Regulation of Blood Flow Assoc. Prof. MUDr. Markéta Bébarová, Ph.D. Dept. of Physiology, Faculty of Medicine, Masaryk University This lecture is focused on the blood flow, methods for its measurement and its regulation. This presentation includes only the most important terms and facts. Its content by itself is not a sufficient source of information required to pass the Physiology exam. Definition of Blood Flow mathematical formulation – analogy with the electric current Ohm´s law I = U / R Q = DP / R Q blood flow DP difference of pressure at the R resistance of the vessel (peripheral resistance) beginning and at the end of a vessel According to the Ohm´s law, the electric current is equal to the ratio of voltage and resistance. The blood flow can be mathematically expressed analogically to the electric current, as the ratio of difference of pressure at the beginning and the end of a vessel, and of the resistance of the respective vessel (or all vessels in case of the total body blood flow which equal to the cardiac output). Definition of Blood Flow Hagen - Poiseuille formula r radius of the vessel η viscosity of the blood l length of the vessel This formula applies to the steady laminar flow in a rigid tube! Q = DP / R R = 8ηl / πr4 Q = DP . πr4 / 8ηl Viscosity of the blood is not constant, it is proportional to the haematocrit and to the velocity of blood flow. The blood flow is not laminar in fact, erythrocytes concentrate in the middle (plasma skimming). The turbulent flow. Elasticity of vessels. P Q rigid tube critical closing pressure vessel Resistance from the previous equation may be expressed by the equation below. The most important parameter influencing resistance is the radius of vessel - it is present in this equation as its biquadratics (r^4), thus, a subtle change of the radius results in a considerable change of the resistance. The radius is inversely proportional to the resistance, thus, the lower is the radius, the higher is the resistance. Both these equations may be combined into the final Hagen-Poiseuille formula. Applicability of physical laws to biological systems is always limited. The Hagen-Poiseuille formula actually applies just to the steady laminar flow in a rigid tube which is not the case of the blood flow in a vessel: (1)The blood flow is not constant due to the variant viscosity of blood (η) which is proportional to the hematocrit and velocity of the blood flow. (2)The blood flow is not laminar in fact because erythrocytes concentrate in the middle of vessels. This effect is called plasma skimming and is physiologically important in some tissues, for example in the renal glomeruli (afferent arterioles branch out the main vessel almost at right angles, thus, contain less erythrocytes and more plasma which is good for the filtration). At specific conditions, the blood flow even changes to the turbulent flow. (3)Vessels are not rigid tubes at all, their walls are elastic (compliant). Thus, at low perfusion pressure, vessels are collapsed (closed). After the pressure exceeds the so called critical closing pressure, the vessel opens and the blood flow first rapidly increases with biquadratics of the vascular radius. Reaching certain radius, compliance of the vessel becomes low and its radius does not further increase with increasing pressure. From this point, the linear dependence between pressure and flow applies as stated by the Poiseuille-Hagen formula. Methods for Measuring Blood Flow A.with a cannula inserted into a vessel 1.Electrical Induction Principle B.without direct contact with the blood flow 3.Plethysmography 2.Doppler Effect 4.Fick Principle The blood flow may be measured either directly, using a cannula inserted into a vessel, or without a direct contact with the blood flow. These methods will be described during the following part of the lecture. Methods for Measuring Blood Flow 1.Electrical Induction Principle (Faraday, 1791-1867) vthe electromagnetic flowmeter van electromotive force is generated in the blood (as a conductor) when it moves through a magnetic field vcan detect changes in the velocity <0.01 s ® recording of both steady blood flow and its pulsatile changes vthis electromotive force (measured with an electrode placed on the vessel surface) is proportional to the velocity of blood flow First, the electromagnetic flowmeter may be attached on the outer surface of a vessel. Since blood is a conductor, an electromotive force is generated in the blood when it moves through the