Microcirculation: introduction 1) Capillaries are the site of diffusion of nutrients and waste between blood and tissue 2) Transcapillary exchange of fluid Maintains plasma & interstitial flluid Volume Opposes edema formation ( Capillary Starling forces) Lymphatic structure & function Edema formation

Microvascular unit Venule Metarteriole Capillaries Arteriovenous shunt (S) Pre-capillary sphincters exist at the origin of each capillary Arteriole

Structures in the microcirculation

Capillary Structure Capillaries: Site of exchange by diffusion (some diffusion occurs in venules also). Capillary walls are porous to small molecules: Intercellular clefts Fused vesicle channels

The Permeability Surface area term for diffusion across a capillary wall The rate of diffusion of a molecule is proportional to area & concentration gradient, & inversely proportional to distance: n = amount, t = time, D = diffusion coefficient, A = area, dC = concentration gradient, dx = distance. Applied to the circulation, the equation for diffusion of molecules across the capillary wall is: Where P is permeability of the capillary & S is surface area. Under most conditions P is constant & determined by the structure of the capillary wall. Physiologically, the area S available for diffusion can be increased by recruiting more capillaries, which also decreases the distance (shorter intercapillary distance).

Transcapillary exchange of lipid soluble substances Lipid soluble substances such as CO2, O2 & many anesthetics penetrate the capillary wall by diffusing via the lipid component of the endothelial cell membranes. Capillary area for diffusion of lipid soluble molecules is maximal. Transcapillary movement of macromolecules & cells Molecules > 40 A can be transported across the endothelium by pinocytosis. Leucocytes & lymphocytes migrate through intercellular clefts by ameboid movement.

Transcapillary exchange of water soluble substances H2O, monosaccharides, amino acids, small peptides & organic acids and inorganic ions (Na+, K+, Ca++, etc) diffuse rapidly through intercellular clefts. The area for diffusion of water soluble molecules is less than for lipid soluble molecules. Capillaries have two types of endothelium: Discontinuous endothelium capillaries have large clefts & gaps in basement membrane, relatively high permeability. Continuous endothelium: basement membrane is continuous, intercellular clefts are ~ 40 angstroms diameter & have tight junctions. Molecules larger than 40 A, like proteins, cannot cross the wall by diffusion. Discontinuous endothelium (liver, spleen, glomerulus, small intestine, endocrine glands, bone marrow) Continuous endothelium (muscle, skin, lung, CNS)

Flow & diffusion limits on exchange` Flow limited exchange: exchange of molecules that diffuse rapidly is limited by the rate of blood flow (examples: H2O and small molecules) Diffusion limited exchange: exchange limited by diffusion because either The molecules diffuse slowly (macromolecules) or Diffusion distances are large Flow-limited; Diffusion is rapid flow Diffusion limited; Diffusion is slow flow With edema increased diffusion distance may limit supply of nutrients to tissues

Transcapillary exchange of fluid impacts plasma & interstitial fluid volumes Total body water content is maintained nearly constant by control mechanisms that operate through thirst (input) and kidney function (output) Total body water can be divided into Extracellular fluid (ECF) Plasma Interstitial fluid including lymph Intracellular fluid (ICF) The distribution of fluid between plasma and interstitium depends on: 1. Osmotic pressure due to plasma proteins 2. Capillary hydrostatic pressure 3.Osmotic pressure due to proteins in interstitial fluid 4. Interstitial fluid hydrostatic pressure (These are the Starling Forces) Imbalances in these factors may produce edema & decrease blood volume. Edema is “a palpable swelling produced by expansion of the interstitial fluid volume.”

Osmosis Osmotic pressure is pressure created by a difference in solute concentration across a semi-permeable membrane. Osmosis is the passive diffusion of water from a region of low solute concentration (dilute solution, low osmotic pressure) to a region of high solute concentration (concentrated solution, high osmotic pressure). Osmotic pressure due to protein molecules is called oncotic pressure.

Definition of an osmole Osmotic Pressure depends on the concentration of particles in a solution.. An osmole is a unit that refers to the total number of particles dissolved in a solution. One osmole = 6.02 x 1023 particles (Avogadro’s number). One gram molecular weight of glucose dissolved in water will liberate one osmole of particles. One mole of NaCl dissolved in water will yield two osmoles (Na+ and Cl-) of particles. One osmole of glucose in one liter of water will yield a one osmolar solution. Osmolarity is the number of osmoles/liter of solution. Osmolality is the number of osmoles/kilogram of solvent. The difference between osmolarity & osmolality for biological solutions is insignificant.

