Arrhythmia MDRs + Tissue Oxygen Monitoring SOTA + Cornell Cardiovascular Videos

What has fast response action potentials and what has slow response action potentials?

Atrial and ventricular myocytes have a fast response action potential with 5 distinct phases

Sinus and Atrioventricular nodes have a slow response action potential

Phase 0 of Fast Action Potentials

Depolarization phase

Rapid upstroke due to opening of fast sodium channels and sodium influx

• + ions going into the cell

Phase 1 Fast Action Potential

Beginning of repolarization due to transient K efflux vi I_Kto channels

• + ions out of the cell

Phase 2 of Fast Action Potential

Early repolarization phase

The plateau is caused by sustained slow calcium influx via I_Ca(L)

K+ still going out so maintaining

Phase 3 of Fast Action Potential

Late repolarization phase

The downward slope is due to the cessation of calcium influx as the potassium efflux continues

• + ions going out, none going in

Phase 4 of Fast Action Potential

Resting phase

Maximum resting membrane potential (RMP) is approximately -90 mV primarily due to Na+/K+ ATPase pump (K+ in, Na+ out)

Entire Fast Action Potential

Phase 0 and 2 Slow Action Potential

No phase 1

Calcium influx (I_Ca-L) via voltage-gated L-type Ca channels (absent Na_v1.5 channels)

Phase 3 Slow Action Potential

Efflux of potassium

Phase 4 Slow Action Potential

No stable phase 4 (not “RESTING”) due to depolarizing currents

• Influx of Na+ (I_f, via HCN channels, aka the “funny” current)

• Influx of Ca2+ (I_CaT via T-type Ca and I_CaL via L-type Ca2+ channels)

Entire Slow Action Potential

Excitability

Ability of a cell to generate an action potential in response to a stimulus depends on availability of Na+ channels to open in response

Automaticity

Ability of a cell to spontaneously generate an action potential

The SA node is the dominant pacemaker due to its faster rate

Classically other subsidiary pacemakers include the AV node, His-Purkinje system

The subsidiary pacemakers are normally inhibited by the faster rate of the sinus node - called overdrive suppression

Refractory Period

Time when myocytes are non-excitable

The refractoriness of the action potential is primarily due to inactivation of Na+ channels soon after onset of the action potential

Total Refractory Period

Effective refractory period + relative refractory period

Effective Refractory Period

Absolute refractoriness - phase 0 until halfway through phase 3 (~-50 mV membrane potential)

Relative Refractory Period

Myocytes can respond to very intense stimuli - from end of effective refractory period to end action potential; that is from last portion of phase 3 to initial portion of T wave → during which Na+ channels progressively re-activate (-50-90 mV membrane potential)

Conduction

Property of cell to propagate impulse from one cell to another depends on: slope and amplitude of phase 0, diameter of cells, number of intercalated discs, and connexins in gap junctions

• Increased slope and lower resting membrane potential = higher conduction

Myocardial Heterogeneity of Action Potential

Action potential duration and shape differs from endocardium to epicardium

• Epicardial myocytes action potential have prominent phase 1 and doming shape whereas mid-myocardium action potential have longer action potential

• Differences in duration and morphology of action potentials reflect different expressions of I_to and I_k potassium channels

  • These differences in action potential generate transmural electrical gradients during repolarization leading to electrical heterogeneity that can serve as substrate for arrhythmias, such as re-entry

Atrio-ventricular and Ventriculo-atrial Conduction

Concealed conduction describes changes to the surface ECG that suggest altered AV nodal conduction caused by an earlier event hidden on the surface ECG

• e.g. an unexplained PR prolongation or blocked P wave due to either partial or complete refractoriness of the AV node

Antegrade conduction through the AV node is also affected by concealed conduction after APC, atrial tachycardia, atrial flutter, atrial fibrillation

Concealed conduction may result from retrograde ventriculo-atrial conduction of VPC, escape rhythm, junctional rhythm, pacemaker beats

It may also occur via accessory pathway, in which atria are activated sequentially

