CARDIOVASCULAR
PHYSIOLOGY
Myocardial Properties - LECTURE 2
Ana-Maria Zagrean MD, PhD
Myocardial Properties
Excitability (bathmotropia)
Rhythmic activity /automaticity (chronotropia)
Conductibility (dromotropia)
Contractility (inotropia)
Relaxation (lusitropia)
Cardiac muscle cells contract without
nervous stimulation
- 1% from the myocardium: pacemaker/autorhythmic cells
(99% contractile cells)
- Pacemaker cells: organized in a specialized excitatory &
conductive system
- anatomically distinct
smaller, contain few contractile fibers
- electrogenic system: EXCITABILITY, CHRONOTROPISM
generate AP spontaneously, rhythmically
- set the rate of the heart beat: CONDUCTIVITY
rapidly conduct APs throughout the heart
generate rhythmical contraction
Specialized excitatory & conductive system
1. S-A Node
- pacemaker of the heart in normal conditions;
exhibits automaticity - generate AP at a higher
rate than the AV node and His-Purkinje system
(latent pace-makers);
- located in the superior posterolat. wall of the
RA; ellipsoid shape: 15/3/1 mm
-P cells: do not have a constant resting
potential; membrane permeability to Na and Ca
during diastole; inward Ca current during
upstroke of AP.
2. Internodal & interatrial pathways
3. A–V Node: inward Ca current during
upstroke of AP; AP delay 0.1 sec (role…)
4. AV bundle (His-Purkinje)
- intercalated disks, gap junctions
- left & right branches of the AV bundle
5. Purkinje fibres: distribute to the
endocardium, causes ventricles to contract, from
bottom up, pushing blood out top of heart
Action Potential (AP) in pacemaker cells
Phases of SAN action potential.
The records in this figure are idealized. IK, INa, ICa,
and If are currents through K+, Na+, Ca2+, and
nonselective cation channels, respectively.
Autorhythmic cells exhibit
PACEMAKER POTENTIALS
You can dissolve an embryonic heart into its individual cell types with
trypsin, an enzyme that destroys the protein glue between the cells. Plate
these cells in a dish and you will see some cells - called myocytes - that
beat independently, some faster, some slower, as long as they do not touch
one another. The cells shown here are from the chick embryo.
http://www.cellsalive.com/myocyte.htm
Modulation of pacemaker activity
to decrease the heart rate:
A. Prolonged slow depolarization
B. Hyperpolarization (a more negative
resting potential)
C. Threshold shift towards a more
positive value
Myocardial Properties
Excitability (bathmotropia)
Rhythmic activity /automaticity (chronotropia)
Conductibility (dromotropia)
Contractility (inotropia)
Relaxation (lusitropia)
Myocardial conductivity = DROMOTROPIA
in a dish…
in the heart…
After two or three days in vitro, the myocytes form interconnected sheets of
cells (monolayers) that beat in unison. Pores (gap junctions) open between
adjacent touching cells, making their cytoplasms interconnected. These gap
junctions ensure the synchronous activity of the connected cells.
Myocardial conductivity =
DROMOTROPIA
1. S-A Node area
2. Internodal & interatrial
pathways
3. A–V Node:
inward Ca current during
upstroke of AP; AP delay 0.1 s
4. AV bundle (His-Purkinje)
- intercalated disks, gap
junctions
- split into left & right branches
5. Purkinje fibres: causes
ventricles to contract, from
bottom up, pushing blood out
top of heart
The myocardial conductivity is needed for an efficient pumping
1. Atria contraction precedes ventricles contraction, because of AV nodal delay:
- the impulse travels rather slowly through AV node (0.09 sec) & penetrating part of the
AV bundle (0,04 sec) (cause of the delay: less gap junctions…)
2. Both atria and ventricles should contract as a unit
-the impulse spreads so rapidly through the conducting system that all myocardial cells in
the atria and ventricles, respectively, contract at about the same time.
The AV node
• composed of three functional regions:
1. the AN region - the transitional zone between the
atrium and the remainder of the node;
2. the N region - the middle part of the AV node
3. the NH region, in which the nodal fibers gradually
merge with the bundle of His
• normally, the AV node and bundle of His are the only
pathways along which the cardiac impulse travels
from atria to ventricles
- accessory AV pathways
- reentry loops
Organization of the A-V node.
The numbers represent the interval of time (sec)
from the origin of the impulse in the sinus node.
