PHYSIOLOGY OF

CIRCULATORY SYSTEM
(PART I)

FOR
2nd Year Pharmacy Students
(2nd Term)

BY
Prof. Walaa Hassan Nazmy
Professor and Head of Medical Physiology Department
Minia Faculty of Medicine

1
 THE CIRCULATORY SYSTEM
i.e. CARDIOVASCULAR SYSTEM (CVS)
 The circulatory system is a closed system of tubes (i.e. vessels) inside which blood
circulates continuously by the pumping action of the heart and in one direction only by
the action of valves present in the heart and veins.
 The circulatory system consists of the heart and blood vessels that is why it is also called
the cardiovascular system (CVS).

Functions of the CVS:

The CVS is a major transport system for:
1. Gas transport (i.e. transporting and supplying O2 to tissues and returning CO2 back to the
lungs).
2. Transporting nutrients from the intestine to the tissues.
3. Transporting wastes from the body to the excretory organs (e.g. kidneys).
4. Transporting hormones and other agents regulating body functions, from their sites of
release to the sites of action.

Functional Anatomy of the Heart;

 The heart is a muscular organ. Its muscle is called the myocardium.
 It is divided into right and left sides.
 Each side is divided into two chambers; atrium and ventricle.
 The atrial myocardium is thinner than that of the ventricle.
 Both atria work together (i.e.as one unit) and act as a reservoir while both ventricles work
together and act as a pump.
 The right atrium is separated from the right ventricle by the tricuspid valve while, the left
atrium is separated from the left ventricle by the bicuspid (i.e. mitral) valve.
 Both tricuspid and mitral valves are called atrioventricular valves.
 The pulmonary artery arises from the right ventricle and separated from it by the
pulmonary valve while the aorta arises from the left ventricle and separated from it by the
aortic valve.
 Both pulmonary and aortic valves are called semilunar valves.
 The heart acts as two separate pumps;
a. The right ventricle pumps the blood to the lungs (i.e. lesser or pulmonary circulation).
b. The left ventricle pumps the blood to the body (i.e. greater or systemic circulation).

2
 Figure 1: Anatomy of the heart (i.e. cardiac muscle)

Circulatory divisions (i.e. circuits):

The circulatory system is divided into:
1. Greater or Systemic circulation; starts from the left ventricle and ends in the right
atrium.
2. Lesser or Pulmonary Circulation; starts from the right ventricle and ends in the left
atrium.

Figure 2: Circulatory divisions (i.e. circuits):

3
 Physiological Properties of the Cardiac Muscle
1. Rhythmicity. 2. Contractility.
3. Excitability. 4. Conductivity.
----------------------------------------------------------------------------------------------------------------

1. Rhythmicity (i.e. Automaticity or Chronotropism):

 It is a property of self-excitation and regular generation of spontaneous action
potentials (AP).
 Rhythmicity is myogenic in origin (i.e. it starts from the muscle itself independent
from autonomic nerve supply that only controls its rate (either ↑ or ↓).
 Spontaneous rhythmicity (i.e. automaticity) of the cardiac muscle is due to the
existence of a specialized excitatory-conductive system, which is composed of
modified self- exciting, non-contractile cardiac muscle cells called pacemaker cells.

Pacemaker(s) of the Heart:

Pacemaker(s) means the part of the heart that has the highest rhythmicity and the whole
heart follows that rhythm. They are classified according to the following order:
1) The sinoatrial (auricular) Node (i.e. SAN);
 It has the highest rhythm (~100-110/min) so, it is considered the normal or primary
pacemaker of the heart.
 Its rhythm is called sinus rhythm.

2) Atrioventricular Node (i.e. AVN);

 It rate is 45-60/min.
 Its rhythm is called nodal rhythm.
 It acts when the SAN is blocked or damaged.

3) Purkinje System;
 It rate is 25-40/min.
 Its rhythm is called ideoventricular rhythm.
 It acts when the AVN is blocked.
N.B.
 Although the rhythmicity of the SAN is high, the resting heart rate is only 75/min, why?
This is due the continuous inhibitory discharge from the vagus nerve on SAN decreasing
its inherited rhythm from ~110 to 75/min. This effect is called vagal tone.
 The vagus nerve supplies the whole cardiac muscle except the ventricles. This
phenomenon is called vagal escape phenomenon and it protects the ventricles from
abnormally high vagal stimulation (which can cause cardiac arrest).