Causes of Cardiac Arrhythmias Due to Abnormal Impulse Generation

Enhanced or suppressed automaticity

Abnormal automaticity

Triggered activity

Enhanced or Suppressed Automaticity

Changes in the spontaneously depolarizing cells of the sinus node, the atrioventricular junction, and cells of the His-Purkinje system

Ionic basis of enhanced automaticity (e.g sinus tachycardia) is explained by a net gain of intracellular positive charge during diastole causing a a steepening of phase 4 depolarization

The sinus nodal discharge rate keeps dominance over latent pacemaker sites because it depolarizes more rapidly by overdrive suppression

• Can cause prolonged suppression of normal pacemakers in proportion to the duration and rate of stimulation by a more rapidly discharging pacemaker

• Mechanism is related to active Na+ extrusion during the more rapid rate that maintains the diastolic depolarization of the latent pacemakers at a level more negative than the threshold potential for automatic discharge

Abnormal Automaticity

Refers to when the dominant pacemaker shifts to a site other than the sinus node such as atrial, junctional, or ventricular myocytes

• These cells gain the ability to generate an ectopic impulse due to ischemic injury or electrolyte disturbances

• May cause premature beats, atrial tachycardia, accelerated idioventricular rhythm, and ventricular tachycardia

Triggered Activity

Caused by membrane potential oscillations, called after-depolarizations, which occur during or immediately after an action potential

• Early after-depolarizations (EAD) - phase 2 or 3 or the action potential

• Delayed after-depolarizations (DAD) - phase 4 of the action potential

After-depolarizations cause arrhythmias when the membrane potential oscillations reach the threshold potential and starts a new AP

• Not all after-depolarizations reach threshold potential, but if they do, they can trigger another depolarization and be self-perpetuating

Predisposing Factors for Early After-Depolarizations

Long cycles (slow HRs)

Hypokalemia

Hypocalcemia

Hypomagnesemia

Cardiac and non-cardiac drugs that prolong the QT interval

How to treat early after-depolarizations?

Magnesium supplementation

What causes delayed after-depolarizations?

Caused by a transient inward current that is small or absent in normal conditions

When intracellular calcium overload occurs (adrenergic stimulation, hypercalcemia, prolonged APDs, rapid repetitive stimulation, digitalis toxicity), increased Ca2+ stimulates both Cl- currents and Na/Ca exchanger, resulting in transient inward currents and after-depolarizations

Delayed after-depolarizations thought to be the primary mechanism of arrhythmias in the failing myocardium and digoxin toxicity

Reentry

Underlying mechanism for most ventricular tachycardias and many supraventricular tachyarrhythmias such as atrial fibrillation, atrial flutter, AV accessory pathway tachycardia

Require a circuit with a fast and a slow pathway

• An ectopic discharge is blocked unidirectionally at the zone of slow conduction

• The impulse travels through the normal tissue and slowly penetrates the zone of slow conduction “backwards” and creates the reentry tachycadia

Therapy for Reentrant Tachycardia

Break the cycle

• Done pharmacologically by prolonging the action potential duration (increasing refractoriness) or increasing conduction impulse speed

How does body temperature affect heart rate?

Increased body temperature increases heart rate by increasing the slope of phase 4 of the action potential

Low body temperature will decrease the heart rate by affecting the rate of discharge from the sinus node

Where are the effects of hyperkalemia most and least pronounced?

Effect is more pronounced in atrial than ventricular myocytes

Spontaneously depolarizing tissue (specifically the sinus node) least sensitive

Effects of Hyperkalemia on Cardiac Rhythm

As extracellular potassium levels increase, the resting membrane potential becomes less negative

Mild to moderate hyperkalemia may increase excitability and conduction velocity by its effect of increased membrane permeability accelerating the rate of repolarization and shortening the action potential duration

With progressive hyperkalemia, the resting membrane potential further depolarizes (becomes less negative) decreasing Na channel availability

• First happens in the atria, leading to a state of constant depolarization and loss of excitability

• Loss of P wave, widening of QRS, and slower than expected HR on ECG are likely first indications of a life-threatening hyperkalemia

  • Atrial standstill or sinoventricular rhythm

• Severe hyperkalemia causes a slowing of conduction velocity eventually to the point of propagation failure and inexcitability of both atria and ventricles → asystole or ventricular fibrillation