magnetic field produced by the device. The electromotive force is proportional to the velocity of the blood flow. Both steady blood flow and its pulsatile changes may be measured with this technique (and also with the following ultrasonic Doppler flowmeter). vchange of the wave length (frequency) is proportinal to the velocity of blood flow Methods for Measuring Blood Flow 2.Doppler Effect (Christian Doppler, Praque 1842) vthe ultrasonic Doppler flowmeter; most common •ultrasonic waves of a known wave length (frequency) are sent into a vessel diagonally along the blood stream from a subtle piezoelectric crystal •waves reflect from the red and white blood cells ® a change (↑) of the wave length (↓ frequency) •reflected waves are picked up by a sensor vboth steady blood flow and its pulsatile changes can be measured The ultrasonic Doppler flowmeter is based on the Doppler effect. The device contains a small piezoelectric crystal which sends ultrasonic waves of a known wave length, so of a known frequency, diagonally into a vessel. The waves then reflect from the moving red and white blood cells which change their wave length and then frequency. If the crystal sends the waves along the blood stream, as is usual in the clinical practise, the wave length of the reflected waves increases, thus, their frequency decreases. These reflected waves are picked up by a sensor located also in the flowmeter. The change of the wave length (frequency) is proportional to the velocity of blood flow. Methods for Measuring Blood Flow 3.Plethysmography vusually as the venous occlusion plethysmography •venous drainage of the limb is stopped (e.g. with an arm cuff) •increasing volume of the limb (expelling water from closed chamber, measured as a change of its volume) is lineary proportional to the arterial inflow of blood vcan be used on limbs The third method is called venous occlusion plethysmography (done in the practicals). A limb, usually a forearm, is placed into a closed chamber filled with water. Then, the venous drainage of the limb is transiently stopped, for example with an arm cuff used for the Riva-Rocchi measurement of the blood pressure. Thus, the volume of the limb increases proportionally to the arterial inflow of blood into the forearm. This increase of the forearm volume expels water from the chamber and this change is recorded. The volume increase may be also registered by another cuff placed on the forearm as you do it in the practicals. Methods for Measuring Blood Flow 3.Plethysmography vusually as the venous occlusion plethysmography •venous drainage of the limb is stopped (e.g. with an arm cuff) •increasing volume of the limb (expelling water from closed chamber, measured as a change of its volume) is lineary proportional to the arterial inflow of blood vcan be used on limbs http://schueler.ws/?page_id=21 A sample record. 4.Fick Principle Methods for Measuring Blood Flow The blood catches 50 ml O2 / 1 l during passage through the lungs. •blood flowing from the right heart to the lungs – about 150 ml O2 / 1 l (a sample of the mixed venous blood bleeded from the pulmonary artery with a catheter inserted to the brachial vene) •blood flowing from the lungs to the left heart – about 200 ml O2 / 1 l (a sample of the arterial blood from any artery, arterial O2 content is uniform) •The total O2 consumption is 250 ml / 1 min. (O2 decay in the expired air compared to the inspired air, oximeter) 250 ml O2 / min = 5 l / min 50 ml O2 / l CO = Q = AV diff A / time - Direct Fick Method A set of methods based on the Fick principle may be also used to measure the blood flow. This principle states that the blood flow (Q) is equal to the ratio of the amount of a substance (indicator) taken up by an organ (or whole organism) per a time unit, and of the arteriovenous (AV) difference of concentration of the substance. The first method based on this principle is called the direct Fick method. It is used to assess the cardiac output which is equal to the pulmonary blood flow. As the indicator substance, O[2] is used. First, a sample of the mixed venous blood entering the pulmonary circulation has to be bleeded from the pulmonary artery with a catheter and O[2 ]concentration is measured (usually about 150 ml/l). Then, O[2 ]concentration in the arterial blood flowing from the lungs is assessed which is constant in all arteries in the body, thus, a sample of blood from any peripheral artery is relevant. The concentration is usually about 200 ml/l. Thus, AV