Cardiovascular Physiology: Action Potential, Excitation-Contraction Coupling, and Inotropic Effects

This article discusses the action potential, excitation-contraction coupling, and inotropic effects in cardiovascular physiology. It covers the role of calcium ions, pacemaker potential, and contractile proteins in cardiac muscle contraction. The article also explores the factors that affect cardiac contractibility, including physiological and pharmaceutical effects.

Running head: CARDIOVASCULAR PHYSIOLOGY
Cardiovascular Physiology
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Cardiac action potential is defined as the temporary phenomenon in which the difference
between the internal and external membrane potential generates an electrical impulse (1). The
variation in the electrical potential difference is evident in the different compartments of the
heart. The excitory and contractile muscle systems detect these differences and constantly react
to the potential maintaining the proper functionality of the heart intact (2). Autorhythmicity of
the heart is maintained by the pacemaker potential, which is the ability of the heart’s excitory
muscles, which detects spontaneous depolarization and maintains the flow of potential
generation slowly, without any external influence (3).
Fig 1: action potential of cardiac muscles
Source: (4)

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Phase 4 is known as the resting phase, which is constant at -90mV since the K+ ions keep
leaking from the membranes through inward rectifier channels. The Na+ and Ca2+ remain closed
during this time (4).
Phase 0 is the depolarization phase where, triggering of action potential makes the pacemaker
cells raise the membrane potential from -90mV onwards. Na+ channels starts opening which
allows the ions to enter the cellular compartment so that the membrane potential is now at -70mv
creating an inward electronic pulse. Rapid Na+ influx causes membrane depolarization at 0mV
temporarily called overshooting. During this time Ca2+ ions starts leaking inside the cell
membrane slowly down the gradient making the membrane potential -40mV (4). (4)
Phase 1 is the early repolarization phase makes the membrane very positive and opens some of
the K+ channels to facilitate movement of the ions outside of the cell making it 0mV (4).
Phase 2 is known as the plateau phase where the Ca2+ ions come inside through the long
opening (L-type) receptors and K+ moves out of the cell and this process isss coupled by the
excitation-contraction process (4).
Phase 3 is the repolarization Ca2+ channels close and the current electric potential returns to
resting phase and the Na+ transmemebrane balance normalizes (4).
The excitation-contraction coupled phenomena are the cascade in which generation of
electric pulse leads to contraction of heart sarcolemma by conversion of electrical energy to
mechanical energy. The primary component for driving the phenomena is Ca2+ (5). The
generation of action potential opens the very slowly after the phase 0 and greater influx of
calcium is seen in the plateau phase. This causes calcium induction of calcium releases via
Sarcoplasmic Reiculum (SR). The calcium binds to calmodulin complex protein, which in turn

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activates the myosin light chain kinase (MLCK), which phosphorylates the endings of myosin
light chain by ATP hydrolysis. The phosphorylated ends form a cross-bridge with the actin
filaments and troponin helps contracting the muscle fibers leading to whole muscle contraction
(6).
Fig 2: Excitation-Contraction Coupled reaction in heart muscles
Source: Benjamin Cummings, Addison Wesley Longman (7)
Cardiac muscles regulate the muscle contractility is different from vascular muscle
contractility as it involves rapid alteration and generation of impulses which is controlled by
contractile proteins called, actins and myosins and the regulatory proteins called troponin (6).
The arrangements of these proteins are in such a way that all the components can freely function
by keeping the tonicity of cardiac muscle contraction and reduction of diameter of the lumen.

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The release of calcium ions happen in the phase 3 of the cardiac muscle cycle, the repolarization
phase where the L-type calcium channels starts to close down and the slow delayed rectifier (IKs )
K+ channels and the ions starts to move outward (8). The whole process creates a positive
current with respect to the negative charge in the electric potentials of the membrane and makes
the channels remain open (8). The calcium is driven out of the cell to balance the influx of K+
and Na+ balance. The calcium efflux phenomenon indicates the relaxation of the cardiac
muscles. The calcium is removed from the cell compartment by active potential into the SR
compartment after the completion of the action potential. This causes the removal of blocked
troponin-myosin complex by inhibiting the active sites in the actin filaments. This causes
relaxation of the cardiac muscles (8).
The intropic condition of the heart can be indced by physiological or pharmaceutical
effects which alter the extendibility of the heart. The phenomena is called myocardial
contractibility (9). Various factors affect cardiac contractibility, like the conduction among
autonomic nervous which negatively regulate the atria. Certain condituion like extensive
workouts, stress and hypertension induce production of epinephrines, which has andregenic
effects on sympathetic nervous system (10). Heart rate elevation is also known to induce intropy.
Physiological drugs like digoxins, beta-andregenic agonists (epinephrine, isoproterenol) and
phosphodiesterase inhibitors like milrinone affect the entropy of the heart. Phenylephrines are
known to have positive effects of the cardiac intropy by activating the α-adrenoreceptors of the
cardiac muscles. The mechanism is based on the activation of adenylyl cylclase and cyclic
adenosine monophosphate (cAMP). Increases of cardiac muscle contraction were evident by the
action of phenylephrine depending on the concentration gradient (10). The positive intropic
effects of phenylephrine were compared with the effect of phentolamine, which produced a

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concentration-based resposnse measured by the curve. α-adrenoreceptors induce the positive
intropic effects of phelephrine while propanolol is present (11). This is due to increases of cAMP
molecules. The action potentials are dependent on the calcium ions which were observed to be
increased productivity with time by the action of phenylephrine and a distinctive rate if elevation
in the deporlarization (dV/dtmax) of the slower electric potentials. The intropic changes according
to the phenylephrine action are reversible, but blocked by the effect of phentolamine. The
increase of (dV/dtmax ) depolarization for slower potentials that the isoprenaline concentration.
According to experiment conducted by 6 voltage gates clamp models were experimented on
which showed that induction of the phenylphrine which increased the positive intropic effects in
heart slowed down the inward current peak in the given graphs as well as slowed down the
inactivation of outward flow and were not changed with effect of phenylephrine (11).
Fig 3: Intropic effect, relaxation time and time to peak tension by the influence of
pheenylephrine taking a mean of 12 experiments and isoprenaline (taking mean average of
11 experiments) shown in graph.

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Source: 10
Analysis of the diagram Cumulative dose-inotropic response curves for isoprenaline and
phenylephrine are shown in Fig 2. Show that positive inotropic effect was induced by
isoprenaline in concentrations ranging from 10-9 to 10-7 M; the phenylephrine effect was
obtained with concentrations ranging from 10-6 to 10-4 M. The endpoint of the concentration-
effect curve for isoprenaline was considerably higher than that for phenylephrine: the maximum
increase of contractile force (AFc) induced by the ,B-adrenoceptor agonist ( 10-7 M) was 337.1
± 53.6 mg, while that induced by the ca-adrenoceptor agonist (10-4 M) was 220.0 ± 23.5 (mean
values of 7 and 12 experiments respectively). Besides this quantitative difference in the inotropic
effect, the two amines also had different effects upon the shape of the isometric contraction
curves. Isoprenaline shortened the relaxation time (t2) whereas this parameter was not affected
by phenylephrine. Time to peak tension (tl) was only slightly and not significantly affected by
both substances (Figure 2). The increase in contractile force (AFc) induced by either isoprenaline
or phenylephrine was linearly correlated to the increase in maximum velocity of force
development (MVfd): the correlation coefficients (r) are 0.908 and 0.803, and the regression
coefficients (b) are 0.020 and 0.023 respectively.

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