Conduction velocity
• Reflects the time required for excitation to spread from SAN
to the entire cardiac tissue
• Fastest in the Purkinje system, slowest in AVN (important for
ventricular filling…)
– 0.02 to 0.1 m/sec in SA & AV nodes
– 1 m/sec. in internodal & interatrial anterior pathways
– 0.3-0.5 m/sec in A & V muscle
– 1.5 - 4 m/sec in Purkinje fibers
longer fibers, distributed in 1/3 of ventricular volume
gap junctions (no., permeability…),
direct connection with myocytes
fast Na currents, “regenerative spread of conducted AP”
 rapid conduction of cardiac impulse
Atrioventricular and ventricular conduction system.
Purkinje network distribution.
Conduction velocity
SAN / AVN: 0.02 to 0.1 m/sec
Internodal&interatrial anterior
pathways: 1m/sec.
AV delay: ~ 0.1 sec
AV bundle
Purkinje fibers: 1.5 - 4 m/sec
EndocardiumEpicardium
(in A&V mm): 0.3-0.5 m/sec
Transmission of the cardiac impulse through the heart,
showing the time of appearance (in fractions of a second after
initial appearance at the sinoatrial node) in different parts of
the heart.
Spreading of excitation from S-A N to the entire cardiac tissue
Chronotropic effect:
on the firing rate of SAN;
positive/negative
Dromotropic effects:
on conduction velocity, especially in AVN;
positive/negative
Distribution of the nervous fibers – PS & S
Modulation of the heart rate by the
autonomic nervous system
Distribution of the nervous fibers - Sympathetic
Sympathetic innervation to the heart is plentiful, releasing
mostly norepinephrine. In addition, the adrenal medulla
releases epinephrine into the circulation.
Autonomic effects on automatism
and conduction velocity
PS vagal innervation
Ach mediated
Muscarinic receptors on SAN, atria, AVN
Negative chronotropic effect: ↓ If , delayed slow depolarization
↓ heart rate (sinus bradycardia)
Negative dromotropic effect: ↓ inward Ca current
↓ conduction velocity through AVN
AP are conducted more slowly from A to V
S innervation
norepinephrine mediated (also epinephrine from adrenal medulla)
Act on b1 receptors
Positive chronotropic effect: ↑ If & ↑ Ca, (both increasing the steepness
of the phase 4 of the AP), shorter APs, ↑ heart rate (sinus tachycardia)
Positive dromotropic effect: ↑ inward Ca current in all myocardial cells
↑ conduction velocity through AVN
! ventricular filling
Positive inotropic effect in atrial and ventricular muscle
Sympathetic innervation - positive inotropic effect (increase in
the strength of contraction) on atrial and ventricular muscle
1) the increased ICa (i.e., Ca2+ influx) leads to a greater local increase
in [Ca2+]i and also a greater Ca2+-induced Ca2+ release from the SR.
2) increase the sensitivity of the SR Ca2+ release channel to cytoplasmic
Ca2+.
3) enhance Ca2+ pumping into the SR by stimulation of the SERCA Ca2+
pump, thereby increasing Ca2+ stores for later release.
4) the increased ICa presents more Ca2+ to SERCA, so that SR Ca2+
stores increase over time  more Ca2+ available to troponin C, enabling
a more forceful contraction.