difference is 50 ml, so 50 ml of O[2 ]is catched by 1 l of blood during its passage through the lungs. Then, O[2 ]consumption has to be assessed by measuring O[2 ]decay in the expired air by an oximeter. It is about 250 ml/min. The pulmonary blood flow and, thus, the cardiac output is then 5 l/min. Methods for Measuring Blood Flow Here, the settlement of a patient and all the necessary instruments during the estimation of the cardiac output using the direct Fick method is shown. The oxygen consumption is measured. To find out the arteriovenous difference of oxygen, the mixed venous blood is bleeded from the pulmonary artery with a catheter inserted through the brachial vene and the arterial blood from any peripheral artery because the concentration of oxygen is the same in all arteries as I have just mentioned. As you can see, the method is challenging, even for the patient. Nowadays, the cardiac output is thus usually estimated by other techniques, namely by the imaging techniques as echocardiography, computer tomography or magnetic resonance. Methods for Measuring Blood Flow 4.Fick Principle – Method of Indicatory Gas vto determine the instantaneous blood flow through a specific tissue vfor example the cerebral or coronary blood flow using inhaled nitrous oxide N2O – Kety method N2O removed from blood by brain / time averaged arteriovenous difference of N2O cerebral blood flow = N2O concentration in the venous blood A similar technique called the method of indicatory gas makes possible to measure the blood flow through various organs. For example, the brain or coronary blood flow may be measured with Kety method when nitrous oxide N[2]O is used as the indicator. It is inhaled for about 10 min till its concentrations in the venous blood and the brain tissue is equal. The course of changes of arterial and venous concentration of N[2]O is assessed by repetitive measurements of the concentrations. The total cerebral blood flow may be then counted as the ratio of N[2]O absorbed by the brain tissue per time (which is equal to its venous concentration) and the assessed time average of AV difference of N[2]O. (Nowadays, other methods are usually used to estimate dynamic changes of the blood flow through particular brain regions (which is not possible using the Kety method), specifically imaging techniques such as PET or fMRI.) Methods for Measuring Blood Flow 4.Fick Principle - Indicator Dilution Technique •known amount of an indicator (dye or radioactive isotope) is injected into a peripheral (an arm) vein (A, [mg]) •concentration of the indicator in serial samples of the arterial blood is determined •estimation of the averaged concentration of the indicator in the arterial blood after a single circulation (C, [mg/ml]) A C (t2 - t1) CO = [mg] [mg.ml-1.s] The Fick principle is also used in case of the indicator dilution technique when a known amount of an indicator A is injected into a peripheral vein and changes of its concentration are determined in serial samples of the arterial blood. The indicator concentration in the arterial blood first rapidly increases, after reaching its maximum, it starts to decrease and then increases again which corresponds to the start of the second circulation. The time of single circulation can be found by a linear extrapolation of the first decrease of the curve to the time axis. The averaged arterial concentration of the indicator during a single circulation C can be estimated. The cardiac output may be then counted as ratio of the amount of injected indicator A, and product of the averaged arterial concentration during the first circulation C and time of the circulation (t2 – t1). Methods for Measuring Blood Flow 4.Fick Principle - Indicator Dilution Technique •known amount of an indicator (dye or radioactive isotope) is injected into a peripheral (an arm) vein (A, [mg]) •concentration of the indicator in serial samples of the arterial blood is determined vthermodilution a cold saline (indicator) is injected into the right atrium through a double lumen catheter; the change of blood temperature (inversely proportinal to the blood flow) is recorded in the pulmonary artery using a thermistor in the other side of the catheter •estimation of the averaged concentration of the indicator in the arterial blood after a single circulation (C, [mg/ml]) A modification of the indicator dilution technique called thermodilution is also often used if catheterization is indicated from other reasons. A bolus of indicator, the cold saline (for example 20 ml, 0°C), is applied through the Swan-Ganz catheter to the right atrium and temperature of the blood is measured in a. pulmonalis (approx. 