Answer to Challenge Question

Derive a formula for GFR based on the following information:

• Inulin is freely filtered by glomeruli and not reabsorbed or secreted by nephrons.

• The amount of injected inulin filtered by the glomeruli is equal to the amount of inulin subsequently found in urine.

Answer:

For inulin (or creatinine)

Amount filtered = Amount in urine

Amount = volume x concentration (VC)

V1C1 = V2C2

V1 = GFR

GFR = (V2C2)/C1

GFR = (U x INu)/INp

Using numbers for normal creatinine; e.g.,

V1C1 = V2C2
100ml/min x 1 mg/100ml = 1ml/min x 100mg/100ml

1 mg/min = 1 mg/min
Note that these numbers show the concentrating ability of the kidney; e.g.,
1 mg/dL of plasma creatinine become 100 mg/dL of urine creatinine
and
100 ml/min of filtrate becomes 1 ml/min of urine production

Challenge Problem

Derive a formula for GFR based on the following information:

• Inulin is freely filtered by glomeruli and not reabsorbed or secreted by nephrons.

• The amount of injected inulin filtered by the glomeruli is equal to the amount of inulin subsequently found in urine.

Feel free to post your answer as a comment.

Answer given tomorrow.

Acute Renal Success

Acute Renal Success

Acute kidney injury used to be called "acute renal failure".  An interesting phenomenon that occurs with damage to the proximal tubule should be called "acute renal success".  Impaired reabsorption of sodium triggers tubuloglomerular feedback due to increased Na+ load to the macula densa.  This, in turn, leads to release of adenosine and vasoconstriction of the afferent arteriole.  The result is decreased GFR and decreased urine formation (oligouria).  This is protective in preventing massive volume loss via excess urine formation.

Vasopressin & water clearance

Urine

Water clearance

Urine = water + solute

Water = urine - solute

Renal Clearance

Renal Clearance

GFR is the volume per minute (ml/min) of plasma filtered by nephrons.  The normal value is 125 ml/min.

For creatinine (Cr) and inulin, the amount filtered by the nephrons is the amount in the urine.  This is because these substances are freely filtered from the plasma in Bowman's capsule* but are not reabsorbed from the filtrate and not secreted* from blood into filtrate.

So for Creatine (or inulin), the amount filtered = the amount in urine.
Definition of amount = volume x concentration.

amount filtered (f) = Vf x Cf
amount in urine (u) = Vu x Cu.

Vf x Cf =  Vu x Cu      V can also mean V/min

normal values =
125 ml/min x 1 mg/dL = 1 ml/min x 125 mg/dL

rearrange to:

Vf = Vu x Cu  = 1 ml/min x 125 mg/dL  = 125 ml/min = GFR
          Cf                      1mg/dL 


*creatinine is filtered to a small extent in the proximal tubules.  This elevates the Cf and lowers the estimation of Vf which is the eGFR.

water mechanisms in kidney


free water clearance

Urine Volume (total clearance) = H2O clearance + solute clearance

H2O clearance = Urine vol - solute clearance


H2O clearance = Vu - (Uosm x Vu)/Posm

Renal Intro

Renal Intro

This is the best ever figure for understanding nephrons

http://www.columbianephrology.org/FORMS/NephronMap.pdf

Extracellular fluid volume includes interstitial and plasma.  why not red cells?

because they are part of the intracellular fluid compartment.

Link to fluid volume powerpoint I put together.
https://drive.google.com/file/d/0B7Q73y7J58PCMmJEVnNrWlpMb0k/edit?usp=sharing

Microcirculation

Microcirculation


Fluid movement (Jv) = Κf [(Pc-Pi)-σ(πc-πi)] 

this applies to GFR in kidneys

Pc

Increased Pc 

• dilation of arterioles
• constriction of veins

Decreased Pc

• constriction of arterioles
• constriction of veins

σ

Reflection coefficient  (0 to 1)  0 = leaky and oncotic pressure doesn't have an effect (multiplied by zero)

