NROSCI/BIOSC 1070 and MSNBIO 2070 September 27, 2017 Cardiovascular 6 Special Circulations Coronary Muscle The coronary arteries branch directly from the aorta, and provide the perfusion of the heart. Although blood actually is pumped through the heart, only ~ 100 µm of the inner endocardial surface can obtain significant amounts of nutrition directly from the blood supply in the cardiac chambers.

Blood flow through the coronary during systole and diastole is different than in most other tissues of the body. The blood flow to the ventricles falls during systole, and increases during diastole. During ventricular contrac- tion, blood flow through the capillaries is obstructed by compression of the vessels. Thus, blood flow increases during diastole when the muscle around the vessels relaxes. Autoregulatory mechanisms are paramount in adjusting the blood flow through the heart. Another major influence on dilation of the coronary arteries is epinephrine released from the adrenal gland. Cerebral Circulation The cerebral circulation is almost completely insensitive to neural and hormonal influences that produce vasoconstriction elsewhere in the body. By far the predominant factor that controls blood flow through the cerebral circulation is paracrine release. In particular, carbon dioxide has a strong vasodilation effect on the cerebral vessels.

Skeletal Muscle Circulation Control of blood flow to skeletal muscle is in many respects similar to that in the heart. Paracrine fac- tors have strong influences, and vasodilation is induced by the release of epinephrine from the adrenal gland. A major difference between the two circulations is that skeletal muscle are richly in- nervated by sympathetic vasoconstrictor fibers, and are major resistance vessels to contribute to total peripheral resistance. Because skeletal muscle mass is so large, vasodilation of muscle vessels would greatly diminish total peripheral resistance unless vasoconstriction occurs in other vascular beds. It is thus necessary that the central nervous system provides control of blood flow through skeletal muscle.

9/27/17 Page 1 Cardiovascular 6 Body Fluid Compartments:

Fluid in the body is located in three distinct compartments: Plasma (~ 3 L) Interstitial fluid (~12 L) Intracellular fluid (~25 L) To reach that intracellular compartment from the plasma, a molecule must diffuse across the plasma membrane into the interstitial compartment, and then across the into the intracellular fluid. Capillaries are composed of a single layer of endothelial cells and a basement mem- brane; the thickness of the wall is only about 0.5 micrometers. Small intercellular clefts typically separate the endothelial cells. Capillaries are often associated with elongated, highly branched cells that form a meshlike layer between the and interstitial fluid. These cells are called pericytes. The pericytes contribute to restricting capillary permeability.

Exchange of materials through capillaries usually occurs through diffusion. Small and uncharged and lipid-soluble molecules

(including O2 and CO2) have no problem passing through the capillary wall. Larger and charged molecules may pass through the intercellular clefts or via vesicular transport.

Water crosses the capillary through both in- tercellular channels and specialized water channels (aquaporins) in the endothelial cell membrane.

In general, large molecules have a very difficult time escaping from capillaries, as shown in the table to the left. There are some exceptions, however. Some capillaries have receptors for particular proteins; once the protein binds it is carried across the membrane via a process called transcytosis.

9/27/17 Page 2 Cardiovascular 6 However, in some organs, very large proteins (and even cellular elements) need to enter or leave the circulation. Thus, some capillaries are fenestrat- ed (or have large pores) to facilitate this exchange. For example, the intestine contains fenestrated capil- laries so that large molecules can be moved from the GI tract to the bloodstream. In other organs (e.g., bone marrow and the spleen), the endothelial cells are discontinuous to permit red blood cells to enter the circulation.

Osmotic Relationships Between Compartments

Osmolarity is a measure of the absolute concentration of osmotically active particles. A solution of one mole/liter of non-dissociable solute is equivalent to 1 osmole/liter (1 Osm). Normal osmolarity of body fluids is about 300 mOsm. The osmotic pressure of a 1 Osm solution is 22.4 Atm, or 22.4 x 760 = 17,024 mmHg. Thus a 300 mOsm solution has an osmotic pressure equivalent of 17,024 x 0.3 = 5,107 mmHg.

The only molecular species for which there is a significant concentration difference between the plasma and interstitial fluid is protein. All of the other solutes, which make up the major component of plasma osmolarity (Na+, Cl-, HCO3-), are present in approximately equivalent concentrations on both sides of the capillary membrane. Hence differences in protein concentration provide the only osmotic driving force at the capillary level. The plasma protein concentration is about 7 gm/100 cc plasma (7 gm%). The osmotic pressure generated by this protein is known as the and is in the range of 25-28 mmHg. The oncotic pressure difference between the capillary plasma and the interstitial fluid tends to draw fluid INTO the capillary.

