MECHANISM OF CONTRACTION
Myocardial cells contract as a result of
the interac-tion of two overlapping, rigid contractile proteins, actin and
myosin. These proteins are fixed in posi-tion within each cell during both
contraction and relaxation. Dystrophin, a large intracellular protein, connects
actin to the cell membrane (sarcolemma). Cell shortening occurs when the actin
and myo-sin are allowed to fully interact and slide over one another. This
interaction is normally prevented by two regulatory proteins, troponin and
tropomyosin; troponin is composed of three subunits (troponin I, troponin C,
and troponin T). Troponin is attached to actin at regular intervals, whereas
tropomyo-sin lies within the center of the actin structure. An increase in
intracellular Ca2 concentration (from about 10–7 to 10–5 mol/L) promotes
contraction as Ca2 ions bind troponin C. The resulting conforma-tional change
in these regulatory proteins exposes the active sites on actin that allow
interaction with myosin bridges (points of overlapping). The active site on
myosin functions as a magnesium-dependent ATPase whose activity is enhanced by
the increase in intracellular Ca2 concentration. A series of attach-ments and
disengagements occur as each myosin bridge advances over successive active
sites on actin. Adenosine triphosphate (ATP) is consumed dur-ing each
attachment. Relaxation occurs as Ca2 is actively pumped back into the
sarcoplasmic reticu-lum by a Ca2–Mg2-ATPase; the resulting drop in
intracellular Ca2 concentration allows the tropo-nin–tropomyosin complex to
again prevent the interaction between actin and myosin.
The
quantity of Ca2+
ions required to initiate con-traction exceeds that entering the cell through
slow calcium channels during phase 2. The small amount that does enter through
slow calcium chan-nels triggers the release of much larger amounts of Ca2+
stored intracellularly (calcium-dependent cal-cium release) within cisterns in
the sarcoplasmic reticulum.
The
action potential of muscle cells depolarizes their T systems, tubular
extensions of the cell mem-brane that transverse the cell in close
approximation to the muscle fibrils, via dihydropyridine recep-tors
(voltage-gated calcium channels). This initial increase in intracellular Ca2+
triggers an even greater Ca2+ inflow across ryanodine receptors,
a nonvoltage-dependent calcium channel in the sarcoplasmic reticulum. The force
of contraction is directly depen-dent on the magnitude of the initial Ca 2+
influx. During relaxation, when the slow channels close, amembrane-bound ATPase
actively transports Ca2+ back into the sarcoplasmic
reticulum. Ca2+
is also extruded extracellularly by an exchange of intracel-lular Ca2+
for extracellular sodium by an ATPase in the cell membrane. Thus, relaxation of
the heart also requires ATP.
The
quantity of intracellular Ca2+ available, its rate of delivery,
and its rate of removal determine, respectively, the maximum tension developed,
the rate of contraction, and the rate of relaxation. Sym-pathetic stimulation
increases the force of contrac-tion by raising intracellular Ca 2+
concentration via a β1-adrenergic
receptor-mediated increase in intra-cellular cyclic adenosine monophosphate
(cAMP) through the action of a stimulatory G protein. The increase in cAMP
recruits additional open calcium channels. Moreover, adrenergic agonists
enhance the rate of relaxation by enhancing Ca 2+
reuptake by the sarcoplasmic reticulum. Phosphodiesterase inhibitors, such as
inamrinone, enoximone, and mil-rinone, produce similar effects by preventing
the breakdown of intracellular cAMP. Digitalis glyco-sides increase
intracellular Ca2+
concentration through inhibition of the membrane-bound Na+–
K+-ATPase;
the resulting small increase in intracel-lular Na+ allows for a greater influx of Ca2+
via the Na+–Ca2+
exchange mechanism. Glucagon enhances contractility by increasing intracellular
cAMP levels via activation of a specific nonadrenergic receptor. The new agent
levosimendan is a calcium sensitizer that enhances contractility by binding to
troponin C. In contrast, release of acetylcholine following vagal stimulation
depresses contractility through increased cyclic guanosine monophosphate (cGMP)
levels and inhibition of adenylyl cyclase; these effects are mediated by an
inhibitory G protein. Acidosis blocks slow calcium channels and therefore also
depresses cardiac contractility by unfavorably alter-ing intracellular Ca 2+
kinetics.
Studies suggest
that volatile anesthetics depress cardiac contractility by
decreasing the entry of Ca2+
into cells during depolarization (affect-ing T- and L-type calcium
channels), altering the kinetics of its release and uptake into the
sarcoplas-mic reticulum, and decreasing the sensitivity of con-tractile
proteins to Ca2+.
Halothane and enflurane seem to depress contractility more than isoflurane,
sevoflurane, and desflurane.
Anesthetic-inducedcardiac depression is potentiated by hypocalcemia, β-adrenergic
blockade, and calcium channel block-ers. Nitrous oxide also produces
concentration-dependent decreases in contractility by reducing the availability
of intracellular Ca 2+
during contraction. The mechanisms of direct cardiac depression from
intravenous anesthetics are not well established, but presumably involve
similar actions. Of all the major intravenous induction agents, ketamine seems
to have the least direct depressant effect on contrac-tility. Local anesthetic
agents also depress cardiac contractility by reducing Ca2+
influx and release in a dose-dependent fashion. The more potent (at nerve
block) agents, such as bupivacaine, tetracaine, and ropivacaine, more
significantly depress left ventric-ular contractility than less potent (at
nerve block) agents, such as lidocaine or chloroprocaine.
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