Kardiovaskulárny systém

Physiology of the circulation

Blood is circulated by the continuous pump function of the heart inside a closed system. In the normal circulatory system, the blood flow rate or velocity varies inversely with the total cross-sectional area of the blood vessels. This means that the velocity is inversely proportional to the cross-sectional area and directly proportional to the blood flow in the blood vessel. As the total cross-sectional area increases, the velocity of flow decreases. All tissues and cells in the body need oxygen and nutrients; however, this demand varies according to tissue type (neurons and cardiac muscle cells require a continuous supply of oxygen). 

The function of circulation are as follows:

• To provide oxygen, nutrients, and hormones to the cells,
• To remove waste, carbon dioxide, and ions from the cells (and to eliminate the heat generated by the mitochondria in the cells);   
• To establish connections between the body's afferent (gastrointestinal system and the lungs) and efferent systems (kidneys, gastrointestinal system, the lungs, and the skin).

The primary function of the heart is to pump blood through the vessels and maintain circulation. The heart output or cardiac output (CO), expressed in liters/minute, is the volumetric flow rate the heart pumps out in one minute. This amount is equal to the product of stroke volume (approximately 5–5.5 l) and the number of beats per minute (heart rate)​​. 

Pressure differences in the systemic circulation

Contraction of the ventricles causes dilation of the large arteries and provides kinetic energy, thus contributing to blood flow. (Since fluids, as well as the blood itself, are compressed.) 

Friction develops in the blood flow between the circulating particles of the blood, and friction of blood occurs against the vessel walls. Friction produces heat. Thus, the energy from a heart contraction is transformed into thermal energy. Friction is the resistance to relative motion or flow, essential in pressure changes inside the blood vessels.  

Perfusion pressure is inversely proportional to resistance: an increase in resistance decreases flow, and a decrease in resistance increases flow. 

Blood flow: laminar versus turbulent

In physics, remarkably fluid dynamics, the volumetric flow rate (also known as volume flow rate or volume velocity) is not uniform in the cross-sectional representation. Fluid layers that adhere to the pipe wall have a decreased flow rate close to the vessel wall, while the velocity is higher in the middle layer.  

Blood flow in the body is typically laminar in most blood vessels (the layers move parallel to the long axis of the blood vessel). If the volume velocity increases (e.g., in the case of a narrowed or obstructed vessel), turbulent flow occurs, and blood particles move forward and in different directions. Blood particles create small whirlpools, eddies, and swirls in the blood that make an audible sound. A stethoscope can hear this noise over a blood vessel during blood pressure measurement. 

Korotkoff sounds

The laminar flow depends on the following factors: diameter of the blood vessel, velocity, and viscosity of the liquid. The Poisseuille-Hagen formula describes the characteristics of laminar flow through a pipe, where the fluid moves steadily, and all the particles stream in the same flow line in parallel layers. The equation of steady, laminar, Newtonian flow through circular tubes is Q=πΔPr⁴/8ηl where Q is the volumetric flow rate, r, and l are the tube radius and length, ΔP the pressure drops in the direction of low, and η is the fluid viscosity. With the roles of Q and η interchanged, this is the basic equation of capillary viscometry. In laminar flow, the flow rate is directly proportional to the pressure difference/perfusion pressure (P1-P2=ΔP), the 4th power of the radius of the pipe, and it is inversely proportional to the length of the pipe and viscosity. 

This means that in a specific section of a vessel, the resistance is directly proportional to the length of the blood vessel and its viscosity. At the same time, it is inversely proportional to the 4th power of the blood vessel's radius. Thus, in case of a short vessel length, a large vessel diameter and low viscosity vascular conductance of the specific blood vessel will be increased. Among many factors that affect circulation, vessel diameter is the most important that can be changed.  

Poisseuille-Hagen formula

The connection between the flow rate and the cross-sectional area

As the total cross-sectional area of the vessels increases, the flow velocity decreases (aorta ⟶ larger arteries ⟶ small arteries). The cross-sectional area of each capillary is small compared to the aorta; the total cross-sectional area of all the capillaries is much greater than the cross-sectional area of the aorta. From the muscular arteries, the blood is distributed into arterioles, which are then terminal arterioles. The capillary bed contains metarterioles and real capillaries. Precapillary sphincters regulate the number of opened capillaries needed for adequate tissue perfusion. Exchange across capillary walls is essential to the survival of the cells and tissues. 

Exchange of nutrients and waste products

Microcirculation is the circulation of terminal arterioles, metarterioles, precapillary sphincters, capillaries, and the smallest postcapillary venules. Its primary function is nutrient and waste exchange inside and outside the vessels.  

