Events in Muscle Contraction - the sequence of events in crossbridge formation:

1) In response to Ca²⁺ release into the sarcoplasm, the troponin-tropomyosin complex removes its block from actin, and the myosin heads immediately bind to active sites.

2) The myosin heads then swivel, the Working Stroke, pulling the Z-lines closer together and shortening the sarcomeres. As this occurs the products of ATP hydrolysis, ADP and Pi, are released.

3) ATP is taken up by the myosin heads as the crossbridges detach. If ATP is unavailable at this point the crossbridges cannot detach and release. Such a condition occurs in rigor mortis, the tensing seen in muscles after death, and in extreme forms of contracture in which muscle metabolism can no longer provide ATP.

4) ATP is hydrolyzed and the energy transferred to the myosin heads as they cock and reset for the next stimulus.

Excitation-Contraction Coupling: the Neuromuscular Junction  

Each muscle cell is stimulated by a motor neuron axon. The point where the axon terminus contacts the sarcolemma is at a synapse called the neuromuscular junction. The terminus of the axon at the sarcolemma is called the motor end plate. The sarcolemma is polarized, in part due to the unequal distribution of ions due to the Sodium/Potassium Pump.

1) Impulse arrives at the motor end plate (axon terminus) causing  Ca²⁺ to enter the axon.

2) Ca²⁺ binds to ACh vesicles causing them to release the ACh (acetylcholine) into the synapse by exocytosis. 

3) ACH diffuses across the synapse to bind to receptors on the sarcolemma. Binding of ACH to the receptors opens chemically-gated ion channels causing Na⁺ to enter the cell producing depolarization.

4) When threshold depolarization occurs, a new impulse (action potential) is produced that will move along the sarcolemma. (This occurs because voltage-gated ion channels open as a result of the depolarization -

5) The sarcolemma repolarizes:

a) K⁺ leaves cell (potassium channels open as sodium channels close) returning positive ions to the outside of the sarcolemma. (More K⁺ actually leaves than necessary and the membrane is hyperpolarized briefly. This causes the relative refractory period) (b) Na⁺/K⁺ pump eventually restores resting ion distribution.  The  Na⁺/K⁺ pump is very slow compared to the movement of ions through the ion gates. But a muscle can be stimulated thousands of times before the ion distribution is substantially affected.

6) ACH broken down by ACH-E (a.k.a. ACHase, cholinesterase). This permits the receptors to respond to another stimulus. 

Excitation-Contraction Coupling:

1) The impulse (action potential) travels along the sarcolemma. At each point the voltaged-gated Na+ channels open to cause depolarization, and then the K+ channels open to produce repolarization.

2) The impulse enters the cell through the T-tublules, located at each Z-disk, and reach the sarcoplasmic reticulum (SR), stimulating it.

3) The SR releases Ca²⁺ into the sarcoplasm, triggering the muscle contraction as previously discussed. 

4) Ca²⁺ is pumped out of the sarcoplasm by the SR and another stimulus will be required to continue the muscle contraction.

HEART DISORDERS

1. Pump failure => Alters pressure (flow) =>alters oxygen carrying capacity.
   1. Renin release (Juxtaglomerular cells) Kidney
   2. Converts Angiotensinogen => Angiotensin I
   3. In lungs Angiotensin I Converted => Angiotensin II
   4. Angiotensin II = powerful vasoconstrictor (raises pressure, increases afterload)
      1. stimulates thirst
      2. stimulates adrenal cortex to release Aldosterone
         (Sodium retention, potassium loss)
      3. stimulates kidney directly to reabsorb Sodium
      4. releases ADH from Posterior Pituitary
2. Myocardial Infarction

    

