1. Local control of blood flow By Dr. Amal F. Dawood MD., Ph.D Assistant Professor of Physiology

2. Learning objectives Describe role of the arterioles as resistance vessels Describe acute mechanism of local control of blood flow Describe mechanism of autoregulation Describe role of the substances secreted from the endothelium in controlling local blood flow Describe chronic mechanism of local control of blood flow

3. Importance of blood flow control Blood is delivered to all organs at the same mean arterial pressure, so the driving force for flow is identical for each organ. Therefore, difference in flow to various organs are determined by difference in the extend of vascularization and by differences in the resistance offered by the arterioles supplying each organ Experiments have shown that the blood flow to each tissue usually is regulated at the minimal level that will supply the tissue’s requirements—no more, no less. By controlling local blood flow in such an exact way, the tissues almost never suffer from oxygen nutritional deficiency and the workload on the heart is kept at a minimum.

4. Mechanism of blood flow control Local blood flow control can be divided into two phases: Acute control local vasodilation or vasoconstriction of the arterioles, metarterioles, and precapillary sphincters. Occur within seconds to minutes. Long-term control Occur over a period of days, weeks, or even months. Better control of the flow in proportion to the needs of the tissues. Increase or decrease in the physical sizes and numbers of actual blood vessels supplying the tissues.

5. Acute Control of Local Blood Flow Effect of Tissue Metabolism on Local Blood Flow Acute Local Blood Flow Regulation according to Oxygen level Decreases oxygen availability to the tissues, such as (1) at high altitude at the top of a high mountain, (2) in pneumonia, (3) in carbon monoxide poisoning (4) in cyanide poisoning the blood flow through the tissues increases markedly. There are two basic theories for the regulation of local blood flow when either the rate of tissue metabolism changes or the availability of oxygen changes. They are (1) the vasodilator theory and (2) the oxygen lack theory.

6. 1- Vasodilator Theory —Possible Special Role of Adenosine. According to this theory, the greater the rate of metabolism or the less the availability of oxygen or some other nutrients to a tissue, the greater the rate of formation of vasodilator substances in the tissue cells. The vasodilator substances diffuse through the tissues to the precapillary sphincters, metarterioles, and arterioles to cause dilation. Some of the different vasodilator substances are adenosine, carbon dioxide, adenosine phosphate compounds, histamine, potassium ions, and hydrogen ions.

7. Adenosine is an important local vasodilator for controlling local blood flow specially for the heart : Decrease coronary blood flow, causes enough local vasodilation in the heart to return coronary blood flow back to normal. Increase heart’s metabolism, causes increased utilization of oxygen, followed by (1) decreased oxygen concentration in the heart muscle cells with (2) consequent degradation of adenosine triphosphate (ATP), which (3) increases the release of adenosine. Adenosine leaks out of the heart muscle cells to cause coronary vasodilation.

8. 2- Oxygen Lack Theory for Local Blood Flow Control. The nutrient lack theory Oxygen (and other nutrients as well) is required to cause vascular muscle contraction. Therefore, in the absence of adequate oxygen, the blood vessels would relax and therefore naturally dilate. Also, increased utilization of oxygen theoretically could decrease the availability of oxygen to the smooth muscle fibers in the local blood vessels. The number of precapillary sphincters that are open at any given time is proportional to the requirements of the tissue for nutrition. The precapillary sphincters and metarterioles open and close cyclically several times per minute, with the duration of the open phases being proportional to the metabolic needs of the tissues for oxygen. The cyclical opening and closing is called vasomotion.

9. Possible Role of Other Nutrients Besides Oxygen in Control of Local Blood Flow lack of glucose,( amino acids or fatty acids) causes vasodilation. In addition, vasodilation occurs in the vitamin deficiency disease beriberi, in which the patient has deficiencies of the vitamin B substances thiamine, niacin, and riboflavin. These vitamins are necessary for oxygen-induced phosphorylation, which is required to produce ATP.