However, another major force is at play in capillaries: hydrostatic pressure, which is due to the pressure in the blood imparted primarily by the contraction of the ventricle. The hydrostatic pressure is higher in the capillary than in the interstitial fluid, and tends to force fluid OUT of the capillary.

The balance between oncotic pressure and hydrostatic pressure across the capillary will determine whether there is a net gain or loss of fluid across the vessel. This balance can be expressed quantita- tively via Starling’s equation (from the same Starling who formulated “Starling’s Law of the Heart.”)

9/27/17 Page 3 Cardiovascular 6 The Starling equation reads as follows:

Jv = Kf ([Pc—Pi] — s [pc—pi]) Where:

Pc = Capillary hydrostatic pressure

Pi = Interstitial hydrostatic pressure

pc = Capillary oncotic pressure

pi = Interstitial oncotic pressure

Kf = Filtration coefficient s = Reflection coefficient

Jv = Net fluid movement between compartments

In essence the equation says that the net filtration (Jv) is proportional to the net driving force. By con-

vention, outward force is defined as positive, and inward force is defined as negative. If Jv is positive,

fluid will tend to leave the capillary (filtration). If Jv is negative, fluid will tend to enter the capillary (absorption). This equation has a number of important physiologic implications, especially when pathologic processes grossly alter one or more of the variables.

The first four variables in the list above (Pc, Pi, pc, pi ) are the forces that contribute to the net driving force.

The filtration coefficient f(K ) is the constant of proportionality. A high Kf value indicates a highly wa- ter permeable capillary. A low value indicates a low capillary permeability. The filtration coefficient is the product of two components: capillary surface area and capillary hydraulic conductance. The val- ues for both of these components are usually relatively high, and are fixed for a vascular bed, but there are exceptions. As you will learn during the renal section, the number of aquaporin channels inserted into the distal convoluted tubule and collecting ducts of the kidney nephrons is dependent on the levels

of circulating vasopressin. In the absence of vasopressin, few aquaporins are present and Kf is low.

The reflection coefficient (s) is often thought of as a correction factor. The idea is that the difference in oncotic pressures contributes to the net driving force because most capillaries in the body are fairly impermeable to the large molecular weight proteins. In fact, some smaller proteins can leak across the capillary membrane through the intercellular clefts, which must be accounted for as it diminishes the driving force. The reflection coefficients ( ) is used to ‘correct for’ the ineffectiveness of some of the oncotic pressure gradient. It can have a value from 0 up to 1. Non-fenestrated vessels have a reflection coefficient close to 1, whereas the value is lower for fenestrated capillaries.

Across a particular capillary, Kf and s are usually constant. As such, when we are considering the dynamics in a particular vascular bed, Starling’s equation can be restated as:

Jv ≈ ([Pc—Pi] — [pc—pi]) Let’s consider a situation where the blood entering the arterial end of a capillary has a hydrostatic pressure of 25 mmHg, and also carries an oncotic pressure of 25 mmHg. In the adjacent interstitial space, hydrostatic pressure is usually slightly negative (approximately -3 mm Hg). Let’s also assume

that interstital oncotic pressure is 5 mm Hg. In this case, Jv ≈ ([25 — (-3)] — [25 — 5]), or 8 mmHg.

Since Jv is positive, fluid will tend to leave the capillary and filtration will occur. 9/27/17 Page 4 Cardiovascular 6 As blood passes along a capillary, it loses hydrostatic pressure due to friction. At the venule end, hy- drostatic pressure is often near 10 mmHg, If there has been no appreciable shift in protein balance be- tween the capillary and interstitial compartments, the relative oncotic pressures won’t change. Thus,

at the venule end of the capillary, Jv ≈ ([10 — (-3)] — [25 — 5]), or -7 mmHg. Since Jv is negative, fluid will tend to enter the capillary and absorption will occur.

Note that there is an imbalance in filtration and - ab sorption (8 mmHg of filtration at the arterial end and 7 mmHg of absorption at the venule end). As such, the net filtration pressure is 1 mmHg. In general, we tend to lose 2-4 liters of fluid per day into the interstitial space due to the filtration-absorption imbalance. The process is illustrated in the figure to the left. Luckily, the excess fluid lost into the interstitial space is collected by the , as de- scribed below.

What Factors Alter the Osmotic Relationships?

1. Increased Venous Pressure (Example B Above)

An increase in arterial or venous pressure will increase Pc, thereby facilitating the movement of fluid out of capillaries. Either an increase in venous or arterial pressure would have this effect, but since the resistance to the flow of blood from arteries into the capillaries (pre-capillary resistance) is 5-8 times greater than the resistance between capillaries and veins (post-capillary resistance), increases in venous pressure have the greatest impact.

