1. (16 pts) Describe the mechanism of regulation of contraction of skeletal muscles and smooth muscles by cytoplasmic Ca²⁺.

Answer: Contraction of both skeletal and smooth muscles involves ATP-powered interaction between myosin and actin. Cytoplasmic Ca²⁺ regulates this interaction. In skeletal muscle, this is done through a steric mechanism. In smooth muscle, this is done through a biochemical pathway.

Skeletal muscle:

1) When [Ca²⁺]_i is low, myosin and actin don’t interact with each other, because this interaction is inhibited by tropomyosin that lies in between them ("off-position").

2) When [Ca²⁺]_i increase, Ca²⁺ binds to troponin C (one of the three subunits of troponin), triggering a conformation change in troponin.

3) Activated troponin T (another subunit of troponin) pulls tropomyosin away from the "off-position", allowing myosin-actin interaction and power stroke to take place.

4) When [Ca²⁺]_i lowers again, Ca²⁺ ions dissociate from troponin C and troponin T releases tropomyosin, which then slides back into the "off-position", blocking the myosin-actin interaction and contraction.

Smooth muscle:

1) Smooth muscle cells lack tropomyosin and troponin. Instead of using a steric mechanism, Ca²⁺ works through a biochemical cascade.

2) Ca²⁺ binds to calmodulin (CaM), forming an activated complex CaM-Ca²⁺;

3) CaM-Ca²⁺ complexes with and activates myosin light chain kinase (MLCK), which becomes dephosphorylated in the active form;

4) Activated MLCK phosphorylates the myosin light chain and thereby increases the ATPase activity of the myosin head such that ATP-powered contraction can occur.

5) The biochemical pathways outlined above reverse when [Ca²⁺]_i drops.

2. (11 pts) a) Define the properties of a motor unit.

Answer:

1. A motor unit consists of a motor neuron and all the skeletal muscle fibers it innervates. It is the smallest contraction unit.
2. All the muscle fibers in a motor unit are of the same type.
3. A muscle fiber receives innervation from only a single motor neuron.

b) Explain how the nervous system grades the force of skeletal muscle contraction?

Answer:

1. By recruitment of motor units: motor neurons and the muscle fibers they innervate are recruited according to the "size principal". Small, low-threshold MNs are recruited first and the muscle fibers they innervate are more resistant to fatigue. Large, high-threshold MNs are recruited later.
2. By increasing the action potential firing frequency of a given motor unit. This results in the summation of force generated by a given muscle fiber. When the frequency is high enough, tetanus can occur.

3. (11 pts) Your hand accidentally touched a burning cigarette and withdrew rapidly and unconsciously. What is this reflex? Describe this reflex and use a diagram to illustrate the neural pathways involved. Label all the major elements in the diagram. For simplicity, assuming that only the biceps and triceps muscles participate in the reflex.

Answer:

1) This is a flexion reflex;

2) The flexion reflex is polysynaptic;

3) The burning cigarette activates nocirecptors (sensory neurons) on the hand, which send action potentials down to axon branches in the spinal cord;

4) One axon branch activates excitatory interneurons which in turn activates motoneurons controlling the biceps muscle (a flexor), resulting in a contraction and withdrawing of the hand;

5) Another axon branch activates excitatory interneurons, which in turn activate inhibitory interneurons, which then inhibit motoneurons controlling the triceps muscle (an extensor), resulting in relaxation of this muscle group.

4. (11 pts) Describe the mechanism of regulation of heart rate by each branch of the autonomic nervous system.

Answer:

Sympathetic stimulation ® increase of NE release ® NE binds to beta1 receptors in the pacemaker cells in the SA node ® (G proteins ® adenylate cyclase ® cAMP ® PKA) ® increase the activity of I_f and calcium channels ® faster pacemaker activity ® higher heart rate.

Parasympathetic stimulation ® increase of ACh release ® ACh binds to M2 muscarinic receptors in the pacemaker cells in the SA node ® G proteins ® Gb g subunits activate K_ACh channels ® hyperpolarization ® slower pacemaker activity ® slower heart rate.

5. (16 pts) a) Explain the Frank-Starling Law of the Heart and draw a Frank-Starling curve for a normal heart, a heart upon sympathetic stimulation and a failing heart (a condition in which the heart is unable to contract forcefully).

Answer:

The Frank-Starling Law states that, within physiological limits, stroke volume (or the force of heart muscle contraction) is proportional to the end-diastolic volume (or stretch of the heart muscles). It basically means that the heart pumps out the blood returned to it.