10. Special Examples of Acute “Metabolic” Control of Local Blood Flow Active hyperemia:  This is the increases blood flow to active tissues.  Increased tissue activity leads to increased production of vasodilator metabolites. The resulting vasodilatation leads to increased blood flow. Reactive hyperemia:  It is the increase in blood flow to a region when its circulation is re-established after a short period of occlusion. When a blood supply to a limb is occluded, arterioles distal to the occlusion dilate due to local effect of hypoxia and accumulation of vasodilator metabolites.  When the circulation is reestablished, blood flowing into the dilated vessels is increased. This makes the limb feels warm and the skin burning red.

11. Autoregulation Metabolic” and “Myogenic” Mechanisms A rapid increase in arterial pressure causes an immediate rise in blood flow. But, within less than a minute, the blood flow in most tissues returns almost to the normal level, even though the arterial pressure is kept elevated. This return of flow toward normal is called “autoregulation” of blood flow. The Metabolic Theory : ↑ arterial pressure lead to ↑ oxygen and other nutrients to the tissues and “washes out” the vasodilators released by the tissues → constriction of blood vessels and return the flow nearly to normal. Vasodilator Metabolites: 1-↓ in O2 tension 2-low pH (acidosis)e.g. lactic acid. 3- ↑ CO2 tension (hypercapnia) 4- ↑ osmolarity(hypertonicity). 5- ↑ in body temperature. 6- ↑ of K+ ions. 7-Adenosine in cardiac muscle. 8-Histamine in injured tissues.

12. Sudden stretch of small blood vessels causes the smooth muscle of the vessel wall to contract. High arterial pressure stretches the vessel, this in turn causes reactive vascular constriction that reduces blood flow nearly back to normal and vice versa. The myogenic response is inherent to vascular smooth muscle and can occur in the absence of neural or hormonal influences. It is most pronounced in arterioles but can also be observed in arteries, venules, veins, and even lymphatic vessels. The Myogenic Theory

13. Myogenic contraction is initiated by stretch-induced vascular depolarization, which then rapidly increases calcium ion entry from the extracellular fluid into the cells, causing them to contract. Changes in vascular pressure may also open or close other ion channels that influence vascular contraction. The myogenic mechanism is important in preventing excessive stretch of blood vessel when blood pressure is increased. Indeed, metabolic factors appear to override the myogenic mechanism when metabolic demands of the tissues are significantly increased, such as during vigorous muscle exercise.

14. Control of Tissue Blood Flow by Endothelial-Derived Relaxing or Constricting Factors Nitric Oxide(NO), —A Vasodilator Released from Healthy Endothelial Cells lipophilic gas After diffusing out of the endothelial cell, NO has a half-life in the blood of only about 6 seconds and acts mainly in the local tissues where it is released. The following stimuli activate eNOS and increase NO production: 1-Acetylcholine 2-Bradykinin 3-Shear stress Shear Stress: It is the tangential drag force produced by blood moving across the endothelial surface, increased by blood flow Also stimulated by some vasoconstrictors, such as angiotensin II, which bind to specific receptors on endothelial cells. The increased NO release protects against excessive vasoconstriction Also Histamine via H1 receptors, VIP, Substance P produce relaxation via endothelium

15. and cGMP-dependent protein kinase (PKG)

16. When endothelial cells are damaged by chronic hypertension or atherosclerosis, impaired NO synthesis may contribute to excessive vasoconstriction and worsening of the hypertension and endothelial damage, which, if untreated, may eventually cause vascular injury and damage to vulnerable tissues such as the heart, kidneys, and brain. Nitroglycerin and other nitrate derivatives are used to treat patients suffering from angina pectoris. These drugs, when broken down chemically, release NO and evoke dilation.

17. Endothelin—A Powerful Vasoconstrictor Released from Damaged Endothelium. This substance is present in the endothelial cells of all or most blood vessels but greatly increases when the vessels are injured. The usual stimulus for release is damage to the endothelium, such as that caused by crushing the tissues or injecting a traumatizing chemical into the blood vessel. After severe blood vessel damage, release of local endothelin and subsequent vasoconstriction helps to prevent extensive bleeding from arteries. Increased endothelin release is also believed to contribute to vasoconstriction when the endothelium is damaged by hypertension.

