The Cardiovascular System, Blood flow and the Control of Blood Pressure

1. Pressure produced by the LV is stored by the elastic walls of the arteries and slowly released through elastic recoil.
2. Arteries are the Pressure Reservoir of the circulatory system
3. Arterioles - give downstream variable resistance - 
1. Arteriole diameter is controlled by:
1. Local factors: [Oxygen]
2. Hormones
3. Autonomic nervous system 
4. Veins are the Volume Reservoir
5. BLOOD VESSELS
1. endothelium - has paracrine function  regulates
1. BP, blood vessel growth, and absorption of material
2. Blood vessels contain Vascular Smooth Muscle
1. arranged in circular or spiral layers
2. Muscle tone
3. Calcium Channels
3. Arteries and Arterioles Carry Blood Away from the Heart 
1. Some arterioles branch into METARTERIOLES - the walls of which are only partly surrounded by smooth muscle - unlike arterioles
2. PRECAPILLARY SPHINCTERS direct blood from the metarterioles, if
1. Dilated directs blood to the capillaries
2. Constricted directs blood to the venous system
3. Metarterioles allow WBC to migrate directly from the metarterioles arterial circulation to the venous circulation 
4. Metarterioles can act as bypass channels
4. Exchange takes place in the Capillaries
1. Many capillaries are associated with pericytes - used to contract capillaries - contribute to the "tightness of the capillary permeability
2. Cerebral circulation - pericytes and glial cells have tight junctions that create the Blood Brain Barrier.
3. Pericytes secrete factors that influence growth and can differentiate to become smooth muscle or new endothelial cells.
1. Loss of pericytes around the capillaries in the retina is a hallmark of diabetic retinopathy, a  leading cause of blindness.
5. Blood Flow Converges in the venules and veins
1. There are more veins then arteries - the veins hold more than half of the of the blood in the circulatory system. 
2. Volume reservoir
6. Angiogenesis Creates new blood vessels
1. Malignant tumours (cancer) are dependent on angiogenesis to grow. So is normal growth, menstruation, and wound healing.
2. Growth Factors:
1. vascular endothelial growth factor (VEGF)
2. fibroblast growth factor (FGF)
3. These are mitogens - promoting mitosis or cell division - 
4. Produced in the smooth muscle and pericytes
5. may be useful in coronary artery disease to form collateral circulation - the collateral circulation is the only reason my father lives with blocked myocardial arteries.
3. Angiostatin inhibits angiogenesis
1. made from plasminogen and endostatin
2. may be useful in cancer treatment
6. Blood Pressure
1. driving pressure for blood flow
1. Blood Pressure is highest in the arteries and lowest in the veins
1. Systolic pressure - diastolic pressure = pulse pressure
2. 120 mmHg - 80 mmHg =  40 mmHg
3. Unidirectional flow aided by valves - 
4. Venous return is aided by the Skeletal muscle Pump and Respiratory Pump
2. Arterial Blood Pressure Reflects the Driving Pressure of for Blood Flow
1. Mean arterial pressure is used to reflect the driving pressure pressure. Closer to diastole than systole as diastole is twice as long as systole.
2. MAP = DP + 1/3 (Systolic - Diastolic Pressure)
3. MAP = 80 + 1/3 (120-80) = 93 mmHg
4. Flow is proportionate to dP/R
1. Flow requires dP - change in pressure
2. Flow from High pressure to low Pressure
3. Flow is opposed by resistance
4. Resistance - viscosity of the blood, length of the system and radius of the blood vessel
5. Flow = ml/min
6. Flow velocity = cm/min or mm/sec
7. Velocity = flow rate / area
5. Hypotension - low blood pressure - blood flow unable to overcome gravity
6. Hypertension (>140/90) 
3. Blood Pressure is estimated by Sphygomanometry
1. Korotkoff sound
4. Cardiac Output and Peripheral resistance Determine Mean Arterial Pressure
1. Blood flow in the aorta is equal to the blood flow in the arteries
2. Blood flow in the arteries is influenced primarily by the peripheral resistance
3. MAP is proportional to the CO x Resistance in the arterioles
5. Changes in Blood Volume Affect Blood Pressure
1. Increase volume increases pressure, vice versa
1. Fast response - compensation by the CVS - vasodilatation and decreased cardiac output
2. Slow response - Increased renal urinary excretion
2. Hypotension - vasoconstriction and increased sympathetic stimulation of the heart 
7. Resistance in the Arterioles
1. R ~= (L x viscosity) / resistance cube
2. as Length and Viscosity are relatively constant, R = 1/r cubed
3. Arterioles are the main site of vascular resistance - 60% of the total resistance to flow of the system
4. Influenced by:
1. Local control of arteriolar resistance: matching blood flow to tissue needs 
2. Sympathetic reflexes: CNS control
3. Hormones: influence Sodium and water renal excretion and altering the autoimmune reflex control
1. Myogenic Autoregulation Automatically Adjusts Blood Flow
1. Stretching the smooth muscle in the arteriole by increased blood pressure - mechanically gated calcium channels in the muscles membranes are opened. Calcium binds with calmodulin. Calcium+Calmodulin activates myosin light chain kinase MLCK. MLCK in myosin heads and increases the ATPase activity. Active myosin cross bridges slide along the actin and create muscle tension.  