Answer:

1) One mechanism used by cardiac muscle cells to maintain a low concentration of cytoplasmic Ca²⁺ is to extrude Ca²⁺ to the external solution by the Na⁺/Ca²⁺ exchangers on the plasma membrane;

2) Na⁺/K⁺-ATPases are required to maintain the Na⁺ (and K⁺) concentration gradient across the plasma membrane;

3) When they are inhibited by digitoxin or ouabain, the cytoplasmic Na⁺ concentration rises and thus reduces the Na⁺ concentration gradient;

4) This leads to a decrease in the activity of the Na⁺/Ca²⁺ exchangers and consequently an increase in the Ca²⁺ concentration in the cytoplasm;

5) Cardiac muscle contraction is graded, depending on the cytoplasmic Ca²⁺ concentration. More Ca²⁺ leads to more forceful contraction.

6. (16 pts) Tin Man gets dizzy very often and sometimes faints. His doctor measured his ECG and told him that he most likely had a condition known as the complete heart block.

a) Explain the clinical cause of complete heart block.

A: In complete heart block, electrical conduction from the SA node to the AV node is completely blocked and the AV node cannot function. Thus, the atria contract under the pacemaker activity of the SA node while the ventricles contract independently under the pacemaker activity of the Purkinje fibers.

b) Draw a trace of Tin Man's ECG (lead II) and label all the important components. What would his heart rate most likely be?

A: P wave at 35/min, QRS and T waves occur at 70/min

His heart rate (in this case = pulse rate) is ~30-35 beats/min. This rate is generated by the Purkinje fibers.

c) Is Tin Man's cardiac output higher or lower than a normal person and why?

A: Lower. CO = stroke volume x heart rate. Tin Man's stroke volume is probably not changed very much. However, his slower heart rate decreases CO (A normal person has a heart rate of ~70 beats/min).

d) Why does Tin Man gets dizzy very often and faints easily? How can his condition be improved?

A: Because his brain receives insufficient blood and, hence, oxygen, supply as a result of a decreased cardiac output. His condition can be improved by implanting an artificial cardiac pacemaker that simulates the ventricles at 70 times/min.

7. (13 pts) John Dolittle is overweight and exercise rarely. During his annual physical checkup, he found that his blood pressure readings were 160/100.

1. What is his systolic pressure, diastolic pressure, pulse pressure and mean arterial pressure (MAP)?

A: systolic pressure = 160 mm Hg, diastolic pressure = 100 mm Hg, pulse pressure = 160 -100 = 60 mm Hg, MAP = 100 + 60/3 = 120 mm Hg.

b) Describe the potential major factors that may contribute to his high MAP.

A: MAP µ (stroke volume x heart rate) x peripheral resistance

1) The most likely factor is an increased arterial resistance, possibly due to high LDL.

2) High salt intake ® more water reabsorption ® increased blood volume

3) An increased heart rate (less likely)

c) John's doctor discussed with him two antihypertensive drugs that can be used to lower his blood pressure, verapamil (a calcium channel blocker) and phentolamine (an a -adrenergic receptor blocker). Explain how each of these two drugs would lower MAP.

A: Verapamil:

1) block of calcium channels in the heart (ventricles) ® decreased force of ventricular contraction ® decreased stroke volume ® lower MAP

2) block of calcium channels in the blood vessel smooth muscles ® decreased contraction as a result of reduced contractility and reduced vasoconstriction ® vasodilation ® decreased arterial resistance ® lower MAP

Phentolamine:

Much of the peripheral resistance comes from arterioles, which maintain a constricted basal tone under the tonic sympathetic input. NE secreted from the sympathetic nerve terminals bind to a -adrenergic receptors to cause this vasoconstriction. Blocking these receptors will thus cause vasodilation ® decreased arterial resistance ® lower MAP.

8. (6 pts) Briefly describe two key pieces of evidence obtained by Furchgott and Zawadzki demonstrating that ACh causes vasodilation through the release of EDRF. What is the molecular identify of EDRF?

Answer:

1. ACh does not cause vasodilation if the endothelial cells are removed from isolated blood vessels, indicating the endothelial cells are necessary.
2. When an isolated stripe of blood vessel devoid of endothelial cells are sandwiched by blood vessel stripes with an intact endothelium, ACh can then cause vasodilation of all the blood vessels, indicating that endothelial cells secrete a diffusable relaxing factor.
3. EDRF is nitric oxide.