*can also be increased under pathophysiological conditions (burns and inflammation)*

should  be "decreased"

Kf  

= hydraulic conductivity (permeability to water)

*can also be increased under pathophysiological conditions (burns and inflammation)*


Edema

• cardiogenic
• increased Pc 
• noncardiogenic
• decreased capillary oncotic pressure
• obstructed lymphatics

Ascites (malnutrition - low protein edema)

Local Control of Blood Flow

Active Hyperemia  -  metabolites dilate arterioles

Reactive hyperemia  -  after reduced flow, flow increases (low O2, metabolites)

Hypoxia vasodilates in peripheral circulation but vasoconstricts in pulmonary circulation

• alveolar hypoxia triggers inhibition of voltage gated K+ channels in arterioles leading to depolarization then activation of voltage gated Ca++ channels = vasoconstriction.

Hemodynamic Forces on Vasculature

muscle types; endothelin; pulse pressure

no troponin in smooth muscle.  Calcium binds to calmodulin, activates MLCK, phosphorylation triggers actin-myosin crossbridge = contraction.

Beta agonists lead to increased cAMP which inhibits MLCK = relaxation.  Same receptor but opposite effects on vascular and cardiac muscle.


Viagra targets  PDE5  Mainly in groin and lungs.

Good reference for this stuff


Part 2:  Endothelium

ET-1  most potent vasoconstrictor of any

compliance = delta Vol/delta P

pulse pressure = delta P    stroke volume = delta V

pulse pressure = stroke volume/compliance

decreased compliance (aterosclerosis) = increased pulse pressure

Electrolytes and ECG; Pressure Volume Loops; Reflex control of the heart

electrolytes and ECG

K+   Nernst equation shows that hypoK = hyperpolarization and hyperK = hypopolarization
Major effect, hower, is due to changes in ion currents

Mg++
hypoMg++ similar to hypoK+  for ECG changes

Ca++
hyperCa++  

• shortens QT
• ST segment abolished

Ischemia

• depolarization of resting membranes
• inactivates fast Na channels = slows phase 0 = slows conduction cell to cell
• local acidosis
• K leakage from cell
• arrythmias due to dispersion of refractoriness in different parts of heart
• ST segment elevation in infarct zones and depression in reciprocal leads

Arrhythmia mechanisms associated with ischemia 

• A-V Block, Bundle Branch & Fascicular Blocks 
•  Bradyarrhythmias 
• Enhanced Automaticity 
• PVCs 
• Triggered Activity 
• Polymorphic VT 
• Reentry 
• Monomorphic VT 
• Ventricular Fibrillation

Hypothermia

• Osborn or J wave: A hump-like elevation of the J-point at the onset of ST segment. 
• Caused by dispersion of endocardial to epicardial phase 1 repolarization. 
• Shivering (muscle) artifact. 
• QT prolongation.

Pressure - Volume loops

Positive inotropic agents (digoxin, dopamine, dobutamine, eicosanoids, epinephrine, inamrinone, isoprenaline, milrinone, norepinephrine, phosphodiesterase inhibitors, theophylline)


Negative inotropic agents (beta-blockers, calcium channel blockers, disopyramide, flecainide, procainamide, quinidine)

Reflex control of the heart

read more

Of these two sites for arterial baroreceptors, the carotid sinus is quantitatively the most important for regulating arterial pressure. The carotid sinus receptors respond to pressures ranging from 60-180 mmHg 

important to know that carotid baroreceptor activity is proportional to blood pressure.

switch from sympathetic stimulation to sympathetic inhibition due to GABA release by CVLM

summary figure  P = QR

Efferent Limb: Autonomic Responses

MABP = CO x TPR          

memory tool: alphabet rule  ABC 

PQR   or P = QR

Cardiac Pathology

Cardiac Pathology


dilation = loss of overlap of actin and myosin = weaker contraction
            = distorted gap junctions

Heart Failure = defined as decreased cardiac output

• pressure overload -  concentric hypertrophy = sarcomeres added in parallel
• volume overload - dilated ventricle = sarcomeres added in series - eccentric hypertrophy