Normal plasma osmolality Plasma solutes, millimoles/liter Cations Anions Na+ 135 Cl- 108 K+ 3.5 HCO3- 24 Ca++ 2 Lactate 1 Sum 140.5 Albumin 0.6 133.6 Glucose 5 Urea 5 Grand total 284.1 mM = millimole = 1/1000th of a mole mOsm = milliosmole = 1/1000th of an osmole Normal plasma osmolality = 280 to 296 mOsm/liter

Starling forces in capillaries OUT IN F = K [(Pcap + i) – (Pi + cap)] F = net movement of fluid across the capillary wall (ml/min) Pc ap = capillary hydrostatic pressure (mmHg) cap = capillary oncotic pressure* (mmHg) Pi = interstitial fluid hydrostatic pressure (mmHg) I = interstitial fluid oncotic pressure (mmHg) K = filtration constant: (determined by capillary surface area and permeability to water (ml/min)/mmHg) *oncotic pressure = osmotic pressure due to proteins

Calculation of net filtration pressure F ~ Pcap – cap F = K [(Pcap + i) – (Pi + cap)] Blood flow  Pc ap = 37 mm Hg i= 0 Pi = 1 mm Hg cap = 25 mm Hg Arterial end: Pcap > cap Net filtration pressure = (37 + 0) - (1 + 25) = 11 mm Hg Venous end: Pcap < cap (17 + 0) - (1 + 25) = - 9 mm Hg Pcap =17 mm Hg Negative value for net filtration pressure indicates net force favors absorption

Starling forces & lymph flow in various tissues Pcap Pi cap i Lymph flow NFP** Hind limb (dog) 13.0 -5 21 4 0.015 +1.0 Skeletal muscle (rest) 10.1 -3 20 8 0.005 +1.1 Intestine (rest) 16.0 2 23 10 0.08 Intestine (digesting) 3 5 0.10 -5.0 Liver 7.0 6 22 -1.0 Lung 12 Cardiac muscle 23.1 15 13 0.12 +0.1 Glomerulus 50.0 28 2.0 +7.0 Peritubular capillary* 25.0 7 32 -7.0 *in the kidney ** NFP = net filtration pressure Pressures are all mm Hg; lymph flow units are ml/min per 100 g tissue

Factors that influence lymph flow Lymph flow is increased by  Interstitial hydrostatic pressure  Lymphatic contractions (smooth muscle) & valves  Sympathetic stimulation of lymph vessels Skeletal muscle pump

Lymphatic circulation 2 to 4 liters of fluid per day is filtered out of the capillaries, taken up by the lymphatics and returned to the systemic circulation. systemic capillaries Venous system Interstitial fluid Filtration 20 liters/day Absorption 16 to 18 liters/day Lymph flow 2 to 4 liters/day systemic arteries Right heart Pulmonary circulation Left heart Terminal lymphatics are highly permeable to protein Lymphatics are the only route for return to circulation of protein that leaves capillaries

Arteriolar Tone and Capillary Hydrostatic Pressure Arteriolar constriction decreases Pcap Arteriolar dilation increases Pcap Changes in PCap will affect filtration & absorption Effect on mean arterial pressure: MAP = CO x TPR Constriction of arterioles in one organ or tissue may be offset by dilation elsewhere, without causing a change in TPR and MAP Widespread arteriolar constriction in many tissues will increase TPR and MAP (if CO doesn’t change). Arterial pressure Capillary hydrostatic pressure dilation constriction Capillary Artery Arteriole

Absorption of interstitial fluid into the circulation compensates in hemorrhage MAP = CO x TPR Hemorrhage  sympathetic nerve activity  heart rate  cardiac contractility Restore MAP  TPR Cardiovascular reflexes hypotension  absorption of fluid into capillaries Restore blood volume  CO Vasoconstriction (skin, kidney, GI tract)  capillary hydrostatic pressure  hematocrit

Three physiological roles of arteriolar tone Support arterial blood pressure Direct distribution of flow between organs & tissues Influence capillary filtration & absorption

Capillary hydrostatic pressure, mm Hg Edema safety factors 30 (cap - i), mm Hg A 30 Lymph flow B 30 Pi, mm Hg C Capillary hydrostatic pressure, mm Hg A: As capillary hydrostatic pressure & filtration increase, tissue protein is diluted, i decreases, so cap - i increases, limiting further filtration. (The y-axis in panel A is cap - I, the oncotic pressure gradient influencing filtration) B: As filtration increases, lymph flow increases, limiting accumulation of fluid in the interstitium. C: As filtration increases, fluid added to the interstitium increases Pi, decreasing the hydrostatic pressure gradient favoring filtration (Pcap – Pi)

Edema formation Edema is a pathological accumulation of excess fluid in the interstitial space Causes of edema: Decreased plasma oncotic pressure Kidney disease   urinary excretion of plasma protein Liver disease  inadequate albumin synthesis Increased capillary permeability to proteins Tissue trauma Anaphylactic shock Increased venous & capillary hydrostatic pressure Congestive heart failure Blockage of lymphatics Tumors Parasites