A good example is standing for a prolonged period, which results in increased venous pressure in the feet. This increase in venous pressure will result in additional blood being present in the capillary, which raises pressure within the capillary. Assume that prolonged standing results in the pressure at the arterial end of the capillary reaching 60 mmHg, and that at the venous end reaching 40 mmHg. 9/27/17 Page 5 Cardiovascular 6 As such:

At the arterial end: Jv ≈ ([60 — (-3)] — [25 — 5]), or 43 mmHg

At the venous end: Jv ≈ ([40 — (-3)] — [25 — 5]), or 23 mmHg In this example, considerable filtration would occur across the entirety of the capillary, resulting in an accumulation of fluid in the interstitial space, a condition callededema . 2. Hypoproteinemia (Example C Above) Hypoproteinemia can result from a number of causes, including starvation, liver disease (and result- ing deficits in protein metabolism), and kidney disease that causes protein to be lost in the urine. In a patient with hypoproteinemia, the concentration of plasma and interstitial plasma proteins decreases,

lowering both pc and pi. Assume that the former drops from 25 to 11 and the latter from 5 to 2. In such a case:

At the arterial end: Jv ≈ ([25 — (-3)] — [11 — 2]), or 19 mmHg

At the venous end: Jv ≈ ([10 — (-3)] — [11 — 2]), or 4 mmHg

In this example, considerable filtration would occur across the entirety of the capillary, resulting in .

3. Increased Capillary Permeability The gaps between the endothelial cells that comprise the capillary wall can expand under a variety of

conditions, including the release of histamine from mast cells. This will increase Kf, such that net fluid

movement will increase. Let’s assume that Kf, rises 40%, such that at the arterial end of the capillary

Jv increases to (1.4 x 8)=11.2 mmHg. At the venous end, Jv is also altered: (1.4 x -7) = -9.8 mmHg. A such, there is a 40% increase in the ratio of filtration to absorption, and fluid would accumulate in the interstital space.

4. Decreased Arterial Pressure Following hemorrhage, arterial pressure decreases due to a reduction in blood volume. As a conse- quence, the baroreceptor reflex elicits vasoconstriction in many vascular beds in an attempt to return blood pressure towards normal. Due to a combination of reduced blood pressure and increased arteri-

ole resistance, pressure in the capillaries (Pc ) downstream from the constricted arterioles is very low.

This tends to favor absorption of fluid from the interstitial space. As an example, let us assume thatP c

at the arterial end of the capillary drops to 15 mm Hg, and Pc at the venous end is 5 mm Hg.

At the arterial end: Jv ≈ ([15 — (-3)] — [25 — 5]), or -2 mmHg

At the venous end: Jv ≈ ([5 — (-3)] — [25 — 5]), or -12 mmHg

Consequently, fluid is absorbed from the interstitial space into the intravascular compartment. Over time, this movement of fluid will serve to increase blood volume, thereby increasing blood pressure. If the hemorrhage is only moderate, it may be possible to almost completely replace the lost blood volume with fluid from the interstitial space. This movement of fluid will tend to “dilute” the concen- tation of red blood cells, so hematocrit decreases.

9/27/17 Page 6 Cardiovascular 6 Does a Change in Hematocrit Affect Plasma Oncotic Pressure?

Since blood cells (mainly red blood cells) occupy half of the volume of blood, it may seem that a change in hematocrit would grossly alter plasma oncotic pressure. In fact, this is NOT the case, because the blood cells have plasma membranes that place their contents in a separate osmotic compartment from the plasma. The Lymphatic System

Because filtration typically exceeds absorption in capillaries, there is a net loss of fluid (about 2-4 L/ day) into the interstitial space. It is the job of the lymphatic system to collect this fluid and return it to the circulation. Other functions include picking-up materials in the liver and intestine, and serving as a filter to capture and destroy foreign pathogens.

In addition to the capillaries of the cardiovascular system, an extensive collection of capillaries exists in the body. These lymph capillaries are close to “real” capillaries in all tissues of the body, except the central nervous system and kidney.

9/27/17 Page 7 Cardiovascular 6 The thin walls of the lymph capillaries are held open by attachments to surrounding cells. Adjacent cells overlap in the lymph capillaries, providing valves that allow materials to enter from the inter- stitial space, but not to leave. The lymph capillaries coalesce to form larger “collecting” lymphatics, the largest of which is the thoracic duct, which empties fluid from the entire lower body back into the cardiovascular system. The lymphatic system makes connections with the cardiovascular system near the collarbones, near the junction between the subclavian veins and the internal jugular veins.

