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48 Cards in this Set
- Front
- Back
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What is tropomyosin?
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An actin-binding protein that helps regulate muscle contraction by regulating the binding of myosin.
It inhibits myosin binding in the resting state. |
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What are the 3 units of the troponin complex and what are their significance?
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Troponin C - Calcium binding to troponin C increases its interaction with Troponin I. This causes the tropomyosin complex to shift which allows myosin to bind actin.
Troponin I - inhibits the actin myosin complex from forming Troponin T - Anchors Troponin to actin and tropomyosin. |
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What would an increase in PKA have on this complex?
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It increases TnI-TnC affinity and releases actin-myosin inhibition.
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Describe the 4 steps of muscle contraction.
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1) ATP hydrolysis by myosin to ADP +P
2) SR Ca binds TnC, alters Tn-Tm, allows acto-myosin formation at 90 degrees 3) ADP + P dissociate from myosin which induces a 45 degree bend (powerstroke) 4) ATP binds myosin, actin-myosin and Ca-TnC complexes dissociate and sarcomere resets |
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What is the Frank-Starling law?
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Greater end diastolic volume - Greater systolic stroke volume.
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What 3 things occur with a greater myocyte stretch (relaxation)?
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- More calcium-TnC and actin-myosin binding sites
- More calcium release from SR - Greater power-stroke during systole |
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Describe the coupling of pacemaker induced depolarization to muscle contraction.
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The pacemaker causes a wave of depolarization. This wave activates voltage-gated Calcium channels on the sarcolemma of muscle cells. Calcium influx occurs into the cell which triggers Calcium release from the Sarcoplasmic reticulum. This Calcium is free to bind to muscle machinery and activate muscle contraction.
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What type of channel is the voltage-gated Ca channel?
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L-type Calcium channel
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Discuss the regulation of calcium across the sarcolemma.
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3 Pumps
Na/K ATPase Pump - Maintain's RMP and Na/K gradients Na/Ca exchanger (NCX) - coupled with Na/K ATPase Pump. A bidirectional exchange of Na and Ca - dependent on ion concentrations Ca ATPase Pump - extrudes Ca from myocyte. |
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Discuss the regulation of calcium across the sarcoplasmic reticulum.
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Ryanodine Receptor - Ca sensitive calcium release. The trigger is Ca through the L-type Ca channel activation. This opens the ryanodine receptor (functional coupling)
ATP favors channel opening |
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What is the SERCA?
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Sarco/Endoplasmic reticulum Ca-ATPase
Pumps Ca from cytosol into Sarcoplasmic reticulum |
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What two things increase its activity?
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Ca and ATP
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What inhibits its activity?
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Phospholamban (PLB) - Controls rate of myocyte relaxation by controlling Ca uptake into the SR
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Discuss the regulation of calcium across the sarcolemma.
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3 Pumps
Na/K ATPase Pump - Maintain's RMP and Na/K gradients Na/Ca exchanger (NCX) - coupled with Na/K ATPase Pump. A bidirectional exchange of Na and Ca - dependent on ion concentrations Ca ATPase Pump - extrudes Ca from myocyte. |
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Discuss the regulation of calcium across the sarcoplasmic reticulum.
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Ryanodine Receptor - Ca sensitive calcium release. The trigger is Ca through the L-type Ca channel activation. This opens the ryanodine receptor (functional coupling)
ATP favors channel opening |
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What is the SERCA?
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Sarco/Endoplasmic reticulum Ca-ATPase
Pumps Ca from cytosol into Sarcoplasmic reticulum |
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What two things increase its activity?
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Ca and ATP
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What inhibits its activity?
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Phospholamban (PLB) - Controls rate of myocyte relaxation by controlling Ca uptake into the SR
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What relieves the inhibition induced by PLB?
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PKA-mediated phosphorylation
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Beta 1 activation stimulated adenylate cyclase and increases cAMP which activates PKA. Describe the effects of PKA on muscle contraction.
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- PKA stimulates L-type Ca-channel opening therefore increasing intracellular Ca. Conversely, it phosphorylates PLB thereby relieving its inhibition on SERCA. This allows Ca to be stored more easily into the SR after contraction takes place.
- PKA also increases TnI-TnC affinity thereby facilitating muscle contraction while also decreasing Ca-TnC affinity which allows Ca to be stored more quickly after contraction |
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Beta stimulation via the sympathetic nervous system produces positive inotropic, chronotropic, and lusitropic effects. Talk about how each of these effects are produced.
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Inotropic - Increased Ca during systole
- Increased blood pumped Chronotropic - SA nodal effects Lusitropic - Increased diastolic relaxation. Increased blood pumped |
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What is the consequence of a CV pathology on the heart? (MI, Ischemia, Hypertension)
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Increased deposition of ECM leading to fibrosis and eventually HF.
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HF patients exhibit decreased Ca homeostasis. Describe the two things that lead to this effect.
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1) Decreased PLB which would increase the amount of Ca being pumped into the Sarcoplasmic Reticulum
2) Increased NCX expression which would increase Calcium pumped out of the cell across the sarcolemma and too much Na pumped into the cytosol. |
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HF patients have altered regulation/expression of contractile proteins. Discuss the two things that lead to this effect.