2. Paracrines Alter Cascular Smooth Muscle Contraction
1. Local Hypoxia
1. Increases CO2, Extracellular Potassium, Acidosis - increased Hydrogen ions
2. Reduced Oxygen
3. NO  best known for its role in erectile dysfunction
4. ADENOSINE release by the myocardial cells in the presence of local hypoxia 
2. Following hypoxia, when restoring blood flow, there is a period of reactive hyperemia as the paracrines are washed away.
3. The Sympathetic Branch Controls Most Vascular Smooth Muscle
1. Hormones: 
1. Atrial natriuretic peptide and angiotensin II (ANGII) have significant effect on kidney excretion of ions and water
2. Arteries are innervated by the sympathetic nervous system
1. EXCEPT the penis and clitoris - the parasympathetic nervous system - paracrine NO is released for engorgement
3. Tonic discharge norepinephrine from the sympathetic system gives the myogenic tone of the arterioles Norepinephrine binds to alpha receptors causing vasoconstriction. This is useful in diverting blood to central organs in prolonged fight or flight response - like from GUT to heart, liver and skeletal muscle.
4. Epinepharine - Adrenal Medulla - 
1. augments the effects of norepinepharine but has a lower affinity for the alpha receptor
2. Binds to the non-innervated B2 receptors, found in the heart, liver and skeletal muscles - and therefore respond primarily to epinepharine - causing vasodilatation 
8. Distribution of Blood to the tissues
1. regulated by the local metabolic needs, local control and homeostatic reflexes
2. parallel arrangement of blood vessels
3. Blood flow rate is equal in all tissues - equal to the cardiac output
4. Flow is inversely proportionate to resistance
5. metartrioles provide precapillary sphincters that restrict flow to the capillaries
9. Exchange at the Capillaries
1. distance of interstitial tissue from capillaries - diffusion over a short distance
2. density of capillaries reflects the metabolic activity of the tissues - oxygen, nutrients, 
3. There are two types of capillaries
1. Continuous capillaries that have "leaky" junctions
1. evolved to form the blood brain barrier that protect the neural tissue from toxins that may be present
2. Fenestrated capillaries that have large pores - supported by a basal lamina
1. transport large volumes of fluid to pass rapidly between the plasma and the interstitial fluid.
2. Found in the Kidney and the large intestine - where they are associated with absorptive transporting epithelia. 
3. Sinusoids: non-typical capillaries - found in three tissues - bone marrow, spleen, and liver. 
1. 5 times wider, with gaps and fenestrations- 
1. allowing newly produced blood from the bone marrow to enter the circulation, and 
2. proteins to enter circulation from the liver - as there is no basal lamina in the liver.  
1. Velocity of Blood Flow is lowest at the capillaries
1. at a consistent flow rate, velocity of flow is fastest in the smaller vessel, than the larger vessel - moving rapidly through the capillaries. The primary determinant for velocity is the TOTAL CROSS SECTIONAL AREA OF ALL THE CAPILLARIES. As the total cross sectional area of the capillaries covers an area larger than all the arteries and veins the flow is low in the capillaries. Allows time for diffusion. 
2. Most Capillary Exchange Takes Place by diffusion and transcytosis
1. diffusion of small molecules - oxygen, CO2, 
2. dissolved solutes can diffuse freely through the fenestrations
3. Larger proteins can not pass through the junctions, however proteins and large molecules - transcytosis
3. Capillary Filtration and Absorption Take Place by bulk flow
1. Bulk flow as a result of Hydrostatic and osmotic pressure gradients
1. Absorption - flow into the capillary
2. Filtration - flow out of the capillary
3. The presence of protein in the plasma and the absence in the interstitial fluid is the main difference between the plasma and interstitial fluid. The pressure of the proteins is the colloid osmotic pressure (oncotic pressure).
