Lecture 5: Regulation of Cardiac Output: Heart Rate and Stroke Volume
1a. Regulation of Heart Rate: Sympathetic Mechanisms
The effects of sympathetic regulation upon the heart rate can be rather complex. At the level of the
pacemaker cells, noradrenaline (released from sympathetic nerves and the adrenal gland) and
adrenaline (released from the adrenal gland) bind beta adrenergic receptors on the pacemaker
cells. These, in turn, activate stimulatory G proteins, which go onto to activate adenylyl cyclase, to
produce cyclic AMP (cAMP). A phosphorylation cascade occurs, activating protein kinases, and
these open funny channels, and T-type Ca channels. Na , in the first phase of the pacemaker
potential, and Ca in the second phase of the pacemaker potential, enter the cell rapidly (more so
than in the absence of sympathetic stimulation) and trigger a quicker depolarization than normal.
This means firing threshold is reached sooner and heart rate can increase.
1b. Regulation of Heart Rate: Parasympathetic Mechanisms
The parasympathetic innervation also influences ion currents associated with the pacemaker
potential, except that parasympathetic innervation slows down, rather than speeds up, the rate of
depolarization (and therefore heartrate). Parasympathetic signals from the brainstem move via the
cardiac branch of the vagus nerve and ultimately cause the release of acetylcholine onto the
pacemaker cells. This neurotransmitter acts on the muscarinic receptors of the pacemaker cells,
activating both inhibitory G protein (Gi) and stimulatory G protein (Gs). The Gi protein will
trigger the closure of T-type calcium channels, and as we know that calcium is important in the
second phase of depolarization during the pacemakerpotential, we can understand why the closure
of these channels would slow heart rate. The Gs protein will cause potassium channels to open,
leading to an exodus of K + ions and hyperpolarization of the cell (again, slowing the rate of
depolarization). None of these effects can actually stop depolarization, except in extremely rare
cases - all they can do is slow it down.
In summary, sympathetic innervation increases the slope of the pacemaker potential, increasing
heart rate, whilst parasympathetic stimulation does the opposite. However, the actual situation is
slightly more complex, because at any one time bo th sympathetic and parasympathetic innervation
are acting upon the heart at the same time. Unregulated, the pacemaker cells would cause a heart
rate of about 100-110 beats/minute, whilst a normal heart rate is about 60-70/minute. The input
(or, 'tone') from the sympathetic nervous system is far more powerful than the tone of the 2
parasympathetic nervous system; however, most of the time the parasympathetic tone
predominates, leading to a lower heart rate than the endogenous rate of the pacemaker.
2. Quantifying Sympathetic and Parasympathetic “Tone” to the Heart
It is possible to quantifythe actual amount of thesympathetic and parasympathetic tone(input)
influencing the heart. Parasympathetic stimulation activates muscarinic receptors on the heart;
sympathetic stimulation activates alpha and beta adrenoceptors although on the heart, there are
almost exclusively beta receptors – alpha receptors are more common in blood vessels. We can
pharmacologically manipulate these receptors to see how much sympathetic or parasympathetic
innervation is affecting the heartat any given moment: muscarinicreceptors can be blocked with a
drug calledatropine, and we can block beta adrenoceptors with a drug calledatenolol. If we block
the adrenergic receptors, heart rate will slow down. If we block muscarinic receptors, heart rate
will speed up. By comparing heart rate following sotalol or atropine treatment, and comparing it to
resting heart rate, we can obtain a measure of th e amount of sympathetic and parasympathetic tone
to the heart.
In the absence of any sympathetic or parasympathetic input, the pacemaker cells in the SA node
usually depolarise around 100 times per minute. However, resting heart rate is normally around
60-70 beats per minute. In other words, resting heart rate is lower than the endogenous rate of
unaltered SA node depolarisation. This means thatin a normal person, something must be slowing
the rate of pacemaker depolarisation to produce the lower heart rate. This “something” is
parasympathetic stimulation. The fact that resting heart rate is lower than resting (on its own) SA
node depolarisation means that parasympathetic stimulation must (in a normal person at rest) be
more powerful than sympathetic stimulation.