The exchange occurs in the capillaries and postcapillary venules; in the capillaries, the precapillary sphincters control the pressure and the blood flow. This means that 1 red blood cell “spends" about 1 second in a certain capillary; this is the exchange time of gases and other materials. In addition to that, at rest, blood flows only in some of the capillaries (as precapillary sphincters are closed and open only in metabolically “active” tissues). 

The endothelial cell structure in the wall of capillaries is permeable to lipid-soluble materials (such as gases: O2, CO2, alcohol, and lipids). The vessel wall's water permeability depends on the quantity of aquaporins, while most of the solute particles transverse the membrane via transport mechanisms. 

Aquaporins or water channels

The Starling Principle

According to Starling's hypothesis, the extracellular fluid movements between blood and tissues are determined by the differences in hydrostatic pressure and colloid osmotic (oncotic) pressure between blood plasma in the microvessels and the interstitial fluid. Hydrostatic pressure within a blood vessel is determined by where resistance to flow occurs; constriction of the arterioles raises pressure, while vasodilation decreases it. The larger the venulas’ diameter is, the elevated the pressure in the capillaries gets. Meanwhile, dilatation of the veins decreases pressure.  

Colloid osmotic pressure of the blood (Пk= ~25 mmHg) occurs due to albumin that attracts positively charged molecules and, ultimately, water into the intravascular compartment. Hydrostatic pressure (the opposite of colloid osmotic pressure) is the force exerted by the fluid inside the blood capillaries against the capillary wall: ~35 mmHg, and in the veins: ~17 mmHg. 

Fluid is reabsorbed into the venules and returns to the heart via venous circulation, while excess interstitial fluid is absorbed by lymph capillaries and drained into the larger vessels of the lymphatic system. When the lymphatic system fails, venous insufficiency, or malfunctioning blood vessels cause excess fluid to accumulate in the interstitial space. This is called edema. 

Intravascular hydrostatic pressure (P_c) is the principal force driving fluid out of the vasculature into the interstitial space. Proteins cannot pass through most capillary walls; thus, ultrafiltrate is produced in the tissue space.  

The interstitium is mainly composed of collagen, elastin, and glycosaminoglycans, which are mechanically entangled and cross-linked to form a gel-like material. Matrix proteins (e.g., glycosaminoglycans and collagen) determine the composition and organization of the interstitium's mechanical properties, such as its strength, elasticity, and hydration. The volume of interstitial fluid in the tissues varies (e.g., ~10–12% of the muscle tissue and ~35% of the skin consist of interstitial fluid).   

In the microcirculation, 2‒4 liters of fluid circulate daily upon entering the lymphatic capillary, and the collected fluid becomes lymph. Lymph eventually drains into larger lymphatic vessels and is filtrated by lymph nodes or tonsils (secondary lymphatic organs). 

Following that, lymph drains into larger lymphatic ducts (e.g., thoracic duct, right lymphatic duct), and then it reaches the left venous and the right venous angle (angulus venosus sinister et dexter), where lymph flows with carbon dioxide-rich blood in the circulation. (See previous chapters in The hematopoietic system and the blood

‒ Secondary (peripheral) lymphoid organs) 

Lymph flow is managed by the movements of organs, such as the intestines and skeletal muscles, which exert external pressure on the lymphatic walls (extrinsic forces). The rhythmic contractions of smooth muscles embedded in the walls of the lymphatic vessels (intrinsic forces) also play a major role in lymph circulation. 

Luminal valves in larger lymphatic vessels also ensure the forward flow of lymph. Inhalation decreases intrathoracic pressure and dilates the thoracic vena cava, which facilitates lymphatic circulation.    

Central and local control of blood flow and volume

In the wall of arterioles and precapillary resistance arteries, the structure of smooth muscles is homogenous. These arteries have basal vascular tone (in a quiescent state, smooth muscles are partially constricted, i.e., the contractile filaments are partially activated). 

The basal vascular tone might be different in the parallel blood vessels. Local circulatory control mechanisms rely heavily on changes in myogenic tone, which is influenced by the stretch state of muscles.  

In most blood vessels and organs, blood flow is proportional to perfusion pressure. When intravascular pressure increases (as occurs following systole), the resulting stretch on muscle cells leads to contraction and increased myogenic tone. Nevertheless, blood flow is relatively independent of perfusion pressure in some organs, known as flow autoregulation.  

In vascular beds with high myogenic tone, pressure changes do not significantly affect vessel diameter, maintaining stable blood flow. This is known as arterial autoregulation, and it is observed in the cerebral and coronary arteries. 

As a result of cerebral autoregulation, the cerebral vasculature maintains stable blood flow, between 60‒160 mmHg, despite the changes in the mean arterial pressure. 