Cardiomegaly

• bigger is not better
• increased size does not come with increased capillaries
• Exception - physiological hypertrophy

Heart Failure

dead myocytes are replaced by scar tissue

Chronic ischemic heart disease

at autopsy:

• Enlarged, heavy hearts 
• Left ventricular hypertrophy and dilation 
• Discrete scars = healed infarcts 
• Increased fibrosis 
• Subendocardial vacuolization

Acute MI

at autopsy:

• normal

Hypertensive Heart Disease

Cardiomyopathies - mechanical & electrical (gap junction) problems

Dilated = systolic dysfunction (decreased overlap of actin-myosin); 

• Genetic - 20-50%
• Infections – VIRAL 
• Toxins - ALCOHOL 
• Metabolic – thyroid disorders 
• Neuromuscular disease – muscular dystrophy 
• Storage disorders – glycogen storage disease 
• Infiltrates – leukemia 
• Immunological; e.g, lupus
• Peripartum
• Restrictive 

Hypertrophic

• myocyte disarray
• outflow obstruction due to hypertrophy
• genetic - mutations in genes that encode sarcomeres

Restrictive

• decrease in ventricle compliance (deltaV/deltaP
• Causes 
• Radiation fibrosis 
• Amyloidosis -amyloid deposited between myofibrils
• Sarcoidosis - granulomas
• Metastatic tumors - multiple transfusions - iron overload
• Inborn errors of metabolism 

Myocarditis - inflammation of myocardium

Viral myocarditis 

• Causes MOST cases in the US 
• Coxsackie viruses A and B most common 
• Also see other enteroviruses, CMV, HIV, etc 
• Presentation ranges from sudden death to heart failure 
• Other 
• Rickettsiae, bacteria (diphtheria, Lyme disease), fungal 
  

  (candidal), protozoal (Chagas disease and 

  toxoplasmosis) 
• Hypersensitivity myocarditis - eosinophils present
• Giant-cell myocarditis - giant cells = collection of macrophages

Miscellaneous Myocardial Disease

• Cardiotoxic drugs 
• Catecholamines 
• Amyloid 
• Iron overload 
• Hyper and hypothyroidism

Cardiac Tumors

• myxoma - most common - usually in left atrium
• etc.

Pericardial Disease

• fluid volume in pericardium normally < 50 ml
• pericarditis = inflammation of pericardium = increased fluid (effusion)
• serous = non infectious inflammation
• fibrinous = most common; acute MI, radiation, autoimmune, trauma
• purulent = infections

Cardiac Muscle

 Cardiac Muscle

actin - thin   regulated by calcium in cardiac muscle
Myosin - thick - regulated by calcium in smooth muscle

Autonomic Control of Heart Rate

NB: factors other than autonomic tone affect heart rate

• adenosine and high K lower heart rate by moving resting membrane potential toward K equilibrium potential.  from Katzung:potassium concentration has more to do with the permeability rather than resting membrane potential!
• Hyperkalemia: reduces eq. potential for K+ but on the other hand increases permeability therefore potassium current will be higher and RMP will come closer to K+ eq. potential!  significance: in cardiac pacemaker cells during phase IV ,due to high K+ permeability it will effectively counteract hyperpolarization induced depolarizing current via rectifier channels therefore late approach towards threshold!
• Hypokalemia: increases eq. potential for K+ but on the other hand reduces permeability ;therefore K+ current will be low and RMP will be farther away from the eq. potential (K+ eq. pot. has the major influence on RMP) in other words membrane will be destabilized!  significance: in cardiac pacemaker cells low K+ current during phase IV will not be able to effectively counteract the depolarizing current and therefore early approach towards threshold [enhanced automaticity]

• Hypoxia - interferes with If - slows inward Na current and slows heart rate
• Thyroid hormone (T3)  - upregulated beta receptors (1 and 2), increase chronotropy, inotropy, vasodilation.  (results in increased stroke volume SBP and decreased DBP  = increased pulse pressur ("bounding pulse")

does calcium channel blocker slow heart rate?  yes

In normal subject with resting HR of 60, the intrinsic heart rate is about 100 (blockade of sympathetic and parasympathetic tone).  e.g., resting HR is determined mainly by vagal tone.