18 cm behind the place of saline application). The cardiac output is inversely proportional to the temperature change. Regulation Systemic Local Regulation of Blood Flow Q = DP . πr4 / 8ηl Resting Tone (intermediary vascular muscle tone at rest) vdue to tonic activity of vasocontrictive sympathetic fibres va role might play also: myogenic response of vessels to the blood pressure (later), high concentration of O2 in the arterial blood, Ca2+ Basal Tone vin response to denervation; due to spontaneous depolarizations of the vascular smooth muscles As mentioned at the beginning of this lecture, the blood flow, at a constant pressure, is mainly determined by the radius of a vessel according to the Hagen-Poisseuille formula. Thus, the blood flow may be easily influenced by vasoconstriction or vasodilatation. At rest, an intermediary, so called resting tone of the vascular smooth muscles is present, namely due to a tonic activity of the vasoconstrictive sympathetic fibres. In response to denervation, the tone decreases to the basal tone which is due to spontaneous depolarizations of the vascular smooth muscles. The resting tone may be regulated by various signals, local or systemic, which causes either vasoconstriction or vasodilatation as is shown in the next slide. The systemic regulation of the vessel tone is neural and humoral. The neural regulation mediated by the sympathetic and parasympathetic systems was a subject of some of other lectures in physiology during this semester, thus, will not be discussed in this lecture. Most factors contributing to the humoral systemic regulation of the blood flow are discussed during the endocrinne lectures, thus, will not be discussed in detail in this lecture. In this lecture, we are going to focus on local regulatory mechanisms including pO2, metabolites, histamine, kinins etc. Note that some factors, for example endothelin-1, may act in both directions. Endothelin-1 induces vasoconstriction through binding to its specific ET[A] receptor. On the other hand, it may also cause vasodilatation through its ET[B ]receptor and increase of NO (see later). Regulation of Blood Flow - Local 1.Metabolic Autoregulation 2.Myogenic Autoregulation 3.Regulation Mediated by Local Substances A.Acute B.Chronic seconds to minutes, but incomplete (about ¾ of the desired effect) hours, days to weeks , even months A.Acute 1.Metabolic Autoregulation The local regulation of vessel tone is either acute proceeding within seconds to minutes, or chronic taking hours to weeks or even months in some cases. First, the acute regulation will be discussed which usually covers about ¾ of the desired effect. The acute regulation may be mediated by the metabolic autoregulation, the myogenic autoregulation, or by regulation mediated by local substances formed mainly (but not only) by the endothelium. Regulation of Blood Flow - Local Metabolic Autoregulation Preferred to the systemic regulation in case of hypoxia (to preserve the adequate tissue perfusion). insufficient blood flow ↑ concentration of metabolites (CO2, lactic acid, adenosine, K+, phoshate), ↓ pH, ↑ osmolarity in the interstitium, ↑ tissue temperature (the metabolic heat); ↓ pO2 (the second theory based on the lack of O2 and nutrients) vasodilatation It plays the key role in e.g. brain, heart and skeletal muscles. ↑ metabolic demands of a tissue ↓ or stopped blood supply The metabolic autoregulation asserts in case of insufficient blood flow which may be caused either by an increase of the metabolic demands of a tissue (active hyperemia), or by a decreased or even stopped O[2] supply. The insufficient blood flow results in an increased concentration of various metabolites in the tissue, namely CO[2], the lactic acid, K^+ or adenosine. The intersticial pH decreases and osmolarity increases. The tissue temperature also increases due the metabolic heat. Another theory stresses the importance of the lack of O[2] and nutrients in the tissue. All these factors lead to the local vasodilatation which is preffered to the systemic regulation in case of hypoxia to preserve the adequate perfusion of the tissue. The metabolic autoregulation plays the key role in the brain, heart and skeletal muscles. Regulation of Blood Flow - Local Metabolic Autoregulation active hyperemia (increase of the blood flow induced