Cardiac Muscle Contraction.

Cellular Basis of Cardiac Contraction

The Cardiac Ultracontraction

A shows the branching myocytes making up the cardiac myofibers.

B illustrates the critical role played by the changing [Ca²⁺] in the myocardial cytosol. Ca²⁺ ions are schematically shown as entering through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca²⁺ ions "trigger" the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually the small quantity of Ca²⁺ that has entered the cell leaves predominantly through an Na⁺/Ca²⁺ exchanger, with a lesser role for the sarcolemmal Ca²⁺ pump. The varying actin-myosin overlap is shown for (B) systole, when [Ca²⁺] is maximal, and (C) diastole, when [Ca²⁺] is minimal.

D. The myosin heads, attached to the thick filaments, interact with the thin actin filaments.

The Contractile Process

Four steps in cardiac muscle contraction and relaxation. In relaxed muscle (upper left),

ATP bound to the myosin cross-bridge dissociates the thick and thin filaments.

Step 1: Hydrolysis of myosin-bound ATP by the ATPase site on the myosin head transfers the chemical energy of the nucleotide to the activated cross-bridge (upper right). When cytosolic Ca²⁺ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the troponin complex on the thin filament do not allow the active sites on actin to interact with the cross-bridges. Therefore, even though the cross-bridges are energized, they cannot interact with actin.

Step 2: When Ca²⁺ binding to troponin C has exposed active sites on the thin filament, actin interacts with the myosin cross-bridges to form an active complex (lower right) in which the energy derived from ATP is retained in the actin-bound cross-bridge, whose orientation has not yet shifted.

Step 3: The muscle contracts when ADP dissociates from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which the chemical energy derived from ATP hydrolysis has been expended to perform mechanical work (the "rowing" motion of the cross-bridge).

Step 4: The muscle returns to its resting state, and the cycle ends when a new molecule of ATP binds to the rigor complex and dissociates the cross-bridge from the thin filament. This cycle continues until calcium is dissociated from troponin C in the thin filament, which causes the contractile proteins to return to the resting state with the cross-bridge in the energized state. ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; ADP, adenosine disphosphate.

Signal systems involved in positive intropic and lusitropic (enhanced relaxation)

effects of beta-adrenergic stimulation.

When the beta-adrenergic agonist interacts with the beta receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and to phosphorylate the Ca²⁺ channel protein (right). The result is an enhanced opening probability of the Ca²⁺ channel, thereby increasing the inward movement of Ca²⁺ ions through the sarcolemma (SL) of the T tubule. These Ca²⁺ ions release more calcium from the sarcoplasmic reticulum (SR) to increase cytosolic Ca²⁺ and to activate troponin C. Ca²⁺ ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C explaining increased peak force development. An increased rate of relaxation is explained because cAMP also activates the protein phospholamban, situated on the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect).

P, phosphorylation / PL, phospholamban /TnI, troponin I.

The Ca²⁺ fluxes and key structures involved in cardiac excitation-contraction coupling.

The arrows denote the direction of Ca²⁺ fluxes. The thickness of each arrow indicates the magnitude of the calcium flux. Two Ca²⁺ cycles regulate excitation-contraction coupling and relaxation. The larger cycle is entirely intracellular and involves Ca²⁺ fluxes into and out of the sarcoplasmic reticulum, as well as Ca²⁺ binding to and release from troponin C. The smaller extracellular Ca²⁺ cycle occurs when this cation moves into and out of the cell. The action potential opens plasma membrane Ca²⁺ channels to allow passive entry of Ca²⁺ into the cell from the extracellular fluid (arrow A). Only a small portion of the Ca²⁺ that enters the cell directly activates the contractile proteins (arrow A1). The extracellular cycle is completed when Ca²⁺ is actively transported back out to the extracellular fluid by way of two plasma membrane fluxes mediated by the sodium-calcium exchanger (arrow B1) and the plasma membrane calcium pump (arrow B2). In the intracellular Ca²⁺ cycle, passive Ca²⁺ release occurs through channels in the cisternae (arrow C) and initiates contraction; active Ca²⁺ uptake by the Ca²⁺ pump of the sarcotubular network (arrow D) relaxes the heart. Diffusion of Ca²⁺ within the sarcoplasmic reticulum (arrow G) returns this activator cation to the cisternae, where it is stored in a complex with calsequestrin and other calcium-binding proteins. Ca²⁺ released from the sarcoplasmic reticulum initiates systole when it binds to troponin C (arrow E). Lowering of cytosolic [Ca²⁺] by the sarcoplasmic reticulum (SR) cause this ion to dissociate from troponin (arrow F) and relaxes the heart. Ca²⁺ may also move between mitochondria and cytoplasm (H).