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VETERINARY CLINICAL CARDIOLOGY
CARDIOLOGY CONCEPTS
Cardiovascular Physiology
Electro - Mechanical Association:
1. What occurs during the action potential with respect to Ca ions?
The action potential results in an influx of Ca into the cell.
  • Ca enters the cell via the long type Ca channels during the plateau phase of the action potential (Phase 2).
  • The entry of Ca into the cell is the first step toward contraction of the cell.
  • The entry of Ca into the cell does so because/as a result of the electrical excitation of the cell (depolarization).
2. How does the process of vascular smooth muscle contraction differ from myocardial contraction?
  • The production of cAMP in the myocardium induces contraction but inhibits myosin light chain kinase causing dilation in vascular smooth muscle.
  • Depolarization is not essential for the initiation of the contractile cycle in vascular smooth muscle, because it can be set off by the increase in Ca released from the SR by IP3 or increased Ca entry into the cell.
  • Peripheral vascular contraction is tonic, whereas cardiac contraction is short-lived and generates considerable force.
  • In the vascular smooth muscle Tn-C is absent from the actin filaments.
  • Ca regulates actin-myosin interaction by binding to calmodulin which promotes phosphorylation of the myosin light chain kinase which promotes cross bridging between actin and myosin.
  • 3. Describe the process of relaxation.
    For relaxation to occur a number of events must take place:
  • Cytosolic Ca must fall to promote:
    • The removal of Ca from binding sites of Tn-C to enable:
      • Tn-I, Tn-T and tropomyosin to take up their inhibitor roles hiding action binding sites to prevent the interaction of actin and myosin heads
  • Cytosolic Ca falls as it is taken up mainly into the SR where it is stored for the next contractile cycle
    • A transmembrane protein in the SR called SERCA (Sarcoendoplasmic Reticulum Ca ATPase) is a Ca pump that moves Ca into the SR.
    • At rest the SERCA pump is inhibited by the protein phospholamban, thus Ca movement into the SR is impaired. When phospholamban is phosphorylated by protein kinase A, the inhibition of SERCA is removed, allowing it to remove Ca from the cytoplasm.
  • Thus beta adrenergic stimulation initiates both contractility and relaxation. Relaxation is promoted by cAMP-mediated protein kinase A activation that promotes the activity of the SERCA pump reducing intracellular Ca. In addition, the increased Ca entry into the cell activates calmodulin which in turn enhances the activity of phosphodiesterase. Phosphodiesterase increases the rate of breakdown of cAMP. This in turn reduces Ca entry into the cell promoting relaxation.
  • 4. Why might one want to increase contractility?
    Some cardiac disorders are associated with a reduction in contractility. In these circumstances we attempt to enhance contractility.
    5. How can contractility be enhanced?
    Any process that increases the influx of Ca into the cell results in more Ca induced Ca release from the SR.

    Normally the Ca concentration in the cardiac cytosol during systole is such that the contractile sites are half activated. Thus the heart has considerable contractile reserve which can be used by increasing the Ca occupancy of the Tn-C binding sites.

    Beta adrenergic stimulation is the common method of increasing cytosolic Ca by increasing the flow of Ca across the Ca channel (L type) into the cell. This is mediated by increasing cytosolic cAMP.

    Inhibiting the degradation of cAMP (the second messenger of beta stimulation) also increases cytosolic Ca. Phosphodiesterase degrades cytosolic cAMP. Phosphodiesterase inhibitors thus increase cAMP.

    Blocking the Na/K-ATPase pump increases cytosolic Ca. As Na accumulates in the cell in the face of an inhibited Na/K pump, Na is extruded from the cell by way of the Na/Ca exchange mechanism and Ca accumulates in the cell. Digoxin functions by blocking the Na/K ATPase pump.

    Independent of increasing cytosolic Ca, contractility can be enhanced by increasing the affinity of Tn-C for Ca. Calcium sensitizers function this way (e.g. Pimobendan).

    6. How does contractility occur?
    The thin actin fibers slide between the thicker myosin fibers as a result of repetitive movements of the myosin heads. The sliding of the actin filament results in the Z lines approaching each other. The linkage between the myosin head and the actin filament is the crossbridge. The crossbridge cycle is the repetitive attachment and detachment of myosin heads to and from actin filaments.

    ATP is required for the process of attachment and detachment. The terminal phosphate bond of ATP is split off by myosin ATPase releasing energy for attachment.

    Crossbridging is inhibited at rest by both the avid binding of Tn-T and tropomyosin that promotes the positioning of the tropomyosin molecule which is twisted in such a way blocking the interaction of the myosin heads with actin.