by an increased metabolic activity of the tissue) reactive hyperemia (transient increase of the blood flow exceeding its common level after release of an occlusion; it gradually returns to the control level) (15-, 30- and 60-s occlusions of the femoral artery in a dog) The active hyperemia means increase of the blood flow during increased metabolic activity. During the reactive hyperemia, the blood flow is transiently increased above the common level after an occlusion of the arterial blood flow is released. During the occlusion, the metabolic vasodilatation occurs in the region without the blood supply. Thus, after release of the occlusion, the blood flow rapidly increases as the blood flushes into the dilated vessels. The effect of three gradually prolonging periods of occlusion of the femoral artery in a dog are shown here causing gradually higher increase of the blood flow which subsequently exponentially decreases back to the common level. Both active and reactive hyperemia are recorded during the task Pletysmography within physiological practicals. Regulation of Blood Flow - Local 1.Metabolic Autoregulation 2.Myogenic Autoregulation 3.Regulation Mediated by Local Substances A.Acute B.Chronic seconds to minutes, but incomplete (about ¾ of the desired effect) hours, days to weeks , even months A.Acute 2.Myogenic Autoregulation It plays an important role in the brain and kidneys. Regulation of Blood Flow - Local Myogenic Autoregulation (Bayliss effect) blood pressure ↑ ↑ blood flow and tension in the vascular wall ↑ mechanical stimulation, depolarization and subsequent contraction of the smooth muscle cells in the vascular wall ® vasoconstriction return of the blood flow back on the original level T = P . r Law of Laplace Q = DP / R The second type of local autoregulation of the blood flow is represented by the myogenic autoregulation based on the Bayliss effect. When the blood pressure rises, the blood flow increases as well according to the equation that you have already seen sooner. The tension in the vascular wall also rises according to the law of Laplace. These changes cause mechanical stimulation, depolarization and contraction of the vascular smooth muscles (due to activation of strech-sensitive calcium channels). The resulting vasoconstriction shifts the blood flow back to the original level. The myogenic autoregulation asserts especially in tissues requiring stable blood flow, as in the brain and kidneys. Regulation of Blood Flow - Local Myogenic Autoregulation The graph shows that this type of local regulation stabilizes the blood flow, here namely in muscles, despite marked changes of the blood pressure. If the myogenic regulation was absent, the blood flow would be unstable, highly dependent on the actual blood pressure (full circles). Regulation of Blood Flow - Local 1.Metabolic Autoregulation 2.Myogenic Autoregulation 3.Regulation Mediated by Local Substances A.Acute B.Chronic seconds to minutes, but incomplete (about ¾ of the desired effect) hours, days to weeks , even months A.Acute 3.Regulation Mediated by Local Substances The third type of local autoregulation is the regulation mediated by various substances released from various cell, namely from the endothelial cells. Regulation of Blood Flow - Local Regulation Mediated by Local Substances vimportant in the intermediate and larger arteries back upstream where the metabolic tissue changes causing dilatation of the microvessels cannot directly reach endothelial-derived relaxing factor (EDRF) – NO (half-life in the blood only 6 s) ® vasodilatation vsynthesized in the endothelial cells of arteriols and small arteries due to the shear stress induced by the flowing blood (deforms the endothelial cells in the direction of flow) vits synthesis stimulated by the products of thrombocyte aggregation (to keep vessels with intact endothelium permeable) and also by many primary vasoconstrictive substances Among the most important, the endothelial-derived relaxing factor belongs. It is constituted by nitric oxide NO and plays the key role in vasodilatation of intermediate and larger arteries where the metabolic autoregulation playing crucial role in the small tissue arteries cannot reach. If this larger arteries did not dilate, the local blood flow would never reach the required level in the case of higher tissue metabolic rate. NO is sythetized in the endothelial cells due to the shear stress causing deformation of the cells in the direction of the blood flow. By the