The major force driving fluid to enter the lymph capillaries is interstitial fluid pressure (once the fluid is inside the lymphatic system, it is called lymph). The higher the pressure in the interstitial fluid, the more fluid will enter the lymph capillar- ies. This arrangement is convenient, as it helps to assure that all the fluid leaving the cardiovascular system is returned.

Fluid flow into lymph capillaries will increase under any of the following conditions that raise inter- stitial fluid pressure:

• Capillary pressure is elevated (which enhances filtration) • Plasma oncotic pressure is reduced (which retards absorption) • Interstitial fluid protein is increased(which retards absorption) • Capillary permeability is increased

As noted above, large molecules can easily enter the lymph capillaries. This mechanism is taken ad- vantage of in the liver and digestive system to allow large molecules to enter the circulation. In fact, most large fat molecules absorbed by the intestine make their way to the blood via the lymphatic system. Pathogens in the interstitial fluid will also enter the lymphatic system, and for this reason lymph passes through collections of immunologically-active cells in the lymph nodes. No pump moves fluid in the lymphatic system. The major forces inducing lymph movement comes from compres- sion of lymph vessels during muscular contraction (if a limb is immobilized, you have to elevate it because muscular contraction is not sufficient to induce lymph flow). Furthermore, large lymph vessels have valves that permit only one- way flow of fluid, and the largest lymph vessels have smooth muscle in the walls

9/27/17 Page 8 Cardiovascular 6 that contracts automatically when stretched.

As discussed above, edema results when interstitial fluid builds up in an area. This often happens after injury because the breakage of blood vessels increases the amount of protein in the interstitial space (which pulls fluid from the cardiovascular system). Although increased interstitial pressure usually leads to increased lymphatic drainage, this doesn’t happen after some injuries because lymph capillar- ies are also damaged. Furthermore, there are limits to the rate of fluid flow into the lymphatic system.

Another factor that can lead to edema is blockage of the lymphatic system. In elephantiasis, for ex- ample, lymph vessels are blocked by parasites, which compromises fluid drainage. In addition, protein concentration gradually increases, diminishing the gradient in oncotic pressure that typically attracts fluid back into capillaries.

Ramifications of the Actions of the Lymphatic System

• As noted above, the hydrostatic pressure in the interstital space is slightly negative. This is largely due to the presence of the lymphatic system, and the movement of fluid into this system. As long as the interstital pressure is negative, no edema will occur. • In addition to removing fluid, the lymphatic system is a conduit for protein to leave the interstitial space. Without the actions of the lymphatic system, the oncotic gradient between the plasma and interstital space would equalize, which would contribute to the development of edema.

Changes in Plasma Osmolarity and Cell Size

In the examples above, we have mainly considered the effects of plasma oncotic pressure on the entry of fluid into the interstitial space. However, it must be remembered that thee compartments are in equilibrium:

As noted above, most capillaries are highly permeable to small ions such as Na+ and Cl- and water. Although cell membranes normally are quite selective about the ions that enter, and ac- tively maintain very low intracellular Na+ levels through Na+/ K+ ATPase, they are freely permeable to water.

Let us consider the example where a patient is given an intra- venous hypertonic saline solution. “Normal” saline is a 0.9% solution of sodium chloride, about 300 mOsm/L, which is the typical osmolarity of plasma. Sometimes, however, 3% and 5% saline solutions are given intravenously. Such solutions increase the osmolarity of the plasma relative to the interstitial space. Consequently, Na+ and Cl- diffuse into the interstital space from capillaries, while there is an increased driving force for water to enter the capillary until the osmolarity in the plasma and interstitial space are balanced. This causes the osmolarity of the interstitial fluid to be higher than the intracellular fluid. Consequently, water leaves the cells and as a result they shrink (intracellular volume decreases). 9/27/17 Page 9 Cardiovascular 6 Hypertonic solutions are sometimes provided to patients to combat edema, particularly brain edema, since there will be a loss of fluid from the interstital and intracellular spaces.

In contrast, intravenous infusion of hypotonic saline causes the plasma osmolarity to be lower than the osmolarity inside cells or in the interstitial compartment. Consequently, water leaves the plasma in the capillaries, while NaCl enters the capillaries. As the interstital space becomes hypotonic relative to the inside of cells, water will move down its concentration gradient into the cells, which will swell.

Hypotonic solutions are not typically infused, as their use is risky. This is because red blood cells can swell and burst when the plasma osmolarity is reduced suddenly.

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