Cardiac Signal Transduction Mechanisms

Beta agonists produce increased inotropy (contractility) AND lusitropy (relaxation) due to inhibition of phospholamden and increased activity of SERCA

Frank-Starling Law of the Heart - 

increased preload causes increased stroke volume

Myocardial Response to Increased Afterload

will reduce stroke volume initially.  However, smaller SV means larger ESV.  Then, when normal venous return enters ventrical, the EDV will now be greater, and SV will return to normal.  e.g., people with hypertension do not have low SV and high heart rate.

Cardiovascular Intro; Hemodynamics; Cardiac Cycle

Cardiovascular Physiology

systemic circulation arteries branch ultimately into 40 billion capillaries (huge surface area for diffusion between blood and tissues)

compliance of elastic structure = delta volume/delta pressure

• aorta compliance allows steady flow through vessels (hydraulic filtering)
• can rearrange this to look at delta pressure (called pulse pressure = systolic - diastolic)*
• pulse pressure = delta volume/compliance  e.g., goes up with increasing stroke volume and goes up with decreasing compliance (e.g., hardening or aorta)
• Hyperthyroidism upregulates beta receptors causes increase and stroke volume AND decreased resistance (peripheral vasodilation) = increased Systolic and decreased diastolic pressures = increased stroke volume ("bounding pulse")

venous return to the heart - alpha 1 mediated venoconstriction = increased cardiac output

Pressures in CV system

Mean arterial pressure = 2/3 diastolic + 1/3 systolic  (because 2/3 of time is spent in diastole during one cardiac cycle).  Mean = 100 for 120/90.

*Pulse Pressure

what could elevate pulse pressure?  decreased compliance or increased stroke volume

diastolic pressure = pressure in aorta when aortic valve closes.  if compliance were zero (never true in elastic structures but can be really low; e.g., golf ball) with completely rigid aorta, systolic pressure would go way up but diastolic pressure would not change (aortic valve closes when pressure in ventricle falls below aortic pressure)

Velocity of Flow vs. Cross Sectional Area

• flow cm3/min =  Velocity cm/min x Cross Sectional Area cm2  = cm3/min
• slow velocity in capillaries helps exchange.
• Flow is the same in aorta and all capillaries, but velocity is much different.

Determinants of Blood Pressure

• alphabet rule  =  PQR   use algebra to rearrange
• P = QR
• Q = P/R
• R = P/Q  or TPR/cardiac output   (Q = cardiac output)

Poiseuille's Law  - R = 8nl/pi r4

radius to 4th power dominates

• vasoconstriction
• thickening of vessel wall

• viscosity can be important with anemia or polycythemia (downside of blood doping)  other name for polycythemia = erythrocytosis

natives of high altitude: = higher in Himalayan and Andean natives - mean hematocrit of 50% in Himalayans and 54.1% in Andeans. 

click on: 

Brain blood flow in Andean and Himalayan high-altitude populations: evidence of different traits for the same environmental constraint

hematocrit of high altitude natives

Go to:

Abstract

Humans have populated the Tibetan plateau much longer than the Andean Altiplano. It is thought that the difference in length of occupation of these altitudes has led to different responses to the stress of hypoxia. As such, Andean populations have higher hematocrit levels than Himalayans. In contrast, Himalayans have increased circulation to certain organ systems to meet tissue oxygen demand. In this study, we hypothesize that cerebral blood flow (CBF) is higher in Himalayans than in Andeans. Using a MEDLINE and EMBASE search, we included 10 studies that investigated CBF in Andeans and Himalayans between 3,658 and 4,330m altitude. The CBF values were corrected for differences in hematocrit and arterial oxygen saturation. The data of these studies show a mean hematocrit of 50% in Himalayans and 54.1% in Andeans. Arterial oxygen saturation was 86.9% in Andeans and 88.4% in Himalayans.

