Physiology Week 1 Flashcards
NCX
Na/Ca exchanger in plasma membrane. Move Ca uphill by exploiting the Na gradient. Can work in reverse.
PMCA
plasma membrane Ca ATPase. Not v. important to cardiac myocytes, but it is present. Moves ca out of cell
What does SERCA do?
transports calcium back to the sarcoplasmic reticulum. SR and outside cell have similar Ca levels.
How are calcium gradients maintained?
By SERCA and NCX
How do large amounts of ions move?
Through channels - much faster/greater volume than through pumps and transporters. Ex: L-type Ca channel, Na channel
What are some differences between cardiac and skeletal muscle?
Cardiac muscle requires extracellular calcium influx to contract, skeletal muscle does not (vast majority from SR).
Skeletal muscle requires activation by neurons at neuromuscular junctions, cardiac muscle does not.
Skeletal muscle contractions can sum to a larger contraction, cardiac cannot.
Both cardiac and skeletal muscle contraction are fast (versus slow smooth m., smooth muscle also not arranged in sarcomeres)
What is the A band?
middle, thick filaments, dArk
what is the I band?
area that does not contain thick filaments, lIght.
What is the Z line?
scaffolding proteins (alpha actinin) that anchor thin filaments. In middle of I band.
What are thick filaments made of?
myosin heavy and light chains
What are thin filaments made of?
actin, tropomyosin, troponin
How do cross bridges form in cardiac and skeletal muscle?
Calcium binds to troponin-C, causing tropomyosin on thin filaments to change conformation
so binding site is exposed and myosin can bind to actin.
How does skeletal muscle excitation occur?
Motor neurons release Ach at neuromuscular jxn. Ach binds to nicotinic cholinergic receptors in motor endplate. Na flux through the Ach receptors initiates skeletal muscle action potential.
Tetanus?
Chronically contracted muscle
What’s different about smooth muscle?
No troponin/tropomyosin. Actin and myosin interaction occurs when myosin light chain is phosphorylated. MLCK is activated by calcium binding, regulated by calmodulin. Contraction can occur with or without APs. Uses many diff sources of calcium
What stimulates contraction in smooth muscle?
alpha adrenergic stimulation - produces IP3 and Ca is released from SR.
What stimulates relaxation in smooth muscle?
beta adrenergic stimulation and nitric oxide. BAS activates adenylyl cyclase and cAMP inhibits MLCK. NO similar in that it activates guanylyl cyclase.
What is the order of conduction through the heart?
sinoatrial node - atrium - atrioventricular node - bundle of His/bunde branches - Purkinje fibers - ventricles
What’s an SA nodal cell like?
SA nodal cell IS a muscle cell, doesn’t really contract much though. NOT neurons within myocardium - they fire spontaneously. SA cells don’t need to pump blood, don’t need to be as big.
Note that it never goes back down to -85 like a ventricular cell, more like -60.
What are the ion movements in a ventricular AP?
0) Na influx (upstroke)
1) Na in vs. K out (notch)
2) Ca in and K out (plateau)
3) K out (repolarization)
4) K out and NCX in (resting membrane)
What are the ion movements during an SA nodal AP?
0) Ca influx (upstroke)
1) not listed
2) Ca in vs. K out (plateau)
3) K out (repolarization)
4) NCX in AND funny current If in (resting)
What’s a negative current?
positive charge flowing into the cell. A positive current would be positive charge flowing out of the cell.
What’s the deal with L-type calcium currents?
channels open at more positive voltages, opens and closes more slowly than sodium. Otherwise looks like sodium.
supply a significant amount of Ca for AP plateau/SR Ca release in ventricular myocytes
Are the AP upstroke in SA and AV nodal myocytes
Reversal potentials?
K= positive above -90 Na= negative below +70 Ca= negative below +130
Inward rectifying K current
open at resting potential, closes at positive potentials.. reason that cardiac myocytes are at -85mV resting potential
Delayed rectifying K current
closed at resting potential, opens with delay during plateau to repolarize membrane. There are actually 2 - one rapid and one slow (Ikr and Iks)
Funny current
closed at positive voltages, opens at negative voltages.
Funny current supplies depolarizing current to drive voltage up again.
This is opposite behavior from the Na current, Ca current, and delayed rectifier K channel, which all open at positive voltages.
Where is the funny current present?
In the SA node, but not the ventricle. Also called HCN in the heart (hyperpolarization-activated cyclic nucleotide-gated)
Where is the inward K rectifier current present?
In ventricle but not SA node.
Where is the delayed K rectifier current?
in both SA node and ventricles
What happens when you block sodium channels?
Reduced upstroke velocity and slow conduction
What happens when you block delayed rectifier K channels?
Prolonged AP
What happens when you block Ca channels?
Slow HR and AV conduction, weaker contractions.
What happens to channels in heart failure? What happens to Ca?
downregulated K channels. Less inward rectifier and less slow delayed rectifier. SERCA is downregulated so less Ca is pumped into SR, less Ca is available to be released, smaller Ca transients. Leads to weaker contractions and slower relaxation. T-tubules also change, making is more difficult to trigger SR Ca release (poor EC coupling).
Beta1 receptors are also downregulated, beta2 have greater role
What do transverse tubules do?
allow calcium levels to rise uniformly throughout large ventricular myocyte cells
What does caffeine do to CICR (calcium induced calcium release)?
blocks SR release at Ryanodine receptors
EC coupling sequence of events?