Myocardial properties
1. Excitability (bathmotropia)
2. Rhythmic activity/automaticity (chronotropia)
3. Conductibility (dromotropia)
4. Contractility (inotropia)
5. Relaxation (lusitropia)
Myocardial cell structure
Involuntary striated muscle, contracting in a synchronous fashion
Cardiac muscle cells: 10-20 μm in diameter, 50-100 μm in length
Sarcolema - T tubules & terminal cisternae
- sarcoplasmic reticulum (SR)
“Excitation-contraction
coupling”
Sarcomere - contractile unit, aligned across the cell (give the striated
appearance), myofibrilary proteins:
- contractil: myosin, actin
- regulatory: tropomyosin, troponin
- accesory, non-contractile cytoskeletal filaments:
tropomodulin, titin/connectin, nebulin
Intercalated disks: mechanical connections (fascia adherence, desmosomes)
& electrical junctions (gap junctions)  syncytium
(! AP through the entire heart ~220 msec, contraction of a cardiac muscle cell ~300 msec)
Sarcoplasme: myoglobin (3.4 g/l) ~O2 store, 50% saturated at pO2=5mmHg,
facilitates the diffusion of O2 through the sarcoplasme
Single central nucleus
Mitochondria: up to 30% of the volume of the heart  great oxidative capacity
Rich capillary supply: ~ 1 capillary / myocardial cell; short diffusion distances…
Myocardial cell structure: major components
Myocardial cell structure: Sarcolema
-Transverse T-tubule
- particular to myocardium: radial, but also axial T tubules
-invagination of the sarcolemma; extension of ECF…
-more developed in the ventricles;
-scanty in atrial & Purkinje cells
-oriented at the Z lines
-enable fast impulse transmission / almost simultaneously
stimulation of myofibrils
-Sarcoplasmic reticulum
-developed from ER, Ca store
-closed set of anastomosing tubules wandering through the
myofibrils:
network SR (Ca re-uptake: Ca-ATPase pumps, phospholamban)
junctional SR (close to sarcolemma/T-tubules, Ca store)
corbular SR (sac-like expansion) along the SR network,
in I band (Ca store, calsequestrin…)
Myocardial cell structure: Sarcomere
SARCOMERE: basic contractile unit of cardiac muscle,
located between two Z lines; 1.8-2 mm in resting
myocytes
Z line = a thin dark-staining partition comp. of a-actinin
Actin (thin, 6 nm/1.05mm) filaments extend from the Z
lines toward the center of the sarcomere and overlap
myosin (thick, 11 nm/1.6mm) filaments.
Actin filaments form the pale I band (‘I’ from isotropic)
Myosin filaments lie in parallel in the central region of the
sarcomere called the A band (‘A’ from anisotropic).
Each myosin is surrounded by six thin filaments forming a
hexagonal array.
Cardiac sarcomere: major components
Myosin - actin interaction; ATP-ase activity
Actin - ATP and Ca/Mg binding sites; interaction with myosin and
troponin-tropomyosin
Contraction = shortening of the sarcomeres (I band shortens,
but not A band); sliding filament mechanism (repeated making and breaking
of crossbridges between A & M filaments); the crossbridges are the heads of the
myosin molecules, which change their angles by binding to the actin sites, after
tropomyosin Ca-dependent displacement ...
Cardiac sarcomere: major components
Z line
nebulin
M line
actin
myosin
Z line
titin
H Zone
tropomodulin
A Band
I Band
MC thin filaments - actin, troponin, tropomyosin
The various troponin subunits lie along the two-stranded tropomyosin
(Tm), that in turn lies along an actin.
Troponin C (TnC), binds to Ca2+ to produce a conformational change in TnI
Troponin T (TnT) binds to tropomyosin, interlocking them to form a troponintropomyosin complex
Troponin I (TnI) binds to actin in thin myofilaments to hold the troponintropomyosin complex in place
Contraction and relaxation function
myosin
PI
ADP
ADP
troponin
actin
tropomyosin
Ca2+
Excitation-Contraction Coupling in Cardiac Muscle
STEPS:
1.
AP in adjacent myocytes travels through gap junctions. AP spreads from the cell
membrane to the T tubules
2.
Inward Ca current (L-type Ca channel) during the AP’s plateau (critical
dependence on extracellular Ca…)
3.
↑ [Ca]i (10%) triggers the Ca-induced Ca release from SR (depends on Ca
stores, inward Ca current; ryanodine rec.)
4.
↑↑ [Ca]i (90%) promotes actin-myosin interaction and contraction
5.
Ca binds to troponin C  tropomyosin is moved out  myosin binding
sites on the actin filament are exposed
6.
myosin cross-bridges bind to the underlying actin ratchet /one direction
movement of the myosin head, which pulls the actin filament toward the
center of the sarcomere
7.
Actin & myosin binding  myocardial cells contract, developing a tension
proportional to [Ca]i
8.
Relaxation occurs when [Ca]i is restored by active Ca-ATPase pump
(SERCA), electrogenic 3Na-1Ca antiporter or by sarcolemmal Ca++ pump
9.
ATP is needed to release myosin from the actin
10.
partial hydrolysis of ATP energizes the myosin head for another cross-bridge cycle.
AP plateau - voltage-dependent
L-type Ca2+ channels.
Ca2+ influx is small but critical for
the opening of SR Ca++ channels.
Ca2+ release from the SR increases
[Ca2+]i sufficiently to expose myosin
binding sites on actin thus allowing
contraction.