4
Mechanism of Auto-rhythmicity (i.e. Prepotential & Pacemaker AP):
 It is due to the following properties of the cell membrane of pacemaker cells:
1. ↑ Permeability to Na+ (via non-gated sodium channels).
2. ↓ Permeability to potassium.
3. Existence of two types of calcium channels (i.e. T- and L- type).
 Accordingly, the pacemaker cells don’t have an actual or stable RMP (i.e. unstable),
instead their membrane potential shows spontaneous gradual depolarization ranging
between (-55 to -60 mv) called prepotential or pacemaker potential or diastolic
depolarization (as it occurs during cardiac diastole).
 When this spontaneous gradual depolarization reaches the threshold or firing level,
(about - 40 mv) → a spontaneous action potential is generated in the pacemaker cells
(i.e. without need for external stimulus).
 The prepotential or pacemaker potential is mainly due to:
1. Initial part → ↓ K+ efflux along with slow Na+ entry.
2. Late part → ↑ Ca+2 influx (via T- type Ca+2 channels).
 While, the pacemaker action potential (i.e. AP) is due to:
1. Depolarization phase → due to ↑ Ca+2 influx (via L-type Ca+2 channels).
2. Repolarization phase → due to ↑ K+ efflux (via voltage-gated K+ channels).

Figure 3: Pacemaker prepotential and action potential.

5
Factors affecting Cardiac Rhythmicity (i.e. inotropism):
I. Factors that increase the rate (i.e. + ve chronotropic factors); e.g.
1. Sympathetic stimulation (via β1 adrenergic receptors).
2. Sympathomimetic drugs (e.g. adrenaline).
3. Thyroid hormones (due to ↑ metabolism of pacemaker tissue).
4. Mild alkalinity.
5. Moderate warming.
II. Factors that decrease rhythmicity (i.e. - ve chronotropic factors); e.g.
1. Parasympathetic (i.e. vagal) stimulation (via M2 cholinergic receptors).
2. Parasympathomimitics (e.g. methacholine, pilocarpine, etc.)
3. Digitalis (via its vagal like effect).
4. Mild acidity.
5. Toxins (as typhoid & diphtheria toxins).
6. Metabolites (i.e. ↓O2, ↑H+, ↑CO2) → ↓ rhythmicity.
7. Moderate cooling.
N.B.
- K+ helps diastole, but excess K+ → cardiac arrest (i.e. stops rhythmicity) in diastole.
- Ca+2 helps systole, but excess Ca+2 → cardiac arrest in systole (i.e. calcium rigor).
- Na+ → initiates rhythmicity but cannot maintain it.
- Excessive heating or cooling → stop rhythmicity.
- Excessive acidity or alkalinity → stop rhythmicity.

2. Contractility (i.e. inotropism):

It means the ability of the cardiac muscle to contract both isotonically and isometrically
to push the blood to circulation.
Mechanism of Excitation – Contraction Coupling:
 The depolarization wave → increases Ca+2 release from SR (main source) + opening of
voltage gated (L-type) Ca+2 channels (limited ↑Ca+2 influx) → both effects → ↑
intracellular Ca+2 level.
 Calcium binds with troponin C → allows sliding if actin over myosin → muscle
contraction.
 Muscle relaxation occurs by active reuptake of Ca+2 back to the SR.
N.B.
In the cardiac muscle, the Ca+2 required for contraction comes from two sources;
a) Intracellular; from the SR (major source).
b) Extracellular, via voltage gated (L-type) Ca+2 channels (although limited source, but it
is very important as it promotes more Ca+2 release from the SR)
6
Physiological Properties of Cardiac Contraction:
a. All or None rule;
Under constant conditions, the cardiac muscle either;
 Contracts maximally if stimulated by threshold or higher stimuli.
 Or does not respond at all on using subthreshold stimuli.

b. Staircase (Treppe) Phenomenon:

 It is a gradual increase in cardiac muscle contraction following rapidly repeated
stimulation (due to improved physiological conditions by each contraction).

c. Starling Law of the Heart:

 Within limits, the cardiac muscle contraction is directly proportional to the initial
length of the muscle (i.e. the End Diastolic Volume = EDV).
 If the muscle is over stretched → marked decrease in contractility.

Physiological significance of Starling’s Law:

1. Allows the heart to pump excess blood returning to it from veins e. g. during ME.
2. Prevents stagnation of blood in the heart and veins.
So, the heart is considered a smart pump.

d. The cardiac muscle cannot be tetanized:

 This is due to the long absolute refractory period (i.e. ARP) of the cardiac muscle that
occupies the whole systole and early part of diastole.
 Tetanic contraction of the cardiac muscle is fatal → as it stops the pumping action of
the heart → Circulatory failure → Death.

Factors affecting Cardiac Contractility (i.e. inotropism):

I. Factors that increase contractility (i.e. + ve inotropic factors):
1. Sympathetic stimulation.
2. Catecholamines, thyroid hormone.
3. Digitalis (via ↑ Na+- Ca+2 exchange 2ry to (-) of Na+- k+ pump) → ↑ Ca+2 influx →
+ve inotropic effect.
4. Xanthines (e.g. caffeine and theophylline) via ↑ cyclic AMP.
5. Mild alkalinity.
6. Moderate warming.

