 time as long as the duration of the action potential and reaches its maximum at the end of the plateau. Relaxation of the muscle starts with the early partial repolarization.

Factors , affecting excitability of cardiac muscle:

I. Positive bathmotropic effect :

1. Sympathetic stimulation : It increase the heart , and thus reduces the duration of the action potentia; . This will shorten the duration of the absolute refractory period , and thus increase the excitability .
2.  Drugs : Catecholamines and  xanthines derivatives .
3. Mild hypoxia and mild ischemia
4. Mild hyperkalemia as it decreases the K+ efflux and opens excess Na+ channels .
5. Hypocalcemia

II. Negative bathmotropic effect :

1. Parasympathetic stimulation: The negative bathmotropic effect is limited to the atrial muscle excitability , because there is no parasympathetic innervation for the ventricles. Parasympathetic stimulation decreases the heart rate , and thus increases the duration of cardiac action potential and thus increases the duration of the absolute refractory period.
2. moderate to severe hypoxia
3. hyponatremia , hypercalcemia , and severe hyperkalemia.

Clinical Physiology : Extrasystole is a pathological situation , due to abnormal impulses , arising from ectopic focus .It is expressed as an abnormal systole that occur during the early diastole .
Extrasystole  is due to a rising of excitability above the normal , which usually occurs after the end of the relative refractory period ( read about staircase phenomenon of Treppe)

1.Rhythmicity ( Chronotropism ) :  means the ability of heart to beat regularly ( due to repetitive and stable depolarization and repolarization )  . Rhythmicity of heart is a myogenic in origin , because cardiac muscles are automatically excited muscles and does not depend on the nervous stimulus to initiate excitation and then contraction . The role of nerves is limited to the regulation of the heart rate and not to initiate the beat.

There are many evidences that approve the myogenic and not neurogenic origin of the rhythmicity of cardiac muscle . For example :
-  transplanted heart continues to beat regularly without any nerve supply.
-  Embryologically the heart starts to beat before reaching any nerves to them.
-  Some drugs that paralyze the nerves ( such as cocaine ) do not stop the heart in given doses.

Spontaneous rhythmicity of the cardiac muscle due to the existence of excitatory - conductive system , which is composed of self- exciting non-contractile cardiac muscle cells . The SA node of the mentioned system excites in a rate , that is the most rapid among the other components of the system ( 110 beats /minute ) , which makes it the controller or ( the pacemaker ) of the cardiac rhythm of the entire heart.

Mechanism , responsible for self- excitation in the SA node and the excitatory conductive system  is due to the following properties of the cell membrane of theses cells :
1- Non-gated sodium channels
2- Decreased permeability to potassium
3- existence of slow and fast calcium channels.

These properties enable the cations ( sodium through the none-gated sodium voltage channels , calcium through calcium slow channels) to enter the cell and depolarize the cell membrane without need for external stimulus.

The resting membrane potential of non-contractile cardiac cell is -55 - -60 millivolts ( less than that of excitable nerve cells (-70) ) . 

The threshold is also less negative than that of nerve cells ( -40 millivolts ).

The decreased permeability to potassium from its side decrease the eflux  of potassium during the repolarization phase of the pacemaker potential . All of these factors give the pacemaker potential its characteristic shape

Repeating of the pacemaker potential between the action potentials of contractile muscle cells is the cause of spontaneous rhythmicity of cardiac muscle cells.

Factors , affecting the rhythmicity of the cardiac muscle :

I. Factors that increase the rate ( positive chronotropic factors) :
1. sympathetic stimulation : as its neurotransmitter norepinephrine increases the membrane permeability to sodium and calcium.
2. moderate warming : moderate warming increases temperature by 10 beats for each 1 Fahrenheit degree increase in body temperature, this due to decrease in permeability to potassium ions in pacemaker membrane by moderate increase in temperature.
3. Catecholaminic drugs have positive chronotropic effect.
4. Thyroid hormones : have positive chronotropic effect , due to the fact that these drugs increase the sensitivity of adrenergic receptors to adrenaline and noreadrenaline .
5. mild hypoxia.
6. mild alkalemia : mild alkalemia decreases the negativity of the resting potential.
7. hypocalcemia.
8. mild hypokalemia

II. Factors that decrease rhythmicity ( negative chronotropic):

1.Vagal stimulation : the basal level of vagal stimulation inhibits the sinus rhythm and decrease it from 110-75 beats/ minute. This effect due to increasing the permeability of the cardiac muscle cell to potassium , which causes rapid potassium eflux , which increases the negativity inside the cardiac cells (hyperpolarization ).
2. moderate cooling
3. severe warming : due to cardiac damage , as a result of intercellular protein denaturation. Excessive cooling on the other hand decrease metabolism and stops rhythmicity.
4. Cholenergic drugs ( such as methacholine , pilocarpine..etc) have negative chronotropic effect.
5. Digitalis : these drugs causes hyperpolarization . This effect is similar to that of vagal stimulation.
6. Hypercapnia ( excessive CO2 production )
7. Acidemia.
8. hyper- and hyponatremia .
9. hyperkalemia
10. hypercalcemia
11. Typhoid or diphteria toxins.