Relaxation occurs as the [Ca2+]i is
lowered from the combined actions
of the sarcolemmal 3Na+-1Ca2+
antiporter (3/4), Ca2+ uptake by the
SR and Ca++ extrusion by the
sarcolemmal Ca2+ pump (1/4).
AP in cardiac muscle (≈300 msec)
overlaps the contraction, resulting
in a long refractory period
(modulation of L-type Ca2+ channel
used as an alternative strategy to
increase the force of contraction).
Excitation-Contraction Coupling in Cardiac Muscle
Movements of Ca++ in excitation-contraction coupling in cardiac muscle.
- influx of Ca from the interstitial fluid during excitation triggers the release of Ca from
SR.
- free cytosolic Ca activates contraction of the myofilaments (systole).
- relaxation (diastole) occurs as a result of the uptake of Ca by the SR and the extrusion
of intracellular Ca by Na-Ca exchange and, to a limited degree, by the Ca pump.
βR, β-adrenergic receptor; cAMP, cyclic adenosine monophosphate; cAMP-PK, cAMP-
Contraction and relaxation function
myosin
PI
ADP
ADP
Troponin C
actin
tropomyosin
Ca2+
[Ca2+]i increases  Ca2+ binds to troponin C (cardiac isoform TNNC1) 
releases the inhibition of troponin I (cardiac isoform TNNI3) on actin
tropomyosin (TPM1) filaments bound to cardiac troponin T (TNNT2) on the
thin filament shift out of the waymyosin interact with active sites on the actin
ATP fuels the subsequent cross-bridge cycling  thick filaments slide past thin
filaments, generating tension.
450
1 2 3
4
1. Rigor status
(permanent in the absence of ATP)
ATP
1 2 3
4
2. ATP- myosin coupling
ADP
PI
1 2 3
4
3. ATP hydrolysis
900
PI
ADP
1 2 3
4
4. “myosin swing”
ADP
PI
1 2 3
4
5. Movement of actin filaments
ADP
1 2 3
4
6. ADP releasing
Rigor status
Mechanism of muscle contraction (animation)
Phosphorylation of Phospholamban and Troponin I Speeds
Cardiac Muscle Relaxation
-Late stage of AP ph 2 - plateau: influx of Ca2+ through L-type Ca2+
channels decreases  less Ca2+ released by the SR  prevent a
further increase in [Ca2+]I relaxation of the contractile proteins
that depends on:
(1) extrusion of Ca2+ into the extracellular fluid,
(2) re-uptake of Ca2+ from the cytosol by the SR,
(3) dissociation of Ca2+ from troponin C.
N.B. (2) & (3) are highly regulated.
(1) Extrusion of Ca2+ into the Extracellular Fluid
! Even during the plateau of AP the myocyte extrudes some Ca2+.
After the membrane potential returns to more negative values, the
extrusion processes trigger a [Ca2+]i fall.
In the steady state (i.e., during the course of several action potentials),
the cell must extrude all the Ca2+ that enters the cytosol from the
extracellular fluid through L-type Ca2+ channels.
Ca2+ extrusion into the extracellular fluid occurs by
(1) sarcolemmal Na-Ca exchanger (NCX1), which operates at
relatively high levels of [Ca2+]i;
(2) a sarcolemmal Ca2+ pump (cardiac subtype 1, 2, and 4 of
PMCA), which may function at even low levels of [Ca2+]I, but contributes
only modestly to relaxation.
N.B. Because PMCA is concentrated in caveolae, which contain receptors
for various ligands, its role may be to modulate signal transduction.
(2) Re-uptake of Ca2+ by the SR
Even during the plateau of the action potential, some of the Ca2+
accumulating in the cytoplasm is sequestered into the SR by the cardiac
subtype of the Ca2+ pump SERCA.
Phospholamban (PLN), an integral SR membrane protein with a single
transmembrane segment, is an important regulator of SERCA.
In SR membranes of cardiac, smooth, and slow-twitch skeletal
muscle, unphosphorylated PLN can exist as a homopentamer that
may function in the SR as an ion channel or as a regulator of Clchannels.
The dissociation of the pentamer allows the hydrophilic cytoplasmic domain of
PLN monomers to inhibit SERCA2a.
Phosphorylation of PLN by any of several kinases relieves
phospholamban's inhibition of SERCA2a, allowing Ca2+
resequestration to accelerate. The net effect of phosphorylation is an
increase in the rate of cardiac muscle relaxation.