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1) Decreased TnI phosphorylation which would lead to decreased affinity for TnC and decreased contraction.
2) Decreased efficiency of myosin ATPase which would inhibit muscle contraction |
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HF patients have altered Beta Adrenergic Receptor signaling. Discuss the two things that lead to this effect.
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1) Increased SNS input to compensate for increased CO. This leads to Beta receptor desensitization/downregulation. This leads to a decreased ability of the autonomic nervous system to increased CO output in stressful situations.
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What is the mechanism of Cardiac Glycosides? Example? Long or short term?
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Increased intracellular Ca
Digoxin Long-term |
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What is the mechanism of Beta-AR agonists? Example? Long or short term?
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Increased cAMP
Dobutamine Dopamine Short-term |
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What is the mechanism of Beta-AR antagonists? Example? Long or short term?
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Block SNS, restore Beta-AR signaling
Carvediolol Metoprolol Bisoprolol Long-term |
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What is the mechanism of PDE3 Inhibitors? Example? Long or short term?
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Increase cAMP
Milrinone Inamrinone Short-term |
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What is the mechanism of Ca-sensitizers?
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Increase TnC sensitivity to Ca
Levosimendan Short-term |
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Name 3 Cardiac Glycosides.
How do these compounds increase intracellular Ca? |
Digoxin
Digitoxin Ouabain They inhibit Na/K ATPase |
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Describe how the inhibition of the Na/K ATPase increased intracellular Ca levels?
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The Na/K ATPase pumps Na out and K in. If inhibited, Na can't be pumped out and levels inside increase. In the Ca/Na exchanger, Na is pumped in but this is inhibited by the increased Na buildup in the cell and therefore Ca can't be pumped out. Ca levels also increase as a result.
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What do these increased Ca levels lead to?
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Increased Ca into SR
Increased Ca release from SR so more Ca TnC binding and stronger contraction Therefore positive inotropy |
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Digoxin inhibits Na pumps throughout the body. Name 3 main effects outside of the heart.
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1) Decreased SNS outflow
2) Prolonged refractory period/decreased conduction velocity 3) Increased automaticity in ventricular conduction system leading to escape rhythm |
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How is drug eliminated?
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Renal
Digitoxin can be used as a substitute in renally compromised patients but has a half life of 7 days vs 36 hours for digoxin |
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What is the pharmacodynamic DDI's related to digoxin?
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Beta Blockers have a additive or synergistic decrease in AV conduction leading to Heart Block
Beta Blockers/CCB's attenuate the effects of digoxin on contractility (physiologic antagonism) |
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What are the pharmacokinetic DDI's related to digoxin?
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Antibiotics kill gut bacteria that would normally metabolize digoxin and increase absorption
Some antiarrhythmics can alter distribution/clearance of digoxin |
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Beta-AR agonists (catecholamines) are chronotropic, inotropic, and lusitropic but cannot be used for a long period of time. Why?
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Long term treatment with positive inotropes is assocaited with increased mortality in HF patients.
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Discuss Dopamine's relative receptor targets, local effects, outcomes and inidcations
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D1 - low = Vasodilation (Decreased afterload)
B1 - intermediate = Increased contraction, HR (Increased CO) A1 - high = Vasoconstriction (Increased afterload) Sepsis, anaphylaxis |
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Discuss Dobutamine relative receptor targets, local effects, outcomes and inidcations
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B1 - strong = Increased contraction, HR (Increased CO)
B2 - weak = Vasodilation (decreased afterload) Acute HF |
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Discuss Epinephrine relative receptor targets, local effects, outcomes and inidcations
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B1 - low and high = Increased contraction, HR (Increase CO)
B2 - low = Vasodilation (Decreased afterload A1 - high = Vasoconstriction (Increased afterload) Resuscitation, Bronchospasm |
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Discuss Norepinephrine relative receptor targets, local effects, outcomes and inidcations
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B1 - strong = Increased contraction, HR (Increased CO)
A1 - strong = Vasoconstriction (Increased afterload) Shock |
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Discuss Isoproterenol relative receptor targets, local effects, outcomes and indcations
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B1 - strong = Increased HR, contraction (Increase CO)
B2 - less than B1 = Vasodilation (decreased afterload) Bradycardia Beta-blocker overdose |
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How are Beta Blockers used in the long term treatment of HF?
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They counter the increased stimulation of the SNS and therefore decrease desensitization and down-regulation
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What is the mechanism of PDE3 inhibitors in treating HF?
Name 2 of these drugs. |
Milrinone
Inamrinone They inhibit the metabolism of cAMP by PDE3. Increased cAMP stimulates more PKA, stimulates contraction. |
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Why is it known as an inodilator?
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It also dilates blood vessels thereby increasing CO and decreasing after-load. It is shown to increase mortality with chronic use however and only used in the short term.
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How do Calcium sensitizing agents work?
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They stabilize the Ca bound conformation of TnC primarily
Secondarily, they open K channels in peripheral circulation causing vasodilation and inhibit PDE3 causing vasodilation and increase contraction |
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An increase in mortality in HF patients is associated with long-term use of agents that increase this intracellularly.
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cAMP
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