Series and Parallel Resistors

Rt = R1 + R2 + R3   for R=1  Rt = 3.  add an R4 = 1 and Rt = 4 (higher)

1/Rt = 1/R1 + 1/R2 + 1/R3   for R1  1/Rt = 3 so Rt = 1/3   add an R4 = 1 and Rt = 1/4 (smaller)

Laminar vs. Turbulent Flow

clarify delta P with turbulent flow.  Tom said no flow with turbulent flow.  If turbulence is not infinitely high, there is flow but requires higher driving pressures.

when rivers make noise, flow is turbulent.  same in vessels (bruits) and heart (murmurs)

Shear Stress = important for releasing nitric oxide (NO)  


Regulation of Resistance     R = deltaP/flow

• intrinsic
• extrinsic
• sympathetic NS  alpha 1 and beta 2
• epinephrine and other circ. hormone
• local metabolites
• Flow
• intrinsic - Starling's Law of the heart
• extrinsic - neural, hormonal

Cardiac Cycle

nice outside resources for this

• cardiac cycle
• Dr. Najeeb lecture (youtube)

Note that with tachycardia, diastole shortens much more than systole.  Impact = reduced filling time.  Not a problem in exercise (increased venous return) but IS a problem with resting tachycardia (e.g., cocaine).

Right Heart Pressures Lower but may equal left heart in normal individuals at high altitude or patients with lung hypoxia due to disease.

Coronary blood flow in cardiac cycle.

• greatest during diastole (muscles relaxed).  additional risk of tachycardia (reduced filling time AND reduced coronary flow during shortened diastolic period)  at same time oxygen demand is increased.
• flow is regulated in the coronary arteries primarily by adenosine.  Adenosine increases if oxygen falls (decreased ATP production = increased adenosine)

Electrophysiology

 Electrophysiology 

channels

• ionotropic; e.g., Na, K channels
• metabotropic; e.g., beta receptors

electrochemical equilibria = membrane potential that would keep any ion at its observed concentration inside and outside

-example; if K channels open the membrane will become hyperpolarized to its equilibrium potential which is - 95 mv.  this is how most inhibitory neurotransmitters work.

Ohm's Law  I = V/R  where I = current; V=voltage; R=resistance

Rectifying currents deviate from Ohm's law; i.e., current is not linear with voltage.

• inward
• outward

Conduction velocity = f(rate of change of voltage) - substances that block Na channels will slow conduction; e.g., high potassium; cocaine

Action potentials

all of heart action potentials summated to ECG

slow cells - pacemaker cells 

T type Ca channels activation by hyperpolarization

L type by depolarization

slope of phase 4, threshold, and resting potential determine heart rate

Another good figure below and explanation (from Lilly)

The maximum negative voltage of pace-maker cells is approximately -60 mV, substantially less negative than the resting potential of ventricular muscle cells (-90 mV). The persistently less negative membrane voltage of pacemaker cells causes the fast sodium channels within these cells to remain inactivated.

fast cells (myocytes; purkinje fibres)

this is a very helpful figure to understand fast action potentials:

Here is another way to understand ion currents in the fast action potential:

From Lilly; Pathophysiology of Heart Disease. Schematic representation of a myocyte action potential (AP) and relative net ion currents for Na+, Ca++, and K+. The resting potential is represented by phase 4 of the AP. Following de-polarization, Na+ influx results in the rapid upstroke of phase 0; a transient outward potassium current is responsible for partial repolarization during phase 1; slow Ca++ influx (and relatively low K+ efflux) results in the plateau of phase 2; and final rapid repolarization largely results from K+ efflux during phase 3.

Conduction velocity (dromotropy) determined by dV/dT

myocardium = .3-1 m/sec
av node = .02 - .1 m/sec  (important to allow time for filling of ventricles)