If the heart is beating at a fairly normal resting rate of 70 beats/minute, we can add sotalol (what is
called a 'beta blocker') to blockbeta adrenergic receptors, dampening sympathetic tone. Heart rate
will decrease to, for example, 50 beats/minute, andthus we know that person's resting sympathetic 3
tone is about 20 beats/minute. Beta blockers are also used in this manner to help with high blood
To quantify the parasympathetic tone, we use a similar process: we measure the resting heart rate
(so, for example, let's say we get about 70 beats/minute), but instead we then add atropine, which
blocks the muscarinic receptors on the heart. This will raise heart rate, in this example, up to 100
beats per minute. This means that the resting parasympathetic tone is about 30 beats/minute.
Atropine is a very commonly used drug for manipulating heart rate, as well as other
3. Other Cardiovascular-Related Output from the Brain
There are other, related outputs from the brain to the cardiovascular system, and vice versa. As
well as the sympathetic and parasympathetic nerves going from the brainstem to the heart, there is
sympathetic innervation of blood vessels (arteries and veins). Norepinephrine is the
neurotransmitter and it causes a constriction of the blood vessels (vasoconstriction) which raises
total peripheral resistance (see lecture 8) and therefore increases blood pressure. Sympathetic
stimulation of the adrenal gland causes the release of epinephrine and norepinephrine into the
circulation. When we look at the effects of epinephrine on blood flow and pressure, we'll see that
its effects change from organ toorgan, depending on the proportionof alpha to beta adrenoceptors.
Generally, alpha receptors cause vasoconstriction whilst beta receptors cause vasodilation. 4
What we haven't looked at yet is input into thecardiovascular control centres. The most important
input comes from baroreceptors (or pressure sensors). There are two major populations of
baroreceptors in the circulatory system: one in the aorta and one in the carotid arteries (in an area
called the carotid sinus). These sense arterial pressure and are very important for regulating
overall blood pressure in the body. Aswell, there are feedback receptors in skeletal muscle that are
also important in cardiac regulation and are thought to play an important role in the control of
breathing during exercise. As an aside, there is no known respiratory control system that can
account for the increase in breathing that occurs during exercise.
4. Stroke Volume (SV) Regulation
So we've looked at sympathetic and parasympathetic influence on the regulation of heart rate, but
heart rate is only halfof cardiac output. How is stroke volum e (ml of blood pumped per heart beat),
the second part of the equation CO=HR x SV, regulated? Whilst regulation of heart rate was fairly
simple, regulation of stroke volume is considerably more complex, with many more factors
Ultimately, three major factors will influence the regulation of stroke volume: 1) the force of
ventricular contraction, 2) the end diastolic volume and 3) the afterload (blood pressure). The
first is relatively easy to modify, as we have justdiscussed: epinephrine and norepinephrine in the
circulatory system adjust it, as does sympathetic innervation. Remember that sympathetic
stimulation of the heart not onlyenhances contraction, but alsospeeds up ventricular relaxation as
well - this is important, because it gives the heart sufficient time to fill which, in turn, will affect
stroke volume (see filling time below).
End diastolic volume is affected by many things (of which we will look at six) such as muscular
and respiratory pumps, but all ofthem will affect what we callpreload, orend diastolic pressure.
Anything which alters the pressure of blood in the ventricles will affect end diastolic volume as 5
well. There are numerous things which affect end diastolic pressure, including atrial pressure (in
turn, affected by venous pressure, and the contraction of the atria).
4a. Regulation of Ventricular Contractility
The first of these factors which affect stroke volume is ventricular contractility. Sympathetic
nerves innervate the cardiac myocytes (muscle cells) and release norepinephrine which acts on the
cardiac cells by binding with beta- receptors. Circulating adrenaline and noradrenaline from the
adrenal gland can do the same thing. Binding of the catecholamines to the beta adrenoceptor
activates a G protein-coupled system which activatesadenylyl cyclase leading to the production of
cyclic AMP, which then activates protein kinase-A. This, in turn, will do four things: first, it will
open up calcium channels on the plasma membrane, allowing Ca ions to flow into the cell.
Second, it triggers further calcium release from the sarcoplasmic reticulum (SR) also by opening
calcium channels. Third, it facilitates the binding together of actin and myosin fibres which is
required for muscle contraction (see below).Fourth, it phosphorylates thecalcium ATPase on the
SR membrane allowing for rapid sequestration of calcium when the heart is relaxing. This is
important because it allows the heart to spend more time in diastole and therefore have more time
to fill (see below – filling time).
The slide illustrating force generation in muscle shows that phosphorylation of the myosin head
causes it to enter the high energy state which is required for contraction. The following slide
illustrates that calcium binds to troponin. This causes a conformational change in tropomyosin
which causes tropomyosin to move off the myosin-binding site on actin a