    The binding of Ca to the Tn-C results in:

    • binding of activated Tn-C with Tn-I is strengthened, Tn-I moves, and this weakens the interaction between Tn-T and tropomyosin causing the tropomyosin to be repositioned on the thin filament and
    • the repositioning of the tropomyosin molecule exposes more binding sites on the actin molecule to myosin heads.
    7. What are the contractile proteins? Regulatory proteins? Structural proteins?
    A number of proteins are involved in contraction including:
  • Contractile Proteins:
    • Myosin: The thick filament contains the myosin heads that bind to actin.
    • Actin: The thin filament consist of 2 actin units that are intertwined in a helical pattern, both being carried on a heavier tropomyosin molecule that functions as a backbone. The actin units contain sites that bind to the myosin heads and contain the regulatory proteins.
  • Regulatory Proteins:
    • Tropomyosin: Part of the thin filament acts as a structural backbone to the actin helix. At rest tropomyosin is structurally positioned to obstruct the interaction of myosin heads with actin binding sites.
    • Troponin-I (Tn-I): Part of the troponin complex and it is positioned on the tropomyosin protein. I stands for inhibitor. When Tn-I is not bound tightly to Tn-C (tight binding occurs as a result of Ca activation), Tn-I promotes a tight interaction between Tn-T and tropomyosin that enables the position of tropomyosin to restrict the interaction between actin and the myosin heads. When Ca binds to Tn-C, activated Tn-C binds tightly to Tn-I. Tn-I now moves to a new position on the thin filament that causes a weakening of the interaction between Tn-T and tropomyosin. This promotes a conformational change (repositioning of tropomyosin on the thin filament) that exposes more actin binding sites to myosin heads.
    • Troponin-C (Tn-C): Part of the troponin complex and it is positioned on the tropomyosin protein. C stands for calcium. Tn-C is activated by Ca binding (the Ca released by the SR). This starts the contraction process (cross bridge cycling). Tn-C, thereby once activated by Ca, binds to Tn-I. Tn-I now moves to a new position on the thin filament causing a weakening of the interaction between Tn-T and tropomyosin. Tropomyosin now moves to expose more actin binding sites to cross bridge with myosin heads.
    • Troponin-T (Tn-T): Part of the troponin complex and it is positioned on the tropomyosin protein. T stands for tropomyosin binding. Tn-T links the whole troponin complex to tropomyosin. When Tn-T is tightly bound to tropomyosin, tropomyosin takes up a position on the thin filament that blocks most of the actin sites that could bind to myosin heads.
  • Structural Proteins:
    • Titin: Consists of 2 segments, an anchoring segment and an elastic segment. It is a very large molecule. Mutations in the titin gene have been incriminated in familial dilated cardiomyopathy in the Doberman Pinscher.
    • It has 2 major roles:
      • It tethers the myosin molecule to the Z line.
      • The folded elastic segment is important to allow the myocardium to regain its original shape in diastole by stretching during systole.
    8. How does calcium mediate contraction?
  • The massive increase in free cytosolic Ca results in Ca binding to troponin complex (specifically troponin C) resulting in a conformational change in the tropomyosin protein resulting in a release of the inhibition of tropomyosin on actin such that the actin sites are now exposed for binding to myosin head enabling cross-bridging and contraction.
  • At rest tropomyosin lays across the actin sites hiding them from the myosin heads to which they attach for contraction to occur.
  • 9. What is the significance of the concept calcium induced calcium release?
  • The calcium that enters the cell as a result of the action potential induces an avalanche of Ca to be released from the sarcoplasmic reticulum (SR) (a tenfold increase in cytosolic Ca compared to the flux of Ca across the cell membrane).
  • The Ca that enters the cell during the action potential binds to the ryanodine receptor of the terminal end of the SR. Binding to this receptor causes an avalanche of Ca, previously stored in the SR, to be released into the cytosol. This is called calcium induced calcium release.
  • 10. What are the following terms:
    a. Systole: refers to the contraction phase of the cardiac cycle.
      Begins at the onset of AV valve closure (onset of isovolumetric contraction) and continues to the closure of the semilunar valves (second heart sound).
    b. Diastole: refers to the filling phase of the cardiac cycle.
      Begins with the closure of the semilunar valves (onset of ventricular relaxation) to the end of ventricular filling (closure of the AV valves).
    c. Inotropy: refers to the ability of the heart to contract.

    d. Chronotropy: refers to the ability to increase heart rate.

    e. Lusitropy: refers to the ability of the heart to relax.

    f. Dromotropy: refers to the speed of conduction.

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