Effects of Hypokalemia on Cardiac Rhythm

Causes decrease in conduction velocity in cardiac tissue, prolongation of the relative refractory period, increased automaticity, and early afterdepolarizations

Increases the resting membrane potential (more negative)

Results in increased QT interval

Increase in the relative refractory period and a decrease in the difference of the resting membrane potential from the threshold potential during terminal phases of the action potential causes cardiac cells to have increased excitability during a considerable portion of the action potential

Causes ventricular ectopic complexes, supraventricular ectopic complexes, and AV conduction disturbances

Effects of Hypercalcemia on the Cardiac Rhythm

Shortens AP duration primarily by reudcing duration and increasing the amplitude of phase 2

Arrhythmias rare but rapid infusion of IV calcium can cause bradycardia, extrasystoles, and AV block

Effects of Hypocalcemia on the Cardiac Rhythm

Can increase atrial premature depolarization by prolonging the duration and amplitude of phase 2

Can see prolonged QT interval

Makes threshold potential more negative so increases excitability

What are the most serious and concerning arrhythmias in dogs?

Sustained and non-sustained ventricular tachycardia, supraventricular tachycardia, atrial fibrillation, high grade AV block, sinus arrest with sick sinus syndrome, and terminal rhythm disorders (e.g. pulseless electrical activity, ventricular fibrillation, etc)

• High grade AV block and ventricular tachycardia most likely to result in arrest in an awake patient

• Atrial fibrillation, supraventricular tachycardia, and sinus arrest more likely to be associated with arrest or decompensation as a result of our interventions

What drugs can contribute to ventricular or supraventricular tachyarrhythmias?

Theophylline

Terbutaline

Phenylpropanolamine

Thyroxine supplementation

What drugs can cause or contribute to bradycardia?

Beta-blockers

Calcium channel blockers

Digoxin

When is ventricular tachycardia associated with a medium to high risk for sudden death?

When sustained (lasting >30 seconds in duration)

When is treatment of ventricular tachycardia indicated in small animals?

Indicated in an awake animals with clinical signs resulting from the arrhythmia (weakness, worsening CHF, collapse, or syncope) and in animals with sustained (>30 seconds) and rapid (>170-200 bpm) ventricular tachycardia

Treatment for Ventricular Tachycardia in Small Animals

IV lidocaine boluses followed by CRI

• If ineffective then procainamide can be used

Potentially amiodarone

Chronic oral therapy

• Beta blockers (sotalol, atenolol, metoprolol, propranolol) or other class I antiarrhythmic drugs, especially mexiletine where available

Treatment for Ventricular Fibrillation

Immediate electrical defibrillation

Success Rate of Electrical Defibrillation for Ventricular Fibrillation

Likelihood of success is inversely proportional to the amount of time in ventricular fibrillation

• Successful defibrillation reduced by approximately 50% for every 3-5 minutes of time delay

IV amiodarone and magnesium can be used in addition to electrical defibrillation for those that are refractory to repeated attempts

Low (standard) doses of epinephrine for support of CPR are preferred to higher doses

Treatments for Supraventricular Tachycardia in Small Animals

Diltiazem

Verapamil

Propranolol

Esmolol

Caution using concurrent beta-blockers and calcium channel blockers as this can lead to hypotension or excessive bradycardia

Chronic management

• Digoxin

  • Drug of choice when accompanied by heart failure

• Calcium channel blockers (diltiazem, verapamil) or beta-blockers (propranolol, atenolol, metoprolol, sotalol)

• Amiodarone

Sinus Arrest

A pause of greater than 2 P-P intervals without evidence of depolarization of the sinus node

Sick Sinus Syndrome

Characterized by bradycardia due to sinus node dysfunction, typically accompanied by short bursts of supraventricular tachycardia

What are traditional methods of detecting altered tissue perfusion as proposed surrogates for oxygen delivery?

Physical examination, body temperature, arterial blood pressure, central venous pressure (CVP), and urine output

• Have poor correlation to microcirculatory perfusion and cardiac preload and may fail to indicate early signs of global tissue hypoxia

How do you assess global oxygenation status?

