The duration of the cardiac AP is similar to the duration of contraction. What is a result?
Cardiac muscle cannot be tetanized bc relaxation is mostly completed by the end of the AP. This is a protective mechanism.
How are cardiac cells in the ventricles and atria depolarized? How is Ca2+ released and what is this process called?
The cardiac AP iniates contraction of the heart. Depolarization of the membrane by voltage gated Na+ channels in the sarcolemma and T-tubules causes the opening of voltage gated Ca2+ channels in the sarcolemma and T-tubules which allow Ca2+ to flow down its concentration gradient into the cell (in atria and ventricles). The SR contains Ca2+ release channels, or ryanodine receptors, that sense the high cytoplasmic Ca2+ concentration and open to release Ca2+ from the SR. This is called calcium-induced calcium release. Ca2+ then binds to TnC to allow for myosin to interact with actin and cause contraction.
What is dystrophin? What are proposed fxns of the dystrophin-glycoprotein (DCG) complex? What diseases are associated with mutations of this complex?
1. Dystrophin is a rod-shaped protein that attaches to non-sarcomeric actin of the cytoskeleton intracellularly on one end adn to membrane associated proteins at the other. Some of these proteins span the membrane and are attached to other proteins that are in turn associated with the ECM (e.g. laminin).
2. -membrane stability: stabilization of the membrane during repeated cycles of contraction. complex anchors inside of cell to extracellular matrix to allows for
ease of contraction. contraction generates force and if membrane is the only connection, then the membrane would collapse. need this complex to form this connection to bear the load of contraction. scientists believe membrane tears occur in muscular dystrophy
-force transduction (linking contractile force produced inside the muscle cell to the extracelluar environment)
-orgainization of membrane specializations
- in cardiac muscle, dystrophin has been shown to be associated with the contractile apparatus at the Z lines and may therefore be involved in the organization of sarcomeres and myofibrils.
3. mutations in dystrophin and the DGC are associated with muscular dystrophy and dilated cardiomyopathies
How does the myoplasmic concentration of Ca2+ relate to force of contraction? How does cardiac muscle reduce Ca2+ concentration to allow for relaxation?
The higher the Ca2+ concentration achieved in the myoplasm durin an AP, the more forceful will be the resulting contraction. (positive inotropic drugs usually increase Ca2+ concentration)
Contraction ends shortly after the end of the cardiac AP (note however that diff cardiac cells have diff APs and thus periods of contraction of diff durations).
As the membrane potential returns to resting at the end of the AP, voltage gated Ca2+ channels in the sarcolemma and T-tubules close. The cease of Ca2+ influx stops calcium-induced calcium release from the SR. Ca2+ is partially sequestered back into the SR by Ca2+ pumps. Ca2+ pumps are also in the sarcolemma. Na+/Ca2+ exchangers are also in the sarcolemma. Note that these exchangers are electrogenic bc they allow 3 Na+ into the cell for every 1 Ca2+ that is pushed out of the cell. Contraction ends as Ca2+ concentration falls around the contractile proteins within the heart cells.
True or false: Mutations in some contractile proteins can result in hypertrophic cardiomyopathy.
What parts of the heart does the sympathetic nervous system innervate? What parts of the heart does the parasympathetic nervous system innervate? What parasympathetic nerve releases NT on the heart and what receptors does this NT bind to? What NTs are released by the sympathetic nervous system and what receptor do they bind to?
Remember that sympathetic and parasympathetic NS are branches of the autonomic NS.
Both branches innervate the heart. The sympathetic NS innervates the walls of the ventricles and atria as well as the SA and AV nodes (but has no effect on ventricular contraction). The parasympathetic NS innervates the SA node, AV node, and the atria (have little effect on the ventricles).
Sympathetic NS releases norepinephrine (NE) on the heart. NE (and also circulating epinephrine, E) bind to ß adrenergic receptors (mostly type 1, but there are some ß2 receptors in the heart). The vagus nerve of the parasympathetic NS releases ACh which binds to M2 muscarinic receptors. Both are GPCRs.
What cellular changes occur when NE binds to ß1 adrenergic receptors in the heart? What changes to the heart does this result in?
NE binds to ß1 adrenergic receptors and activates Gs which stimulates adenylyl cyclase. Adenylyl cyclase converts ATP to cAMP which activates PKA. Active PKA phosphorylates Ca2+ channels (L and T-type), Pacemaker channels (allow Na+ and K+ flow which depolarizes membrane), and K+ channels. It also phophorylates the SR Ca2+ pump (stimulating it) and phosphorylates troponin causing it to have a lower affinity for Ca2+. Phosphodiesterase terminates the response by turning cAMP into AMP.
1. positive chronotropic effect: increases heart rate by acting on the SA node. Opens more Ca2+ channels (Ca2+ is responsible for the upstroke of the SA AP). More Ca2+ allows for the SA node to hit threshold faster and fire more APs. Opening of pacenaker channels also depolarizes the membrane faster and increases HR.
2. Increased conuduction velocity of AV node: Opening more Ca channels increases conduction velocity and decreases the AV nodal delay
3. Inotropic effect: increased force of contraction in atria and ventricles due to increased Ca2+ release. More Ca2+ enters myoplasm from Ca2+ channels in sarcolemma results in more calcium-induced calcium release which increases the force of contraction
4. Shortened AP duration: delayed rectifier K+ (and cAMP dependent Cl-) channels repolarize membrane faster. These channels open more rapidly and are open a greater fraction of the time (remember that K+ is responsible for repolarization. if open more rapidly, will shorten AP duration)
5. Increased Ca2+ removal by the SR Ca2+ pump (due to phosphorylation of phospholamban). This shortens contraction and increases the rate of relaxation. This also causes more Ca2+ to be in the SR which means more Ca2+ can be released during systole which increases the force of contraction.