10. The Lymphatic System
1. Act with 3 systems
1. the cardiovascular system, the lymphatic system and the immune system
2. returns fluid from the CVS, picks up fat from the intestines, destroying foreign pathogens
3. Blind end lymph vessels lie close to all blood capillaries except
1. except in the kidney and the CNS
4. single layer of flattened endothelium anchored by to the surrounding connective tissue by fibers that hold the walled vessel open. Large gaps for protein and bacteria - 
5. Unidirectional semilunar valves - ultimately drain into the lymp duct - drain into the junction of the subclavian vein to the internal jugular vein   
6. Skeletal Muscle Pump drives flow
1. Edema results from Alterations in Capillary Exchange
1. Inadequate drainage of lymph, or
1. Obstruction, especially at the lymph nodes- parasites, cancer or therapeutic radiation, elephantiasis 
2. blood capillary filtration that  that greatly exceeds capillary absorption
1. An increase in capillary hydrostatic pressure  
1. Indicative of increased venous pressure
1. Right Heart failure
2. Decrease in plasma protein concentration
1. Severe malnutrition or liver failure
3. Increase in interstitial proteins
11. Regulation of Blood Pressure
1. Medullary cardiovascular control centre 
1. The Baroreceptor Reflex controls Blood Pressure
1. Stretch sensitive baroreceptors are located in the walls of the carotid arteries and the aorta
2. Baroreceptor reflex that increases the rate of firing when blood pressure increases.
3. to the Medullary Cardiovascular Control Centre via sensory neurons - 
4. rapid adjustment - within 2 heart beats of the stimulus
5. Heart has Tonic Sympathetic Control
1. Increase sympathetic stimulation causes  vasoconstriction, increases rate at SA node, shortens conduction time at AV node, and enhances the force of myocardial contraction.
2. Orthostatic Hypotension Triggers the Baroreceptor Reflex
12. Cardiovascular Disease
1. Risk factors including Smoking and Obesity
1. modifiable risk factors for coronary artery disease 
2. Diabetes is a major risk factor for Coronary artery disease, so is elevated cholesterol.
2. Atherosclerosis is an Inflammatory Process in which microphages release enzymes that convert stable plaques to vulnerable plaques
1. LDL-C Low density Lipoprotein complex, when Apo-B binds with the LDL receptor found in the Clathrin-Coated Pits on the cell membrane - and the Receptor-LDL-C complex is brought into the cell by endocytosis. The receptor recycles to the membrane and the endosome fused with the lysosome. LDL-C is digested to amino acid and freed cholesterol used to make cell membranes and steroid hormones.
2. Endothelial cells transport the LDL-C into the extracellular space so that it accumulates under the intima
3. The Macrophages ingest cholesterol and form lipid-filled foam cells. Cytokines released from the macrophages promote smooth muscle cell division. 
4. Early stage lesion - fatty streak
5. Progressively grows - smooth muscle reproduce - forming bulging plaques - protrude into the lumen of the artery
6. Plaques harden and form calcified regions with fibrous collagen caps. 
7. Stable plaques have thick fibrous caps - 
8. Unstable or vulnerable plaques are have a thin fibrous cap that are more likely to rapture and expose the collagen and activate platelets that initiate blood clots - thrombus 
9. Myocardium infarct - anaerobic metabolism without sufficient ATP to pump the Calcium out of the cell. The combination of unusually high calcium and hydrogen ions in the cell closes the gap junctions in the cell. The closure electrically isolate the damaged cell and forces and alternative electrical pathway. If the damaged area is big enough it may lead to arrythmia and cardiac arrest and death.
3. Hypertension represents a failure in Homeostasis
1. Chronic hypertension - BP > 130/90 mmHg
1. CVS risk doubles with each increase of 20/10 mmHg of BP above 115/75 mmHg
2. 90% essential
3. Adaptation of baroreceptors to the chronically elevated BP
4. promotes Atherosclerotic plaque formation
5. Adds strain on the heart increasing afterload
6. The Stroke volume remains consistent!!! 
7. Ventricular hypertrophy
8. Left Heart failure - pulmonary edema - oxygen exchange in the lung is decreased. Low oxygen for aerobic metabolism further weakens the effective contractions of the heart - creating a vicious cycle of congestive heart failure