   1. Myocardial Cells die from lack of Oxygen
   2. Adjacent vessels (collateral) dilate to compensate
   3. Intracellular Enzymes leak from dying cells (Necrosis)
      1. Creatine Kinase CK (Creatine Phosphokinase) 3 forms
         1. One isoenzyme = exclusively Heart (MB)
         2. CK-MB blood levels found 2-5 hrs, peak in 24 hrs
         3. Lactic Dehydrogenase found 6-10 hours after. points less clearly to infarction
      2. Serum glutamic oxaloacetic transaminase (SGOT)
         1. Found 6 hrs after infarction, peaks 24-48 hrs at 2 to 15 times normal,
         2. SGOT returns to normal after 3-4 days
   4. Myocardium weakens = Decreased CO & SV (severe - death)
   5. Infarct heal by fibrous repair
   6. Hypertrophy of undamaged myocardial cells
      1. Increased contractility to restore normal CO
      2. Improved by exercise program
   7. Prognosis
      1. 10% uncomplicated recovery
      2. 20% Suddenly fatal
      3. Rest MI not fatal immediately, 15% will die from related causes
3. Congenital heart disease (Affect oxygenation of blood)
   1. Septal defects
   2. Ductus arteriosus
   3. Valvular heart disease
      1. Stenosis = cusps, fibrotic & thickened, Sometimes fused, can not open
      2. Regurgitation = cusps, retracted, Do not close, blood moves backwards

Vital Capacity: The vital capacity (VC) is the maximum volume which can be ventilated in a single breath. VC= IRV+TV+ERV. VC varies with gender, age, and body build. Measuring VC gives a device for diagnosis of respiratory disorder, and a benchmark for judging the effectiveness of treatment. (4600 ml)

Vital Capacity is reduced in restrictive disorders, but not in disorders which are purely obstructive.

The FEV₁ is the % of the vital capacity which is expelled in the first second. It should be at least 75%. The FEV₁ is reduced in obstructive disorders.

Both VC and the FEV₁ are reduced in disorders which are both restrictive and obstructive

Oxygen is present at nearly 21% of ambient air. Multiplying .21 times 760 mmHg (standard pressure at sea level) yields a pO₂ of about 160. Carbon dioxide is .04% of air and its partial pressure, pCO₂, is .3.

With alveolar air having a pO₂ of 104 and a pCO₂ of 40. So oxygen diffuses into the alveoli from inspired air and carbon dioxide diffuses from the alveoli into air which will be expired. This causes the levels of oxygen and carbon dioxide to be intermediate in expired air when compared to inspired air and alveolar air. Some oxygen has been lost to the alveolus, lowering its level to 120, carbon dioxide has been gained from the alveolus raising its level to 27.

Likewise a concentration gradient causes oxygen to diffuse into the blood from the alveoli and carbon dioxide to leave the blood. This produces the levels seen in oxygenated blood in the body. When this blood reaches the systemic tissues the reverse process occurs restoring levels seen in deoxygenated blood.

GENERAL VISCERAL AFFERENT (GVA) PATHWAYS

Pain and Pressure Sensation via the Spinal Cord

Visceral pain receptors are located in peritoneal surfaces, pleural membranes, the dura mater, walls of arteries, and the walls of the GI tube.

Nociceptors in the walls of the GI tube are particularly sensitive to stretch and overdistension.

General visceral nociceptors conduct signals into the spinal cord over the monopolar neurons of the posterior root ganglia. They terminate in laminae III and IV of the posterior horn as do the pain and temperature pathways of the GSA system , their peripheral processes reach the visceral receptors via the gray rami communicantes and ganglia of the sympathetic chain

Second-order neurons from the posterior horn cross in the anterior white commissure and ascend to the thalamus in the anterior and lateral spinothalamic tracts,

Projections from the VPL of the thalamus relay signals to the sensory cortex.

The localization of visceral pain is relatively poor, making it difficult to tell the exact source of the stimuli.

Blood Pressure, Blood Chemistry, and Alveolar Stretch Detection

The walls of the aorta and the carotid sinuses contain special baroreceptors (pressure receptors) which respond to changes in blood pressure. These mechanoreceptors are the peripheral endings of GVA fibers of the glossopharyngeal (IX) and vagus (X) nerves

The GVA fibers from the carotid sinus baroreceptors enter the solitary tract of the brainstem and terminate in the vasomotor center of the medulla (Fig-14). This is the CNS control center for cardiovascular activity.