Measure oxygen delivery and consumption (VO2)

• Obtain these values with pulmonary arterial or central venous catheters

What are traditional means of assessing macrocirculation?

Global perfusion parameters, cardiac output, CVP, base excess, and lactate

What are noninvasive methods to detect altered microvascular circulation and occult or compensatory shock?

Near infrared spectroscopy (NIRS)

Dark field videomicroscopy

Doppler flowmetry

Gastric tonometry

Sublingual capnometry

Transcutaneous carbon dioxide measurement

Tissue Spectrometer Technology

• Near infrared spectroscopy measures the absorption of infrared light (wavelengths of 700-1000 nm) by tissues to determine the oxygen hemoglobin saturation of blood in vessels less than 1 mm in diameter within the tissue

• Oxyhemoglobin preferentially absorbs higher near-infrared wavelengths (800-1000 nm) whereas deoxyhemoglobin absorbs wavelengths closer to 600-800 nm

• Scattering of light is one of the biggest problems encountered when utilizing NIRS technology, 80% of the light emitted is lost to scatter

• Probe placement over hematomas, fat, or bone may alter tissue oxygen reading

• Fluctuations in body temperature, as well as excessive movement, can lead to errors in tissue oxygen saturation (StO2) measurement

• The sensor is placed over a muscle bed

  • The most reliable StO2 readings in people were achieved using the thenar eminence (muscle at the base of the thumb) and in dogs using the sartorius

Total Hemoglobin Index (THI)

An indicator of signal strength of near infrared spectroscopy, measures the amount of intravascular hemoglobin, intramuscular myoglobin, melanin, and mitochondrial cytochrome c oxidase

• THI measurements of 5 or less indicate a weak hemoglobin signal and may lead to inaccurate StO2 readings

Vascular Occlusion Testing

• Vascular occlusion testing (VOT) determines the baseline StO2 and then evaluates rate of deoxygenation and reoxygenation following occlusion of regional circulation

  • StO2 is continuously measured at a distal site during occlusion of blood flow using a sphygmomanometer and pressure cuff

  • The ischemic challenge lasts for a defined interval of time or until the StO2 meets a specific threshold

  • Cuff is then deflated rapidly and StO2 recovery slope obtained

• May be useful when examining patients with sepsis or septic shock as they often have decreased oxygen extraction (VO2) from the tissues

  • Decreased oxygen consumption in patients with septic shock results in a prolonged recovery slope in the VOT

• Currently recommended that a target StO2 value be used for monitoring instead of the absolute values determined by the VOT

• VOT is a measure of microcirculatory reserve and not a direct representation of microcirculatory perfusion

• Digital extensors are the muscle belly of choice for VOT in veterinary patients

Tissue StO2 in the Human Literature - Trauma

• Low StO2 can predict the occurrence of multiple organ dysfunction after sustained traumatic shock and is more sensitive to predicting multiple organ dysfunction syndrome, the need for massive transfusions, and death in traumatized patients than other diagnostic tools

• StO2 improves more rapidly than plasma lactate concentration and base deficit after adequate resuscitation which may lead to lower volumes of intravenous fluids administered to trauma patients

• StO2 has been shown to be an early and accurate predictor of the need for life-saving interventions compared to plasma lactate concentration and base excess

• Direct relationship between the magnitude of oxygen deficit and the risk of multiorgan failure -> treatment rationale that optimizes cardiac output and hematocrit to correct deficits in VO2 and tissue oxygen delivery

Tissue StO2 in the Human Literature - Surgery

• StO2 improves with IV fluid administration prior to normalization of other traditional systemic hemodynamics (e.g. arterial blood pressure)

• Lower StO2 values may be associated with increased postoperative complications such as SSI

  • Monitoring of StO2 levels during and after anesthetic events may be helpful to prevent postoperative complications such as SSI, duration of ICU hospitalization, and morbidity and mortality

StO2 in Human Literature - Sepsis

• Due to the vast alterations in microcirculation in patients with sepsis, StO2 can be low, normal, or increased making it difficult to interpret