6. Increased rate of relaxation reduced contraction duration) due dc sensitivity of TnI (due to phosphorylation by PKA, TnI cannot inhibit myosin and actin binding). Although troponin sensitization goes down, more Ca2+ still binds bc have increased Ca2+ entrance into cell which increases Ca2+ release. Decrased sensitization increases the rate of relaxation bc Ca2+ binds with less affinity and unbinds already bound troponin faster. Want this in higher heart rates bc want to get ready for the next beat.
7. Altered gating of the SR Ca2+ release channel (RyR) leading to enhanced Ca2+ (still under investigation)
Note that shortening of AP goes hand in hand with shortening of contraction.
What are the effects of the parasympathetic nervous system on the heart and how are these effects achieved? (how does ACh causes cellular changes)
Main effects are:
1. decreased heart rate
2. decreased AP conduction velocity at the AV node (increased AV nodal delay)
3. decreased force of atrial contraction
ACh binds to M2 muscarinic receptors in the SA node, AV node, and atria (these receptors are sparse or absent in ventricle as are parasympathetic nerve terminals). Binding of ACh to M2 muscarinic receptors activates the G protein Gi which inhibits adenylyl cyclase. This results in less cAMP and less activated PKA which has opposite effect than those of sympathetic innervation. Muscuarinic receptors also activate a resting K+ channel (diff than delayed rectifier channel that is activated in sympathetic innervation).
The slowing of pacemaker activity at the SA node (i.e. reduced heart rate) is brought about by the activation fo these K+ channels as well as the inhibition (de-phophosphorylation) of Ca2+ channels. Inhibition of pacemaker channels may also be involed. These same channels are also responsible for the reduced velocity of the AP at the AV node-increased AV nodal delay.
The reduced force of contraction (negative inotropic effect) in the atria is primarily the result of the inhibition of Ca2+ channels which results in less Ca2+ entering the muscle fibers during the atrial AP and thus a weaker contraction.
Describe tone as it relates to the sympathetic and parasympathetic NS.
There is always a certain amount of symathetic stimulation-just becomes increased or decreased. There is a balance btwn the two. Is not like a switch. Think of as turning volume up and down-tone. When turn up sympathetic NS, typically turn down parasympathetic and vice versa
What are the 3 classes of inotropic drugs? What is the role of these drugs and by what general mechanism do they work? What conditions may they be prescribed for?
Intropic increase the force of contraction of cardiac muscle cells (ventricular) by increasing myoplasmic Ca2+ concnetration during systole. The three classes are cardiac glycoside, sympathomimetic amines, and phosphodiesterase inhibitors. Used in situations in which myocardial fxn has been impaired (e.g. heart failure)
How do cardiac glycosides increase force of contraction in cardiac muscle? What are cardiac glycosides commonly called? What are some drugs in this class? What other effect do cardiac glycosides have?
Cardiac glycosides are often called digitalis bc commonly used drugs of this type are based on extracts of the plant Digitalis purpurea. Digoxin, digitoxin, and oaubain are all in this class. These drugs increase the force of contraction of the heart by inhibiting the Na+/K+ pump. The inhibition of this pump results in a decrease in the Na+ gradient. A decrease in the Na+ gradient causes the Na+/Ca2+ exchanger to be inhibited. This results in increased myoplasmic Ca2+. This increased Ca2+ does not stay in the cytosol (which would be bad bc would have contraction during diastole) but is rather pumped into the SR by the Ca2+ pump. This results in an increased Ca2+ concentration in the SR that can be released during systole and increase the force of contraction. Digitalis can also slow the beating of the ventricles, particularly in pts with atrial flutter or fibrillation. This results from the stimulation of parasympathetic (vagal) discharge to the heart and the suppression of sympathetic discharge to the heart from a direct effect of the drug to slow conduction through the AV node. The sympathetic and parasympathetic effects result from inhibition of the Na+/K+ pump in neuronal cells, particularly the baroreceptors (pressure sensors).
How do symathomimetic amines work? What is another name for them? What drugs are in this class? What factors must be considered as it pertains to side effects?
Sympathomimetic amines are also known as adrenergic agonists. They bind to and activate ß1 adrenergic receptors in the heart (and in other parts of the body). Effects are those discussed with sympathetic innervation of the heart. Norepinephrine, epinephrine dopamine, dobutamine, and isoproterenol are included in this class. Bc there are other adrenergic receptors, the affinities of these drugs to other adrenergic receptors must be considered so side effects can be predicted.
How do phosphodiesterase inhibitors work? What drugs are in this class?
Phosphodiesterase inhibitors work by slowing down the break down of cAMP by phosphodiesterase. Increased cAMP means increased PKA that can phosphorylate Ca2+ channels, pacemaker channels, TnI, SR Ca2+ pumps, K+ channels. This leads to increased Ca2+ entry into the myoplasm during each AP which increases the force of contraction of the heart-mimic sympathetic effects. Amirinone and milrinone are in this class.
What is the big picture as it pertains to inotropic drugs? (Yea they increase myoplasmic Ca2+ and increase force of contraction, but why does that matter?)
More forceful conraction of the heart leads to an increase in stroke volume (remember that SV is dependent on inotropic state of the heart). Increased SV leads to increased CO (note that HR may also increase). Increased CO can lead to an increase in arterial pressure. Increased CO and BP can produce greater perfusion of the tissues of the body.