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Cardiac muscle

Cardiac muscle cells have sarcomeres and the actin/ myosin arrangement of skeletal muscle, but are mononucleated and branched, connecting to each other through intercalated disks that include gap junctions, for chemical and electrical communication. Cardiac muscle has many mitochondria and utilizes most of the O2 that flows through its circulation.

The contractile mechanism is similar to that in skeletal muscle, but changes in cytosolic [Ca] rely much more heavily here on Ca flux across the plasma membrane ² with Ca entering through V-gated Ca channels and exiting mainly through Na/Ca exchangers. SR contributes to these [Ca]in changes, but less prominently than in skeletal muscle.

Cardiac muscle
T-tubules, larger than in skeletal muscle, are aligned with Z-disks (one per sarcomere).

SR is juxtaposed with T-tubules at very small terminal bulbs, rather than large cisternae.

SR is thin and lacy, with much smaller volume than skeletal SR

Fast cardiac action potential

"Fast type" action potential found in most cardiac muscle cells
The Na+ channel (also in cardiac & skeletal muscle and neural axons) opens and closes within a few msec. (The inhibitor, tetrodotoxin, a poison from the Puffer Fish, can be used in isolated heart muscle strips to show the slow plateau phase of a cardiac action potential occurring without the initial sharp spike.) One kind of K+ channel responds to depolarization, a little more slowly than the Na+ channel, by decreasing its open probability ² virtually closing above ~ -20mV. It later reopens to accelerate repolarization. A Ca2+ channel, also slightly permeable to Na+, opens still more slowly. Its open probability is affected by epinephrine, norepinephrine, & acetylcholine) Another K+ channel responds to depolarization by opening very slowly ² starting after ~100 msec and reaching maximum open probability after > 200 msec (mainly responsible for initiating repolarization).

Initial spike of PNa involves fast Na+ channels (as in axons). Late, low level of PNa is because slow Ca2+ channels have a small permeability to Na+. Changes in PK result from depolarization's effects on at least two types of K+ channels, one that closes shortly after the PNa spike and one that opens much later and very slowly.
(Initial PNa spike is shown as lasting far too long on this time scale; it should be only a few msec.)

Fast K closes

Fast K reopens Slow K opens ("Delayed rectifier")

2 ² qPK and oPCa 3a

PK and q PCa


"delayed rectifier" channels


slow K+ channels open


fast K+ channels reopen; Ca2+ channels close

² PK/PNa § 100 (higher than in axon, so qVm)

[Frontiers in Bioscience 7, d650-658, March 1, 2002] STRUCTURAL INTERACTION BETWEEN RYRs AND DHPRs IN CALCIUM RELEASE UNITS OF CARDIAC AND SKELETAL MUSCLE CELLS Feliciano Protasi, Dept of Anesthesia Research, Brigham and Women's Hospital, Harvard Medical School, Boston MA 02115 ABSTRACT

Excitation-contraction (e-c) coupling in muscle cells is a mechanism that allows transduction of exterior-membrane depolarization in Ca2+ release from the sarcoplasmic reticulum (SR). The communication between external and internal membranes is possible thanks to the interaction between dihydropyridine receptors (DHPRs), voltage-gated Ca2+ channels located in exterior membranes, and ryanodine receptors (RyRs), the Ca2+ release channels of the SR. In both skeletal and cardiac muscle cells the key structural element that allows DHPRs and RyRs to interact with each other is their vicinity. However, the signal that the two molecules use to communicate is not the same in the two muscle types. In the heart, the inward flux of Ca2+ through DHPRs, that follows depolarization, triggers the opening of RyRs (calcium induced calcium release). In skeletal muscle, on the other hand, Ca2+ is not needed for RyRs activation; instead the coupling between the two molecules involves a direct link between them (mechanical coupling). Ultrastructural studies show that functional differences can be explained by differences in the DHPR/RyR reciprocal association: whereas the two proteins are very close to each other in both muscles, DHPRs form tetrads only in skeletal fibers. Tetrads represent the structural DHPR/RyR link that allows Ca2+-independent coupling in skeletal muscle.

Ca2+ signaling in cardiac muscle
Affected by epinephrine (o) and ACh (q) Entry of Ca2+ during action potential Inhibited by digitalis & ouabain; 1 Ca2+ out indirectly qNa+/Ca2+ exchange p for 3 Na+ in o[Ca2+]in




Epinephrine affects the voltage-gated Ca2+ channel in the cardiac action potential (not the DHPR), by binding to a F1 adrenergic receptor, activating adenylyl cyclase, ocAMP, phosphorylating the Ca2+ channel, and increasing its open probability at each Vm.

Acetylcholine from parasympathetic nerves binds to muscarinic ACh receptors and activates an inhibitory G protein that inhibits adenylyl cyclase, decreasing phosphorylation of the Ca2+ channel and decreasing Ca2+ entry at each Vm.