Lipids:

• about 40% of the dry mass of a typical cell
• composed largely of carbon & hydrogen
• generally insoluble in water
• involved mainly with long-term energy storage; other functions are as structural components (as in the case of phospholipids that are the major building block in cell membranes) and as "messengers" (hormones) that play roles in communications within and between cells
• Subclasses include:
  • Triglycerides - consist of one glycerol molecule + 3 fatty acids (e.g., stearic acid in the diagram below). Fatty acids typically consist of chains of 16 or 18 carbons (plus lots of hydrogens).
  • phospholipids - Composed of 2 fatty acids, glycerol, phosphate and polar groups , phosphate group (-PO⁴) substitutes for one fatty acid & these lipids are an important component of cell membranes

steroids - have 4 rings- cholesterol, some hormones, found in membranes include testosterone, estrogen, & cholesterol

Remember the following principles before proceeding :
- Reabsorption occurs for most of substances that have been previously filterd .
- The direction of reabsorption is from the tubules to the peritubular capillaries
- All of transport mechanism are used here.
- Different morphology of the cells of different parts of the tubules contribute to reabsorption of different substances .
- There are two routes of reabsorption: Paracellular and transcellular : Paracellular reabsorption depends on the tightness of the tight junction which varies from regeon to region in the nephrons .Transcellular depends on presence of transporters ( carriers and channels for example).

1. Reabsorption of glucose , amino acids , and proteins :

Transport of glucose occurs in the proximal tubule . Cells of proximal tubules are similar to those of the intestinal mucosa as the apical membrane has brush border form to increase the surface area for reabsorption , the cells have plenty of mitochondria which inform us that high amount of energy is required for active transport , and the basolateral membrane of the cells contain sodium -potassium pumps , while the apical membrane contains a lot of carrier and channels .

The tight junction between the tubular cells of the proximal tubules are not that (tight) which allow paracellular transport.
Reabsorption of glucose starts by active transport of  Na by the pumps on the basolateral membrane . This will create Na gradient which will cause Na to pass the apical membrane down its concentration gradient . Glucose also passes the membrane up its concentration gradient using sodium -glucose symporter as a secondary active transport.

The concentration of glucose will be increased in the cell and this will enable the glucose to pass down concentration gradient to the interstitium by glucose uniporter . Glucose will then pass to the peritubular capillaries by simple bulk flow.

Remember: Glucose reabsorption occurs via transcellular route .
          Glucose transport has transport maximum . In normal situation there is no glucose in the urine , but in uncontrolled diabetes mellitus patients glucose level exceeds its transport maximum (390 mg/dl) and thus will appear in urine .
                   
                   
                   
2. Reabsorption of Amino acids : Use secondary active transport mechanism like glucose.

3. Reabsorption of proteins : 

Plasma proteins are not filtered in Bowman capsule but some proteins and peptides in blood may pass the filtration membrane and then reabsorbed . Some peptides are reabsorbed paracellulary , while the others bind to the apical membrane and then enter the cells by endocytosis , where they will degraded by peptidase enzymes to amino acids .

4. Reabsorption of sodium , water , and chloride:

65 % of sodium is reabsorbed in the proximal tubules , while 25% are reabsorbed in the thick ascending limb of loob of Henle , 9% in the distal and collecting tubules and collecting ducts .
90% of sodium reabsorption occurs independently from its plasma level (unregulated) , This is true for sodium reabsorbed in proximal tubule and loop of Henle , while the 9% that is reabsorbed in distal ,collecting tubules and collecting ducts is regulated by Aldosterone. 

In proximal tubules : 65% of sodium is reabsorbed . The initial step occurs by creating sodium gradient  by sodium-potassium pump on the basolateral membrane . then the sodium will pass from the lumen into the cells down concentration gradient by sodium -glucose symporter , sodium -phosphate symporter and by sodium- hydrogen antiporter and others                    
                   
After reabsorption of sodium , an electrical gradient will be created , then chloride is reabsorbed following the sodium  . Thus the major cation and anion leave the lumen to the the interstitium and thus the water follows by osmosis . 65% of water is reabsorbed in the proximal tubule.

Discending limb of loop of Henle is impermeable to electrolytes but avidly permeable to water . 10 % of water is reabsorbed in the discending thin limb of loob of Henle .

The thick ascending limb of loop of Henly is permeable to electrolytes , due to the presence of Na2ClK syporter . 25% of sodium is reabsorbed here .

In the distal and collecting tubules and the collecting ducts 9% of sodium is reabsorbed .this occurs under aldosterone control depending on sodium plasma level. 1% of sodium is excreted .

Water is not reabsorbed from distal tubule but 5-25% of water is reabsorbed in collecting tubules .

Carbohydrates:

• about 3% of the dry mass of a typical cell
• composed of carbon, hydrogen, & oxygen atoms (e.g., glucose is C₆H₁₂O₆)
• an important source of energy for cells
• types include:
  • monosaccharide (e.g., glucose) - most contain 5 or 6 carbon atoms
  • disaccharides
    • 2 monosaccharides linked together
    • Examples include sucrose (a common plant disaccharide is composed of the monosaccharides glucose and fructose) & lactose (or milk sugar; a disaccharide composed of glucose and the monosaccharide galactose)
  • polysaccharides
    • several monosaccharides linked together

Examples include starch (a common plant polysaccharide made up of many glucose molecules) and glycogen (commonly stored in the liver)