Phosphorylation of PLN by protein kinase A (PKA) explains why
β1-adrenergic agonists (e.g., epinephrine), which act through the PKA
pathway, speed up the relaxation of cardiac muscle.
(3) Dissociation of Ca2+ from Troponin C
As [Ca2+]i falls, Ca2+ dissociates from troponin C,
blocking actin-myosin interactions and causing
relaxation.
β1-Adrenergic agonists accelerate relaxation by
promoting phosphorylation of troponin I, which in turn
enhances the dissociation of Ca2+ from troponin C.
Myocardial Contractility = INOTROPISM
-
Inotropism
=
the intrinsic ability of the cardiac muscle to
develop force at a given muscle length
- estimated by the ejection fraction
= stroke volume/end-diastolic volume
= 0.55 -0.6 (55-60%)
- End-diastolic volume: EDV=110-120 ml  150-180 ml
- End-systolic volume: ESV=40-50 ml  10-20 ml
- Stroke volume: volume of blood pumped with each contraction
= EDV - ESV ~ 70 ml
- Heart rate = number of beats per minute
- Cardiac output = volume of blood per minute
= Stroke volume x Heart rate
- Pulse: rhythmic stretching of arteries by heart contraction
Myocardial Contractility
Duration of contraction:
function of AP duration
~ 0.2 sec in A
~ 0.3 sec in V
When cardiac muscle is stretched, it contracts more forcefully:
length-tension relationship in cardiac muscle
(Frank-Starling Low of the Heart: optimal sarcomere lenths, no. of A-M
cross-bridges, troponin affinity for Ca, increase Ca uptake and release
from SR)
Inotrop POSITIVE factors
-Adrenergic agonits - β rec  (+) AC  cAMP  PKA 
phosphorilation 
1. increase activation of L-type Ca channels & Ca inflow;
2. inhibit of phospholamban/calmodulin, thus increasing
SERCA/Ca pump activity (e.g., isoproterenol)
- Cardiac gangliosides –Na/K pump Na-Ca exchanger (NCX1)
- Extracellular Ca2+: decr. Na+-Ca2+ exchange & incr. Ca2+
influx through L-type Ca2+ channels
- Extracellular Na+ : reduce Na+ gradient, decr. Ca2+ extrusion
- Heart frequency : increases SR stores of Ca2+ & increases
Ca2+ influx during AP (staircase phenomenon)
- Intracellular Ca2+
Inotropic negativ factors
- L-type Ca channels blockers
- verapamil - reduce Ca2+ entry during the plateau of the cardiac AP
- diltiazem - used in supraventricular arrhythmias and hypertension
- nifedipine
- PS stim. – Ach  M rec.  (-) AC cAMP  PKA 
decrease activation of L-type Ca channels & Ca inflow
- Ca2+ extracel. : by increasing Ca2+ extrusion through Na-Ca
exchanger & by reducing Ca2+ entry through L-type Ca2+
channels during the AP plateau
- Na+ extracel. : increases Ca2+ extrusion through Na-Ca
exchanger decreasing [Ca2+]i
- K+ extracel.
- H+ intracel.
Coronary Circulation
Main L & R coronary arteries: left for the anterior & left lateral portions of LV, and right for most
of the RV and the posterior part of the LV.
- epicardial arteries on the surface of the heart;
- intramuscular arteries penetrate from the surface into the cardiac muscle mass; compressed
during systole
- subendocardial arterial plexus
- ! inner 0.1 mm of the endocardial surface is also nourished directly from the intracardiac blood
Coronary venous blood flow:
- from the LV returns to the RA by way of the coronary sinus (~75% of the total coronary blood
flow);
- from the RV returns through small anterior cardiac veins that flow directly into the RA.
- ! a very small amount of coronary venous blood also flows back into the heart through very
minute thebesian veins, which empty directly into all chambers of the heart.
Coronary Blood Flow
In resting conditions coronary blood flow in the human being averages about
225 ml/min (4 – 5 % of the total CO).
During strenuous exercise:
 4-7 x increase CO together with increased arterial pressure  6-9 x increased
work output of the heart, with only 3-4 x increase in coronary blood flow
 increase of the ratio (heart energy expenditure / coronary blood flow) 
relative deficiency of coronary blood supply the need for increasing the
"efficiency" of cardiac utilization of energy.