way, the tonic release of NO seems to play an important role in maintance of the blood pressure within physiological boundaries. Synthesis of NO is also influenced by various substances, for example by products of thrombocyte aggregation and even by many substances with primary vasoconstrictive effect as histamine or kinins which, in the end, manifest a pronounced vasodilatory effect. Vasodilatation induced by many substances is likely mediated by NO as you can see on the next slide... …, for example in the case of acetylcholine. NO has also other physiological effects outside the cardiovascular system as its role in the antimicrobial and cytotoxic activity of various inflammatory cells, or in the relaxation of the smooth muscles in GIT. Regulation of Blood Flow - Local Regulation Mediated by Local Substances endothelial-derived relaxing factor (EDRF) – NO Here you can see the scheme of NO synthesis and mechanism of its effect. As I have mentioned a while ago, various factors including the shear stress and some substances (as acetylcholine and bradykinin) stimulate the enzyme NO synthase present in the endothelial cells. It then catalyzes formation of NO which diffuses into the nearby smooth muscle cells. The effect of NO is mediated by stimulation of soluble guanylyl cyclase which stimulates formation of cyclic GMP from GTP. It results in relaxation of the vascular smooth muscles, thus, in vasodilatation. NO is inactivated by hemoglobin, thus, its effect is really local. Clinical remarks: Nitroglycerine and other similar compounds used in the therapy of angina pectoris stimulate formation of the cGMP in the same way. Compounds such as Viagra support the penile erection by slowing breakdown of the cGMP (due to inhibition of the enzyme phosphodiesterase that breaks down cGMP). Regulation of Blood Flow - Local Regulation Mediated by Local Substances prostacyclin vsynthesized in the endothelial cells from the arachidonic acid vinhibition of thrombocyte aggregation and vasodilation thromboxane A2 vsynthesized from the arachidonic acid by thrombocytes vsupport of thrombocyte aggregation and vasoconstriction A balance between them is crucial for formation of the localized clot and preservation of the blood flow. (aspirin) Another vasodilatory mediator released by the endothelial cells is prostacyclin. It also inhibits thrombocyte aggregation. Prostacyclin is synthesized from the arachidonic acid similarly as thromboxane A2 which is released from thrombocytes, support their aggregation and vasoconstriction of the vessel. Thus, these two substances have contradictory (an opposite) effects. Their balance is crucial for formation of the localized clot and preserve the blood flow in the supply area. Clinical remarks: The drug called aspirin causes irreversible inhibition of the enzyme cyclooxygenase which participates in the formation of these substances. Thrombocytes cannot produce new enzyme and their renewal slow (half-life about 4 days) but the endothelial cells can do it. Thus, production of prostacyclin with inhibition of thrombocyte aggregation and vasodilatation overbalances production of thromboxane A2 and its opposite effects. That is why aspirin is used in prevention of the myocardial infarction, stroke and so on. Regulation of Blood Flow - Local Regulation Mediated by Local Substances endothelins vseveral similar polypeptides synthesized by the endothelial cells (ET-1, ET-2, ET-3 ) vET-1 – one of the most potent vasoconstrictive substances v2 endothelin receptors: ETA – specific for ET-1, in many tissue vessels, ® vasoconstriction ETB – ET-1 to ET-3, unknown function (maybe vasodilatation – through increased synthesis of NO - and developmental effects) vthe exact physiological role not known vreleased from the endothelial cells in the damaged tissue ® vasoconstriction ® restricts bleeding vplay a role in closing ductus arteriosus at birth Vasoconstrictive substances, namely endothelins, are released by the endothelium as well. The most important one, at least in the cardiovascular system, seems to be the endothelin-1, one of the most potent vasoconstrictive agents in the body. Endothelin-1 binds to the endothelin receptor ET[A] which is present in many tissue vessels and mediates its vasoconstrictive effect. The exact physiological role is not known. Beside the role of endothelin-1 mediated vasoconstriction in the restriction of bleeding in the damaged tissue or in closing ductus arteriosus at birth, endothelins seem to have also