Stretch receptors in the alveoli of the lungs conduct information concerning rhythmic alveolar inflation and deflation over GVA X fibers to the solitary tract and then to the respiratory center of the brainstem. This route is an important link in the Hering-Breuer reflex, which helps to regulate respiration.

Carotid body chemoreceptors, sensitive to changes in blood PO2 and, to a lesser extent, PCO2 and pH, conduct signals to both the vasomotor and respiratory centers over GVA IX nerve fibers

GVA X fibers conduct similar information from the aortic chemoreceptors to both centers

The Nerve Impulse

When a nerve is stimulated the resting potential changes. Examples of such stimuli are pressure, electricity, chemicals, etc. Different neurons are sensitive to different stimuli(although most can register pain). The stimulus causes sodium ion channels to open. The rapid change in polarity that moves along the nerve fiber is called the "action potential." In order for an action potential to occur, it must reach threshold. If threshold does not occur, then no action potential can occur. This moving change in polarity has several stages:

Depolarization

The upswing is caused when positively charged sodium ions (Na+) suddenly rush through open sodium gates into a nerve cell. The membrane potential of the stimulated cell undergoes a localized change from -55 millivolts to 0 in a limited area. As additional sodium rushes in, the membrane potential actually reverses its polarity so that the outside of the membrane is negative relative to the inside. During this change of polarity the membrane actually develops a positive value for a moment(+30 millivolts). The change in voltage stimulates the opening of additional sodium channels (called a voltage-gated ion channel). This is an example of a positive feedback loop.

Repolarization

The downswing is caused by the closing of sodium ion channels and the opening of potassium ion channels. Release of positively charged potassium ions (K+) from the nerve cell when potassium gates open. Again, these are opened in response to the positive voltage--they are voltage gated. This expulsion acts to restore the localized negative membrane potential of the cell (about -65 or -70 mV is typical for nerves).

Hyperpolarization

When the potassium ions are below resting potential (-90 mV). Since the cell is hyper polarized, it goes to a refractory phrase.

Refractory phase

The refractory period is a short period of time after the depolarization stage. Shortly after the sodium gates open, they close and go into an inactive conformation. The sodium gates cannot be opened again until the membrane is repolarized to its normal resting potential. The sodium-potassium pump returns sodium ions to the outside and potassium ions to the inside. During the refractory phase this particular area of the nerve cell membrane cannot be depolarized. This refractory area explains why action potentials can only move forward from the point of stimulation.

Factors that affect sensitivity and speed

Sensitivity

Increased permeability of the sodium channel occurs when there is a deficit of calcium ions. When there is a deficit of calcium ions (Ca+2) in the interstitial fluid, the sodium channels are activated (opened) by very little increase of the membrane potential above the normal resting level. The nerve fiber can therefore fire off action potentials spontaneously, resulting in tetany. This could be caused by the lack of hormone from parathyroid glands. It could also be caused by hyperventilation, which leads to a higher pH, which causes calcium to bind and become unavailable.

Speed of Conduction

This area of depolarization/repolarization/recovery moves along a nerve fiber like a very fast wave. In myelinated fibers, conduction is hundreds of times faster because the action potential only occurs at the nodes of Ranvier (pictured below in 'types of neurons') by jumping from node to node. This is called "saltatory" conduction. Damage to the myelin sheath by the disease can cause severe impairment of nerve cell function. Some poisons and drugs interfere with nerve impulses by blocking sodium channels in nerves. See discussion on drug at the end of this outline.

Abnormalities of Salt, Water or pH

• Examples:
  • Hyperkalemia: caused by kidney disease & medical malpractice
    • High K+ in blood- can stop the heart in contraction (systole)
  • Dehydration: walking in desert- can lose 1-2 liters/hour through sweat
    • Blood becomes too viscous to circulate well -> loss of temperature regulation -> hyperthermia, death
  • Acidosis: many causes including diabetes mellitus and respiratory problems; can cause coma, death