18. Long-Term Blood Flow Regulation After full activation of acute mechanisms, the blood flow usually is adjusted only about three quarters of the way to the exact additional requirements of the tissues. However, over a period of hours, days, and weeks, a long-term type of local blood flow regulation develops in addition to the acute control. Long-term regulation of blood flow is especially important when the tissue becomes chronically overactive and therefore requires increased quantities of oxygen and other nutrients.

19. Mechanism of Long-Term Regulation—Change in “Tissue Vascularity ” The mechanism of long-term local blood flow regulation is principally to change the amount of vascularity of the tissues. For instance, if the metabolism in a tissue is increased for a prolonged period, vascularity increases, a process generally called angiogenesis ; if the metabolism is decreased, vascularity decreases. The final degree of response is much better in younger tissues than in older Angiogenesis explains the manner in which metabolic factors in local tissues can cause growth of new vessels.

20. Role of Oxygen in Long-Term Regulation. Oxygen is important for long-term control. Premature human babies put into oxygen tents for therapeutic purposes may cause retrolental fibroplasia. Importance of Vascular Endothelial Growth Factor in Formation of New Blood Vessels vascular endothelial growth factor (VEGF), fibroblast growth factor, and angiogenin are angiogenic factors which promote new vessel growth. They cause new vessels to sprout from other small vessels.

21. Certain substances, such as some steroid hormones, have exactly the opposite effect on small blood vessels (inhibit angiogenesis) For example, angiostatin, a fragment of the protein plasminogen, is a naturally occurring inhibitor of angiogenesis. There is great interest in their potential use in arresting blood vessel growth in cancerous tumors Vascularity Is Determined by Maximum Blood Flow Need, Not by Average Need.

22. Development of Collateral Circulation—a Phenomenon of Long-Term Local Blood Flow Regulation When an artery or a vein is blocked in virtually any tissue of the body, a new vascular channel usually develops around the blockage and allows at least partial resupply of blood to the affected tissue. The collateral vessels continue to grow for many months thereafter, almost always forming multiple small collateral channels rather than one single large vessel. Under resting conditions, the blood flow usually returns very near to normal, but the new channels seldom become large enough to supply the blood flow needed during strenuous tissue activity. The most important example of the development of collateral blood vessels occurs after thrombosis of one of the coronary arteries.

23. Humoral Control of the Circulation Vasoconstrictor Agents 1- Norepinephrine and Epinephrine. 2- Angiotensin II. Angiotensin II is powerful vasoconstrictor substance. Acts on many of the arterioles of the body at the same time to increase the total peripheral resistance, thereby increasing the arterial pressure. 3- Vasopressin. antidiuretic hormone one of the body’s most potent vascular constrictor substances.. Its concentration after severe hemorrhage can increase enough to raise the arterial pressure. increase greatly water reabsorption from the renal tubules back into the blood

24. Vasodilator Agents 1- Bradykinin. The kinins are small polypeptides that are split away by proteolytic enzymes (kallikrein) which is present in the blood and tissue fluids in an inactive form. Could be activated by maceration of the blood, by tissue inflammation. Bradykinin causes both powerful arteriolar dilation and increased capillary permeability. 2- Histamine. Histamine is released if the tissue becomes damaged or inflamed or is the subject of an allergic reaction. Most of the histamine is derived from mast cells in the damaged tissues and from basophils in the blood. Histamine has a powerful vasodilator effect on the arterioles and, increase greatly capillary permeability cause large quantities of fluid to leak out of the circulation into the tissues, inducing edema

25. Vascular Control by Ions and Other Chemical Factors An increase in calcium ion concentration causes vasoconstriction. An increase in potassium ion concentration, within the physiological range, causes vasodilation. An increase in magnesium ion concentration causes powerful vasodilation An increase in hydrogen ion concentration causes dilation of the arterioles. An increase in carbon dioxide concentration causes moderate vasodilation in most tissues but marked vasodilation in the brain.