Vessels in the splanchnic area, skeletal muscle, and pulmonary and cutaneous vessels have low basal tone. In response to pressure changes, blood vessel diameter significantly changes.  

At rest, sympathetic nerves release noradrenaline, which acts on the walls of blood vessels (i.e., vasoconstrictor), leading to a neurogenic tone. Cerebral and coronary vessels have some degree of autonomic innervation, although it is not as extensive as that of other blood vessels. Therefore, their blood flow regulation is primarily influenced by local factors rather than neurogenic tone, while splanchnic and skeletal muscle vessels have some degree of neurogenic tone.  

The basal “resting” tone or sympathetic tone is referred to as the normal tone of the vascular wall. (As shown in figure „Regulation of blood pressure”, point I.) 

The sympathetic nervous system controls blood flow in vascularized areas with low basal tone (e.g., in splanchnic areas and cutaneous blood vessels). These areas respond with marked vasoconstriction to noradrenaline/adrenaline released in response to sympathetic action.    

Regulation of blood pressure

Summary of the local regulation of blood flow

In case the resistance of the capillaries decreases, blood flow in the metabolically active tissues rises above the normal or basal vascular tone. This is called functional hyperemia. Functional hyperemia (increased blood flow) can be observed in active skeletal muscles in case of increased metabolic demands of the heart and the digestive system and neuronal activity in specific areas of the brain. In case the resistance of the capillaries decreases, blood flow in the metabolically active tissues rises above the “resting” or basal vascular tone. 

During metabolic activity, chemical factors are produced, such as hydrogen ions (H⁺), carbon dioxide (CO₂), adenosine, and potassium ions (K⁺), which factors and vasoactive mediators cause vasodilation. These chemical factors act on the smooth muscle cells in the precapillary resistance vessel wall to induce relaxation and increase local blood flow.  

Reactive hyperemia occurs if blood flow decreases in a certain blood vessel (e.g., in a limb). If ischemia resolves, the resistance of the blood vessels decreases, and blood flow increases. 

The role of vascular endothelium in the regulation of blood flow

The tunica intima is the inner layer of a blood vessel wall. It comprises endothelial cells, which produce and secrete vasoactive (vasoconstrictor and vasodilator) substances. Nitric oxide (NO) and prostacyclin are two important vasodilator molecules.

Neural control of the cardiovascular system

Mechanisms through which the body regulates systemic arterial pressure: Cardiovascular reflexes

The cardiovascular system rarely functions in a resting state, as circulation has to adjust to constantly changing conditions (e.g., the body's actual position, physical activity, and stress). 

In addition, in specific nonphysiological situations, e.g., when the body loses blood and fluids (hypovolemia) or experiences oxygen (O₂) deprivation (hypoxia), the circulatory system has to adapt and take corrective actions to keep the organs functioning.  

The autonomic nervous system and the medulla oblongata of the brainstem control the cardiovascular and respiratory systems and regulate blood pressure. 

The circulatory system provides some information derived from regulating the cardiovascular system: baroreceptors are a type of mechanoreceptor or stretch receptor in the walls of the heart and blood vessels, while chemoreceptors are sensory receptors that detect changes in the chemical composition of blood.  

Aortic, carotid and cardiopulmonary baroreceptors

High-pressure baroreceptors are found in the aortic body (glomus aorticum), within the aortic arch, and in the internal carotid arteries (carotid sinus – sinus caroticus). These receptors are mechanosensitive nerve endings located in the walls of certain blood vessels that have a range of sensitivity to changes in blood pressure. Typically, baroreceptors are sensitive to changing pulsatile arterial pressure; above 60 mmHg, the action potential frequency also increases. Baroreceptors conduct action potentials if the arterial pressure is low. In normotensive subjects, the frequency of action potentials generated by baroreceptors reaches its maximum when arterial blood pressure is about 200 mmHg. 

Baroreceptors in the carotid sinus are connected to sensory nerve fibers that travel through the glossopharyngeal nerve (CN IX); the aortic body sends sensory information to the brain via the vagus nerve (glomus aorticum). The nucleus tractus solitarii (a part of the medulla oblongata in the brainstem) receives sensory input from the vagus and glossopharyngeal nerve and is the primary integrative center for cardiovascular control. 

An increase in mean arterial blood pressure increases baroreceptor activity, which activates the medulla (nuclei of the CN X). As the medulla processes this incoming (afferent) information about the increased stretch of the vessel wall, this center sends efferent signals via the parasympathetic nervous system to the heart to decrease heart rate. This ultimately results in a decrease in blood pressure.  