• StO2 values have been shown to correlate to the severity of disease and to mortality in patients with severe sepsis and septic shock

• Alternative monitoring sites for StO2 in septic patients due to difficult of using the thenar eminence

  • Knee

  • Masseter

  • Deltoid

• Tissue oxygen monitoring in septic patients is controversial so can be used in conjunction with the VOT, which shows an impaired postischemic hyperemic response in patients with sepsis and septic shock

• StO2 is lower in nonsurvivors than in survivors after early goal-directed resuscitation for septic shock

StO2 in Human Literature - Early Goal Directed Therapy

• Early goal directed therapy (EGDT) is characterized by intensive monitoring for optimization of oxygen delivery in patients with severe sepsis or septic shock

  • Resuscitation endpoints include targeted values for ScvO2, arterial lactate concentration, pH, base deficit, and hematocrit

• Utility of EGDT recently called into doubt

• Methods of evaluating global oxygenation in EGDT resuscitation are invasive (requires central venous catheter and arterial blood pressure monitoring) so use of StO2 may be helpful

  • Conflicting results about utility of StO2

StO2 in Veterinary Literature

• Measurements taken at the sartorius in dogs provided the most consistent readings

• StO2 levels in dogs with shock were significantly different than those in normal dogs

• Strong correlations are present between mean oxygen delivery index and StO2 in an experimental model of hemorrhagic shock in anesthetized Beagles

Potential Applications of StO2 in Veterinary Medicine

• Definitive indications for monitoring of StO2 in clinical veterinary patients not fully described

  • Utility as a tool for triage and evaluation of human patients with trauma, sepsis, and surgical diseases so tissue oxygen monitoring may prove to be of benefit in parallel veterinary applications

    • May improve veterinary clinicians abilities to detect occult shock

• Tissue oxygen monitoring may be useful to provide prognostic information and direct resuscitation in veterinary trauma patients

• Comparison of StO2 and ScvO2 in septic veterinary patients would be useful to determine if StO2 can be used as a noninvasive surrogate in this population

• Has not been evaluated in felines

Uses of Tissue Oxygen Monitoring

• Tissue oxygen monitoring may be used to detect hypoxia in emergency settings where monitoring of initial resuscitation may aid in improving outcome

• May also be helpful to identify states of hypoperfusion

Advantages of Tissue Oxygen Monitoring

Rapid

Continuous

Noninvasive

Portable

Easy to Use

Accuracy of StO2 in People

• StO2 only has a moderate correlation with ScVO2 in people

  • Tissue oxygen monitoring should be considered in patients who may be at high risk of morbidity and mortality or where more invasive means of measuring ScvO2 or mixed venous oxygen saturation are not feasible

• High StO2 levels in patients with sepsis or septic shock may be suggestive of impaired oxygen utilization

Limitations to NIRS Technology

• Lack of standardized variables among machines and measurement sites

• StO2 does not measure microcirculatory flow directly and therefore it is difficult to differentiate states of altered tissue oxygen consumption from states of decreased oxygen delivery

• Dyshemoglobinemias can influence the StO2 level

• The path length of near infrared light will vary depending on the composition or density of tissue as well as the degree of melanin so is altered in animals with different degrees of pigmentation

How does cardiac contraction work, actin/myosin level?

• In normal resting, noncontracted state have actin and myosin tropomyosin

  • Tropomyosin covers the myosin binding sites

  • Have to move it off to allow actin and myosin to bind

• Calcium binds to tropomyosin and pulls it off so myosin binding sites are open

• Myosin only binds to those sites when it has ADP bound to it

• When actin and myosin bind, ADP is released, causing movement of actin and myosin and get sliding of muscle filaments against each other

• In order to release and get ready to do this again, ATP must bind to myosin

• When ATP binds to myosin it releases actin and its ready to rebind again

• ATP is dephosphorylated to become ADP/myosin complex

How does cardiac contraction work at the cellular level?