7
II. Factors that decrease contractility (i.e. - ve inotropic factors):
1. Parasympathetic or vagal stimulation (i.e. limited to atrial contraction).
2. Mild acidity.
3. Excessive warming or cooling.
4. Drugs, e.g. Quinidine, Procainamide, and barbiturates (via ↓ intracellular Ca+2 level).
5. Diphtheria and typhoid toxins.
N.B.
 Excess K+ → stops the heart in diastole (i.e. -ve).
 Excess Ca+2 → stops the heart in systole (i.e. +ve).

3. Excitability:
 It means the ability of the cardiac muscle to respond to an adequate stimulus (i.e.
threshold or more) by generating an action potential followed by mechanical response.
 The cardiac muscle AP is similar to that of the nerve and skeletal muscle, except one
difference, which is the presence of plateau phase (i.e. unique for cardiac muscle).
 The RMP of the cardiac muscle is about (- 80 mv) and caused by;
a) Selective permeability of cell membrane.
b) Na+ - K+ pump.
 When the cardiac muscle is stimulated, an AP (i.e. cardiac impulse) is generated which
is responsible for initiating cardiac muscle contraction.

Phases of cardiac muscle AP:

Phase 0 (i.e. Depolarization phase):
Caused by rapid depolarization (i.e. from -90 to +20 mv) and it is due to rapid sodium
influx (via voltage-gated fast Na+ channels).
Phase 1 (i.e. early partial repolarization);
A small fast repolarization, due to limited K+ efflux along with closure of Na+ influx.

Phase 2 (i.e. Plateau);

In which the membrane remains depolarized (i.e. plateau) caused by a balance between
small inflow of Ca+2 ions (via L-type Ca+2 Channels) along with small K+ outflow.

Phase 3 (i.e. Rapid repolarization);

Due to marked increase in K+ outflow along with closure of Ca+2 channels.

Phase 4 (Returning to RMP);

This due to delayed closure of K+ channels along with the work of Na+ - K+ pump.

8
 Figure 4: Cardiac muscle action potential (i.e. AP).

Differences between Cardiac Muscle AP (Fast) & Pacemaker AP (slow)

Cardiac muscle AP Pacemaker AP

(i.e. Fast) (i.e. slow)

The RMP is ~ -90 mv. The RMP is - 55 to - 60 mv.

Constant (i.e. stable) till excitation. Unstable (i.e. self-excitation or prepotential).

The upstroke (i.e. ascending limb) is rapid. The upstroke is slow.

It is due to Na influx and reaches up to +20 It is due to Ca2+ influx and reaches up to +1 to
+

to +30 mV. +10 mv.

There is prominent plateau. There is no plateau.

The falling (i.e. descending) phase is rapid. The falling phase is slow.

Excitability Changes during Cardiac Activity:

a. Absolute Refractory Period (ARP);
 The excitability is completely lost (= zero).
 It occupies the whole systole and early part of diastole (i.e. long ARF).
 Significance; prevents the heart from being tetanized and prevents cardiac fatigue.

b. Relative Refractory Period (RRP);

 The excitability starts to be restored but still less than normal.
 It occupies the remaining part of diastole.

9
c. Super normal Phase of Excitability:
 The excitability is higher than normal (i.e. can respond to subthreshold stimuli).
 It occupies the end of diastole.
 It is called the vulnerable period of the heart (i.e. common site for extrasystole).

4. Conductivity:
It means the ability of the cardiac muscle to transmit the excitation wave from one part of
the heart to another.

Conduction velocity in Different Parts of the Heart:

 In atrial muscle → one meter / sec.
 In AVN → 0.2 meter / sec (i.e. AV nodal delay).
 In AVB and Purkinje fibers → five meres / sec (i.e. rapid conduction).
 In ventricular muscle → 0.5 meter / sec.
Significance of AV nodal delay:
 Allow sufficient time for ventricular filling before excitation wave reaches the ventricle.
 Prevent ventricular fibrillation (as it limits the conduction in AVN up to 220-230 bpm).

In summary, Factors affecting Cardiac Muscle Properties:

1. Nervous Factors;
 Sympathetic stimulation → ↑ all properties of the cardiac muscle.
 Parasympathetic stimulation → ↓ all properties of the cardiac muscle.
2. Chemical Factors;
 Adrenaline → ↑ all properties of the cardiac muscle.
 Thyroxine → ↑ all properties of the cardiac muscle
 Acetyl choline → ↓ all properties of the cardiac muscle.
3. Physical Factors;
 Worming → ↑ all properties of the cardiac muscle.
 Cooling → ↓ all properties of the cardiac muscle.
4. Mechanical Factors;
e.g. Applied to the relation between the length of muscle fiber and contractility (i.e.
Starling Law of the Cardiac Muscle).

10