developmental effects, maybe through their binding to the other endothelin receptor ET[B] (mice with both endothelin-1 alleles deleted manifest with craniofacial abnormalities, die of the respiratory failure at birth and megacolon). Serotonin (5-OH tryptamine) vvasodilatory effect •in an undamaged tissue •through increased activity of NO synthase vvasoconstrictive effect •in a damaged tissue •direct local effect •released from thrombocytes Regulation of Blood Flow - Local Beside many other effects in the human body (GIT, CNS), serotonin can have both the vasodilatory and vasoconstrictive effects. The vasodilatory effect can be observed in healthy, undamaged tissue and is caused by an increased activity of NO synthase, thus, through production of NO which we have talked about before. The vasocontrictive effect can happen in a damaged tissue, not just in really injured vessels but, for example, in an arteria with atherosclerosis. This is a direct and local effect of serotonin which is released from thrombocytes. (Clinical remark: Serotonin may contribute to a certain acute coronary ischemic syndromes.) Regulation of Blood Flow - Local Other, specific mechanisms vlocal vasoconstriction of damaged arteries and arteriols vvasoconstriction (vasodilatation) induced by a decrease (increase) of the tissue temperature vspecialized tissues (kidneys, brain, etc.) (due to release of serotonin and thromboxane A2 from thrombocytes and endothelin-1 from the endothelial cells) There are some more specific mechanisms of local regulation of the blood flow, for example local vasoconstriction of the damaged arteries due to the release of serotonine and thromboxane A2 from thrombocytes and endothelin-1 from the endothelial cells as mentioned above. Temperature-dependent regulation of the vascular radius is also well known. Regulation of the blood flow in specific tissues is discussed in separate lectures. Regulation of Blood Flow - Local 1.Metabolic Autoregulation 2.Myogenic Autoregulation 3.Regulation Mediated by Local Substances A.Acute B.Chronic seconds to minutes, but incomplete (about ¾ of the desired effect) hours, days to weeks , even months Regulation of Blood Flow - Local Chronic regulation It is especially important in case of the long-term change of metabolic demands of a tissue - to provide sufficient blood flow without circulation overload. The chronic local regulation enables maintainance of the blood flow in a much wider range of the blood pressure than the acute one. Its is especially important in case of a long-term change of the tissue metabolic demands because it may sufficiently increase the blood flow without overload of the circulation. Regulation of Blood Flow - Local Chronic regulation vmediated by changes of the tissue vascularity vproceeds fast (within days) in the young individuals and in newly formed tissue (new scar, tumor tissue) vs. within even months in the elderly and differentiated tissues vthe key role – lack of O2 (higher altitude, retrolental fibroplasia in premature newborns after the curative stay in the oxygen tent) and also nutrients videntified number of factors increasing grow of new vessels - angiogenic or vascular growth factors - small peptides, best characterized: vascular endothelial growth factor (VEGF), fibroblast growth factor, and angiogenin The chronic regulation is mediated by changes of the tissue vascularity which are induced by the lack of O[2] and nutrients. A number of angiogenic factors has been identified, for example the vascular endothelial growth factor or angiogenin. Changes of the tissue vascularity proceed fast in the young individuals and in newly formed tissues, on the contrary, slowly, even within months, in the elderly and in differentiated tissues. Regulation of Blood Flow - Local Chronic regulation Guyton and Hall - Textbook of Medical Physiology (12th edition) unstimulated muscle regularly stimulated muscle Large increase in number of capillaries (white dots) in a rat anterior tibialis muscle that was electrically stimulated to contract for short periods of time each day for 30 days (right image) compared to the unstimulated muscle (left image). Regulation of Blood Flow Local Systemic B.Humoral A.Neural B.Humoral The systemic humoral regulation of the blood flow will be shortly discussed ob the following slides. Regulation of Blood Flow - Systemic Vasoconstrictive substances Humoral regulation vepinephrine (high levels) ® vasodilatation in the skeletal muscles, liver and coronary