The role of high-pressure receptors is an essential mechanism for the short-term stabilization of arterial blood pressure, specifically for controlling blood pressure between systoles. When blood pressure increases the vagal nerve activity increases at the same time. The vagus nerve is responsible for parasympathetic control of the heart, which includes slowing the heart rate and reducing cardiac output. An increase in vagal tone can lead to a decrease in heart rate and a subsequent reduction in blood pressure through decreased total peripheral resistance and cardiac output. A fall in blood pressure inhibits the activity of the vagus nerve, and the increased sympathetic tone raises the cardiac output and the total peripheral resistance, which helps to increase blood pressure. (In individuals with hypertension, the sensitivity of baroreceptors may decrease and adapt to the higher blood pressure ranges and continue to function, albeit with reduced sensitivity.) 

Cardiopulmonary baroreceptors

Low-pressure volume or cardiopulmonary receptors are located within the atria, ventricles, and pulmonary vasculature. They regulate blood pressure and blood volume. 

These receptors are sensitive to changes in the stretch or distension of the blood vessel wall (or blood volume). They are innervated by the vagus nerve (a sensory nerve). Suppose blood volume becomes excessive or the stretch of the vessel wall increases. In that case, the reflexes initiated by the cardiopulmonary receptors may become overwhelmed, leading to tachycardia, as the sympathetic nervous system can quickly and effectively increase heart rate.  

Cardiopulmonary receptors play an essential role in long-term blood pressure regulation by controlling blood volume. Signals sent by the cardiopulmonary receptors can influence the release of vasopressin and the amount of renin produced by the kidneys, thus, consequently, the effects of angiotensin and aldosterone. These hormonal effects occur in different ways, resulting in increased blood volume. This happens in hypovolemia and hypotension. These hormonal mechanisms are inhibited in increased atrial stretch (in hypervolemia).  

Cardiovascular reflexes in upright posture

Sudden changes from lying to an upright posture can cause problems, as the hydrostatic pressure in the arterial vessels increases rapidly in the lower body regions (up to ~80 mmHg).

Increasing blood pressure dilates veins, pooling up to 500 ml of blood in the vessels below the heart. As a result, venous return decreases, and cardiac output and stroke volume decrease as well (in the upright position, the stroke volume can be up to 20–25% lower than in the lying position). In such cases, mean arterial pressure should decrease, but baroreceptors exert controlling mechanisms to keep it in normal ranges.   

Cardiopulmonary receptors sense the decrease in central venous pressure and increase the tone of sympathetic nerve fibers in the precapillary resistance arteries and veins. In addition, they activate the secretion of vasopressin and renin, raising blood pressure and blood volume. 

From the supine to the upright position, nerve impulses from baroreceptors in the carotid sinus decrease because anatomically, the carotid sinus is located approximately 30 cm above the heart; thus, a blood pressure of 90 mmHg measured in lying position drops to 75 mmHg when standing up. Increased vasoconstriction produced by the sympathetic nervous system, intensified sympathetic stimulation that raises the heart rate, and the enhanced secretion of catecholamines by the adrenal glands contribute to normal mean arterial pressure.  

If homeostatic regulation in the upright position is impaired, mean arterial pressure can drop significantly, reduced cerebral blood flow might occur, and individuals may faint (orthostatic hypotension or postural hypotension). Syncope or fainting resolves usually automatically, as lying position restores blood flow to the brain.  

Arterial chemoreceptors

Sensory fibers of CN IX and X work as chemoreceptors in the area of the aortic body (glomus aorticum) and carotid body (glomus caroticum). At normal O₂ level, the firing rate of arterial chemoreceptors is decreased. In case of hypoxia or if the level of blood metabolites (CO₂, H⁺, K⁺) is high, the firing rate increases.  

The firing rate of chemoreceptors can increase in circulatory failure or following significant blood loss. CN IX and X activation stimulate the sympathetic system to constrict peripheral blood vessels. The key function of chemoreceptors is to facilitate breathing. Chemoreceptors maintain circulation in case of very low blood pressure (60‒80 mmHg). 

1. Short-term (1‒30 sec): Neural regulation  

• Carotid sinus reflex (baroreceptors located in the carotid sinus)  
• Chemoreceptors stimulate breathing 
• Cerebral ischemia reflex leads to marked activation of the sympathetic nervous system.

• Renin-angiotensin-aldosterone system: vasoconstriction, retention of sodium
• Vasopressin: vasoconstriction, water retention
• The kidneys regulate circulatory volume by controlling sodium and water balance, thus maintaining homeostasis of extracellular fluid volume (ECFV). Increased sodium and water consumption raise ECFV, increasing blood volume. 

Hormones involved in blood pressure control