• In order to get troponin to move off of myosin binding sites and to get any muscle contraction you need calcium inside the cell

• Calcium goes into the cell through L type calcium channel

  • Voltage gated, won't open until there's enough calcium outside and enough positive charge to open the channel and go down the gradient

• In the cell will cause release of calcium stored in the sarcoplasmic reticulum

  • Specifically the channel the calcium comes out is the ryanodine receptor channel

• This is now called a calcium spark, when there's enough calcium spark it will bind troponin and bind off of the myosin binding site

• Actin and myosin can interact with each other

• When we want a relaxed state, Ca releases from troponin to allow the troponin to go cover the myosin binding sites

• Ca is released from troponin and is stored back in the SR - ATP dependent channel

• Some of the calcium leaves via Na/Ca transporter

  • NCX transporter

  • To have Na pumped back in to exchange Na it must be actively pumped back in via Na/K/ATPase, active process

Describe the Steps of the Ventricular Action Potential

• 0 - sodium rushes into the cell down a gradient

• 2 - to keep a plateau you need + to keep going into the cell, that's Ca2+

• K+ starts to go out quickly after Na+ comes in so need Ca+ to come in to keep the plateau

• 3 - repolarization, lots of Ca2+ out, no more Na+ in, no K+ in

• 4 - back to resting membrane potential

Describe the Steps of the Action Potential of the SA Node

• Starts at a less negative resting membrane potential, -40, a little bit easier to get it depolarized sooner than ventricle, but does drop down to a point where it can't be depolarized again, refractory period

• During refractory period, Na+ will slowly move into the cell until you get to threshold, Na+ still first step, just gradual

• Sharp increase is from Ca2+ rather than causing plateau

• When you repolarize its K+ leaving the cell

• When you have arrhythmia when there's something affecting the SA node, A fib, SVT, most important thing to block is Ca2+, use Ca channel blockers

Draw the Wigger’s Diagram

Wigger’s Digram Systole

• Systole

• When is systole on this diagram

• Systole - peak of QRS to end of T wave

• Systole starts at the top of the QRS wave at highest peak with cloving of AV valve and opening of aortic valve, moves on through blood leaving the ventricle

• Isovolumic contraction occurs when both valves are closed, systole happens, AV valve closes cause ventricle is full, based on pressure in ventricle is equilibrated to atria or higher, isovolumic contraction squeeze the heart until pressure in ventricle exceeds that in the aorta and that opens the aorta, end of isovolumetric contraction

• Then ejection phase

  • Ventricular pressure goes up during isovolumetric contraction until it exceeds aortic pressure, aortic valve opens

  • Ejection phase where it will go a little higher to get blood out, then pressure will fall a little because there's less blood, ventricular pressure falls below the aortic pressure, get closure of aortic valve, get isovolumetric relaxation where ventricle relaxes until pressure is lower than the atria, AV valves open, end of isolumetric relaxation

Wigger’s Diagram Diastole

• Diastole

  • Starts during isovolumetric relaxation phase, beginning of diastole

  • Occurs from end of T wave until middle of the R wave

  • Low ventricular pressure

  • Ventricular volume is going up, filling ventricle

  • At the end of diastole get P wave and atrial contraction so atrial pressure is low and a little oomph to push blood out of the atria into the ventricle

• During isovolumetric relaxation all valves are closed, at the end AV valve opens, then is open for entire diastole because allowing blood in, at the beginning of isovolumetric contraction AV valves close

Draw the Pressure Volume Loop and Label the Points

What tells the kidney to release renin?

Sympathetic stimulation

Hypotension

Decreased sodium delivery

What are the two hormones in the posterior pituitary gland?

ADH and oxytoxcin

What are the stimuli for ADH release?

Low blood pressure

High plasma osmolarity

What antagonizes ADH and the RAAS system?

ANP

Draw Vascular Smooth Muscle Contraction and Relaxation Diagram

What is the process of vascular smooth muscle contraction?

• Still L type voltage gated Ca channel

  • Ca goes into smooth muscle cell

• Ca binds to calmodulin -> Ca/calmodulin complex

  • Stimulates myosin light chain kinase -> phosphorylates the myosin -> myosin releases the actin its bound to be able to bind again and contract

• Smooth muscle contraction often happens in response to an action potential

  • Cell membrane depolarization will be what makes the Ca channel open

• This is how epinephrine/norepinephrine and angiotensin II cause vasoconstriction

What are the major players in vascular tone?