Gi protein

Increased open probability

A skeletal muscle twitch lasts far longer than the refractory period of the stimulating action potential, so many additional stimuli are possible during the twitch, leading to summation of tension and even tetanus.

In cardiac muscle, the action potential ² and therefore the refractory period ² lasts almost as long as the complete muscle contraction, so no tetanus, or even summation, is possible. Sequential contractions are at the same tension, though gradual increases and decreases occur with autonomic nervous system input.

"Slow type" action potential in nodal tissue
Pacemaker cells have relatively few of the "fast" K+ channels; PK/PNa is much lower than in fast-response cardiac cell, so pacemaker potential starts at much higher Vm . Pacemaker potential is caused by small leak (If) of Na+ through "funny" channels that open at Vm more negative than ~ -50 mV. At a threshold of ~ -40 mV, Ca channels like those in fast-response cells start to open, triggering faster phase of depolarization. (Entire process is unaffected by tetrodotoxin.) Slow ("delayed rectifier") K+ channels open to start repolarization and close Ca2+ channels, then close themselves to allow next pacemaker potential to start.

Pacemaker potentials' slow depolarization phase is affected by autonomic NS transmitters and hormones. Epinephrine and norepinephrine accelerate by depolarizing the phase 4 Vm, thus shortening the time to reach threshold for rapid Ca2+ influx, or by increasing the "funny" current, causing a steeper rise in phase 4 Vm. Acetylcholine hyperpolarizes Vm, lengthening time to threshold, or decreases the "funny" current, causing a slower rise in phase 4 Vm.

Conduction of pacemaker potential from nodal tissue to adjacent contractile cells and beyond, through gap junctions in intercalated disks.

Spontaneous depolarization (autorhythmicity) occurs in nodal tissue and in the conducting system of the ventricles. Spontaneous rate of depolarization is fastest in the sinoatrial node, slower in the atrioventricular node, and slowest in the ventricular conducting system (Bundle of His, Purkinje fibers). There may be additional spots throughout the heart ² ectopic foci ² where spontaneous depolarization can occur. Normally, a wave of depolarization initiated by the sinoatrial node reaches these other potential sites of AP generation early enough to override their own slower rate of autorhythmicity. If conduction is blocked through the AV node, the ventricles can beat at their own slow rate, independently of the atria.

The mammalian cardiovascular system functions as one circuit with two pumps at different points in the circuit. Blood is propelled by one pump, passes through vessels that reach the second pump, then passes through more vessels before completing the circuit to the first pump. However, the two luminally separate pumps (right heart and left heart) are combined in one anatomical structure that functionally coordinates the activity of the two pumps to maintain the same average blood flow through the two halves of the circuit. This arrangement has led most people to describe the system as "two circuits" ² a "pulmonary circuit" and a "systemic circuit," though neither is truly a circuit, since blood does not circulate within each, but passes through the two sequentially.

Structure of the heart

Aorta ² accepts output of the left ventricle; first vessel of the systemic vasculature; sustains highest systolic pressure, ~140 mm Hg Pulmonary artery ² accepts output of the right ventricle; first vessel of the pulmonary vasculature; sustains peak pressure of ~25 mm Hg Superior vena cava / inferior vena cava ² largest vessels returning blood to heart (right atrium) from systemic vasculature Pulmonary veins ² largest vessels returning blood (oxygenated) to heart (left atrium) from pulmonary vasculature Coronary arteries ² supply blood to cardiac muscle tissue; branch from the aorta immediately above the aortic (semilunar) valve (heart gets no nutrients or O2 from the blood in the atria and ventricles)

Systole ² contraction of ventricles (systolic P = peak pressure per heartbeat in major systemic arteries) Diastole ² relaxed filling of ventricles (diastolic P = lowest pressure per heartbeat in major systemic arteries) First heart sound (lub) ² sound of atrioventricular valves closing as ventricles start contracting Second heart sound (dup) ² sound of semilunar valves closing as ventricles stop contracting and ventricular pressure drops below pressure in the major arteries Pulse pressure (PP) ² systolic P - diastolic P Mean arterial pressure (MAP) ² diastolic P + 1/3 PP Stroke volume (SV) ² vol. at end of diastole - vol. at end of systole; usually ~70 ml ( = ~130 ml - ~60 ml ) Cardiac output (CO) ² heart rate (HR) x SV CO can increase by a factor of 6 or more, initially due to oHR & oSV; at higher CO, increase is mostly due to oHR.



second heart sound ejection

isovolumic relaxation

isovolumic contraction first heart sound

passive filling

Starling¶s Law of the Heart
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Starling's law of the heart: Ventricular contractile strength increases with greater ventricular filling due to increased venous return of blood.
Once thought to be entirely attributable to the heart functioning in the shorter portion of the sarcomere length-tension curve (below), it is now thought to involve additional factors not well understood, including increased binding affinity of troponin C for Ca2+ when stretch of cardiac muscle is increased.


Sympathetic stimulation effect on Law of the Heart
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