arteries (β2-rec.) ® vasoconstriction in other tissues vnorepinephrine ® generalized vasoconstriction (α1-rec.) (↑ BP ® reflex bradycardia, ↓ CO) vangiotensin II ↓ BP ® ↑ sekretion of renin ® formation of angiotensin II ® generalized vasoconstriction (+ ↑ water intake and ↑ aldosterone) vvasopressin (antidiuretic hormone) ® generalized vasoconstriction (+ ↑ reabsorption of water in the kidneys) Humoral systemic regulation is mediated by various vasoconstrictive and vasodilatory substances released to the circulation which, thus, may influence not just the local blood flow but globally change the radius of vessels in the body. Regarding the vasoconstrictive substances, norepinephrine, epinephrine, angiotensin II and vasopressin are the most important. Their effects on the vessel tone are shortly listed. The graph shows effects of epinephrine and norepinephrine on the cardiovascular system: Since norepinephrine causes generalized vasoconstriction, both the systolic and diastolic blood pressures substantially rise which is accompanied by bradycardia due to baroreflex activity (the cardiac output decreases). Epinephrine causes vasoconstriction at some places but vasodilation at others (namely at muscles and coronary arteries), thus, the diastolic blood pressure may even decrease. The cardiac output increases due to its action on the cardiac muscle. Regulation of Blood Flow - Systemic Vasodilatory substances Humoral regulation •released in tissues (from the mast cells), or from basophiles in the blood, during tissue damage or inflammation (also allergic) vhistamine ®vasodilatation of arteriols + ↑ permeability of capillaries (edemas; anaphylactic shock) vVIP (vasoactive intestinal peptide) ® vasodilatation (+ many other effects in GIT, namely relaxation of the intestinal smooth muscles including sphincters) vatrial natriuretic peptide (ANP) ® ↓ reactivity of the vascular smooth muscles on vasoconstrictive stimulation (+ ↑ natriuresis – relaxation of the measangial cells and, thus, ↑ glomerular filtration rate, + inhibition of vasopressine secretion, + ↓ aldosterone) through EDRF (vasoconstrictor by itself) Beside the atrial natriuretic peptide and vasoactive intestinal peptide (that are lectured within other topics), histamine and, in the next slide, kinins show vasodilatory effects. Histamine is released in the damaged and inflamed tissue to dilate arterioles, which is mediated by NO. Histamine also increases permeability of the capillary wall which may result in edemas. Clinical remark: Histamine is an important mediator during the anaphylactic shock which represents the most serious life-threatening form of the allergic reaction. It is characterized by a highly increased level of histamine causing a marked decrease TPR due to the general vasodilatation and also a decrease of the blood volume due to the leak of fluids from capillaries into the interstitial tissue. Thus, the blood pressure is critically decreased (shock). •small polypeptides, half-life - several minutes Regulation of Blood Flow - Systemic Vasodilatory substances Humoral regulation vkinins - bradykinin and lysylbradykinin (kallidin) ®vasodilatation of arteriols + ↑ permeability of capillaries regulation of the blood flow and leak of fluids from capillaries in the inflamed tissue + regulation of the blood flow in the skin, salivary and GIT glands in common conditions (similar to histamine) Kinins are primary tissue hormones but, in a small amount, they can be also detected in the circulating blood. They exerts effects similar to histamine. They are involved in regulation of the blood flow and leak of fluids from capillaries in the inflamed tissue. Under physiological conditions, kinins play an important role in the regulation of blood flow in the skin, salivary and GIT glands. Here you can see the scheme of their production from the high and low-weight kininogen which is catalyzed by tissue and plasma kallikrein. (Both bradykinin and lysylbradykinin are inactivated by splitting with kininase I and II. The kininase II is the same enzyme as the angiotensin-converting enzyme.) Regulation of Blood Flow - Systemic Other factors Humoral regulation vions vasoconstriction: ↑ Ca2+, slightly ↓ H+ vasodilatation: ↑ K+, ↑ Mg2+; ↑ H+, notably ↓ H+ acetate, citrate (anions) – only mild effect Changes in the plasmatic ionic concentrations may also influence the vascular tone, namely calcium ions cause vasoconstriction, and potassium, magnesium and hydrogen ions do vasodilatation.