Norepinephrine/epinephrine

Angiotensin II

Vasopressin

What is the process of vascular smooth muscle relaxation?

• Relaxation happens in response to many things, NO the biggest player

  • NO produced by NO synthase

    • Diffuses into the cell, no channel

  • NO take GTP and turns it into cGMP -> activates myosin light chain phosphatase -> phosphatase take off the phosphorous from myosin and allows binding between myosin and actin which is released and you phosphorylate the myosin again

  • Causes relaxation of smooth muscle

  • How nitric oxide and ANP cause vasodilation

Effects of Nitric Oxide on K_Ca Channels

Indirect effects by opening K_Ca channels

Direct nitrosylation of the channel

Activates cGMP-dependent protein kinase

Contributes to vasopressor resistance in septic shock

When NO binds to K_ca → K+ efflux out of the cell → vasodilation

How the K+/ATP channel affects vascular smooth muscle tone

• When Ca channel is activated K leaves the cell → interior of cell more negative , inside of cell hyperpolarized, makes L type Ca channel close, Ca can't get into the cell and can't cause cell to contract, can't get vasoconstrictive state, close Ca channel down and hyperpolarize the membrane

What activates the K+ ATPase in vascular smooth muscle?

Increased tissue metabolism

Hypoxia

ANP, calcitonin gene-related peptide, adenosine

• Increased in septic and vasodilatory shock

Draw the “Tree of Life”

Action of a-1 Receptors

Located (central) arteries and veins → vasoconstriction

Action of a-2 Receptors

Located in the GI tract → Decreased secretions, motility, tone

Located (peripheral) arteries and veins → vasoconstriction

Actions of B-1 Receptors

Heart → increase inotropy + chronotropy

Actions of B-2 Receptors

Skeletal muscle vessels, coronary arteries → vasodilation

Actions of B-2 Receptors

Bronchial smooth muscle → relaxation

Dobutamine

Positive inotrope

Synthetic B-agonist

B1 » B2

Primarily increase cardiac contractility

Little to no change in heart rate, vascular resistance

Side Effects of Dobutamine

Arrhythmias, tachycardia, vasodilation

Can cause CNS signs in cats

MOA of Dopamine

Binds to D1 and D2 receptors as well as a1, B1, B2, a2 receptors

Low Dose Dopamine

Binds to D1 and D2 receptors

Splanchnic vasodilation, natriuresis, diuresis, variable alterations renal and GI blood flow

CONTROVERSIAL: improves urine production in oliguric renal failure

Used commonly in hypertension or pulmonary edema

What is dopamine a precursor for?

Norepinephrine

At high enough dosages, metabolized to clinically significant amounts of norepinephrine

Binds to a and B receptors → vasoconstriction

Medium Doses of Dopamine

B»a receptors

Increases cardiac contractility

Mild increase in systemic vascular resistance

High Doses of Dopamine

Primarily an a agonist

Increases systemic vascular resistance

May cause renal, GI, and cardiac ischemia

Side Effects of Dopamine

Arrhythmias, tachycardia, increased systemic vascular resistance

May decrease PaO2 → pulmonary arterial vasoconstriction

Redistribution of GI, renal blood flow → ischemic damage

Epinephrine

Higher dosages have a > B effects

• Greater vasoconstrictive effects

Lower dosages do have more B effects

• Greater increases in contractility with less vasoconstrictive effects

Cannot select for effects

• Typically end up with both pressor and inotropic effects with epinephrine

Side Effects of Epinephrine

Increased oxygen consumption by tissues

Severe vasoconstriction (decrease blood flow to tissues)

• Ischemia more common in the GI tract, kidneys, liver

Norepinephrine

Primarily a > B effects

• Mainly increase systemic vascular resistance (small increases in HR only)

May increase blood flow to the heart, kidneys without ischemia in other locations

• Hope is to vasoconstrict and push blood to some of the tissues

Where is vasopressin synthesized and stored?

Synthesized by magnocellular neurons in the hypothalamus

Stored in the posterior lobe of the pituitary gland