Phasic flow of blood through the coronary capillaries of the LV during cardiac
systole and diastole: strong compression of the LV muscle around the intramuscular
vessels during systolic contraction. For the RV the phasic changes are partial, because
the force of contraction of the RV muscle is far less than that of the LV.
Collateral Circulation in the Heart.
In a normal heart, almost no large communications exist among the larger
coronary arteries. But many anastomoses do exist among the smaller arteries sized
20 to 250 micrometers in diameter.
The degree of damage to the heart muscle (secondary to atherosclerotic coronary
constriction or by sudden coronary occlusion) is determined to a great extent by
the degree of collateral circulation that has already developed or that can open
within minutes after the occlusion.
Minute anastomoses in the normal coronary arterial system
Control of Coronary Blood Flow
1. Regulation through Local Muscle Metabolism
Metabolic factors, especially myocardial oxygen consumption/oxygen demand , are
the major controllers of myocardial blood flow.
Normally ~70% of the oxygen in the coronary arterial blood is removed as the
blood flows through the heart muscle little additional oxygen can be supplied to
the heart musculature  the need to increase the coronary blood flow, through
local arteriolar vasodilation, proportional to cardiac muscle metabolism/ degree
of activity.
Vasodilator substances released from the muscle cells in response to
increased metabolism:
-Adenosine: low oxygen conc. in the muscle cells ATP degrades to adenosine
monophosphate further degraded to adenosine  adenosine release into the
tissue fluids of the heart muscle vasodilation (action maintained for only 1 to 3
hours)
Most of adenosine is reabsorbed into the cardiac cells to be reused.
Obs: Blockers of adenosine effect do not prevent coronary vasodilation caused by
increased heart muscle activity.
- Other vasodilators: adenosine phosphate compounds, potassium ions,
hydrogen ions, carbon dioxide, bradykinin, prostaglandins and nitric oxide.
Control of Coronary Blood Flow
2. Autonomic Nervous Control of Coronary Blood Flow
– Direct & Indirect effects –
Direct effects: action of Ach (vagus nerves) and NE/E (sympathetic nerves) on the coronary
vessels
Ach has a direct effect to dilate the coronary arteries, even the distribution of vagal nerve fibers
to the ventricular coronary system is reduced.
NE has either vascular constrictor or vascular dilator effects, depending on the presence or
absence of constrictor receptors (alpha receptors, > on epicardial coronary vessels) and dilator
receptors (beta receptors, > on intramuscular arteries). Both alpha and beta receptors exist in
the coronary vessels sympathetic stimulation cause slight overall coronary constriction or
dilation, but usually constriction.
Excess sympathetic drive  severe alpha vasoconstrictor effects vasospastic myocardial
ischemia.
Indirect effects: secondary changes in coronary blood flow caused by increased/decreased
activity of the heart, mostly opposite to the direct effects, that play a major role in normal
control of coronary blood flow.
Sympathetic stimulation increases both HR and contractility increases the rate of
metabolism  vasodilation of coronary vessels through local blood flow regulatory mechanisms
 blood flow increases.
Vagal stimulation slows the heart and has a slight depressive effect on heart contractility
 decrease cardiac oxygen consumption...
Particularities of Cardiac Muscle Metabolism
-under resting conditions, cardiac muscle normally consumes fatty acids to supply
most of its energy instead of carbohydrates (about 70% of the energy is derived
from fatty acids).
- under anaerobic or ischemic conditions, cardiac metabolism must call on anaerobic
glycolysis mechanisms for energy (consumes blood glucose and at the same time
forms large amounts of lactic acid in the cardiac tissue ischemic cardiac pain
- >95% of the metabolic energy liberated from foods is used to form ATP in the
mitochondria. ATP is then used for cardiac muscular contraction and other cellular
functions.
-in severe coronary ischemia, ATP degrades to adenosine diphosphate  adenosine
monophosphate  adenosine
 dilation of the coronary arterioles during coronary hypoxia,
 adenosine diffusion from the muscle cells into the circulating blood 
adenosine is lost  serious cellular consequence.
- within 30 minutes of severe coronary ischemia, about one half of the adenine base
can be lost from the affected cardiac muscle cells.
- new synthesis of adenine is only possible at a rate of 2%/hour  for a coronary
ischemia that persisted for ≥30 minutes, relief of the ischemia may be too late to
save the lives of the cardiac cells.