- membrane depolarization
- Ca enters through L type Ca channels
- Ca binds to ryanodine receptors in SR membrane
- ryanodine receptors release 4x more Ca than entered the cell.
- overall increase in Ca initiates contraction
What’s different about RyRs in skeletal muscle?
L type Ca channels physically connect to RyRs. The nicotinic Ach receptor activates and AP, which activates the LTCCs
How does calcium leave the cell so relaxation can occur?
total amount let in by LTCC leaves by NCX. Total amount released through RyRs re-sequestered by SERCA.
How do you modulate the strength of a contraction?
primary mechanism is to alter amount of Ca stored in the SR
What happens when Ca within SR is extremely high?
unstable Ca release. clusters of RyRs randomly release small amts of Ca. Normally this is harmless, but when cellular Ca is too high, this can trigger additional release. High intracellular Ca can also increase NCX exchange, which leads to additional +1 charge increase in cell (3 Na for 1 Ca), which depolarizes membrane and can initiate inappropriate APs.
What does Digitalis do?
Given for HF. Inhibits Na/K pump - Na higher in cell, makes extrusion of Ca less efficient. Less Ca extruded means more pumped into SR. More SR Ca means more released –stronger contractions (positive inotropy). Dangerous due to inappropriate APs from high SR Ca.
What does PS stimulation do to the heart?
negative chronotropy by affecting SA nodal cells. Also affects AV node by reducing calcium current through PKA. Negative inotropy in atria. No activity in ventricles.
PS effects more pronounced when there is high sympathetic activity to antagonize.
At rest, heart predominantly under PS control, so not much effect of increasing PS.
What does sympathetic stimulation do to the heart?
increases HR (positive chronotropy) due to SA nodal effects.
increases ventricular contractility (positive inotropy) due to phosphorylation of multiple targets and increased intracellular calcium.
Increased conduction velocity through AV node (positive dromotropy) and positive lusitropy
Acts on SA node, AV node, and ventricular myocardium.
Does increased HR lead to stronger ventricular contractions?
Yes. through increased intracellular calcium.
When is Ikach activated?
Under PS stimulation
Chronotropy
heart rate
inotropy
contractions
dromotropy
cell-cell conduction
lusitropy
relaxation
What does propranolol do?
beta adrenergic receptor blocker. Inhibits sympathetic, HR down a little.
What does Atropine do?
muscarinic acetylcholine receptor blocker. inhibits parasympathetic. HR up a lot
What is bigger, effects of parasympathetic inhibition or sympathetic inhibition on HR?
Parasympathetic inhibition
What’s bigger, effects stimulation of symp or PS on HR?
sympathetic stimulation. PS tone present at baseline.
What is faster, parasympathetic effects or sympathetic? Why?
PS. Ikach activated by beta/gamma subunit of Gi. In membrane, single step with no intermediates like AC.
What are the mediators of PS effects in the SA and AV nodes?
muscarinic Ach receptors. G protein coupled, cAMP, PKA
What is the mechanism of PS effect on SA node?
Activation of acetylcholine-sensitive K current (Ikach) by G inhibitory protein beta/gamma subunits (GIRK-type K channel). This slows SA nodal firing rate. Ikach adds to Iks and I kr that all oppose funny current and Na/Ca exchange. Funny current stays same.
What receptors does the sympathetic system activate?
beta receptors through epinephrine and norepinephrine. Gs coupled (uses alpha subunit of Gprot), leads to increased cAMP. cAMP directly activates funny current/HCN, no phosphorylation needed. In ventricle, PKA is used.
What does isoproterenol do?
beta adrenergic agonist. Causes stronger contractions and faster relaxation. These are ventricular sympathetic effects.
What are the downstream effectors after beta adrenergic stimulation
PKA goes to LTCC, phospholamban, RyR, Troponin I
What is phospholamban (PLB)?
Partial inhibitor of SERCA. Phosphorylation inhibits it.
where are the preganglionic cell bodies of the sympathetic? parasympathetic?
thoracic and lumbar for S (long postganglionic fiber), craniosacral for PS (short postganglionic fiber)
What tissues receive only sympathetic stimulation (no paraympathetic)?
vasculature, ventricles of heart, adrenal medulla, liver and skeletal muscle, sweat glands, pancreas
Predominant tone
The predominant tone of a tissue usually comes from the branch that makes the tissue contract or move (ex: PS and GI).
Notable Exception
The heart’s predominant tone is parasympathetic, which slows heart rate.
Autoreceptor-mediated inhibition
The terminals of the neuron express receptors for the transmitter they release (autoreceptors).
During intense activity, activation of these receptors inhibits subsequent release, preventing excessive stimulation.
Denervation sensitization
If postsynaptic receptors are deprived of their transmitter for a long time, additional receptors are synthesized and inserted into the postsynaptic membrane.
This can happen when receptors are blocked by an antagonist, or when the presynaptic neuron is damaged.
What’s an indirect agonist?
Can interfere with transmitter degradation
What uses acetylcholine in the ANS?
all preganglionic neurons
all PS postganglionic neurons
What uses norepi in the ANS
most sympathetic postganglionic neurons
What uses epinephrine in the ANS?
Not synaptic in the ANS. It is a hormone that is released by the adrenal medulla.
What uses dopamine in the ANS
Sympathetic postganglionics fibers that innervate the renal vasculature and some other vessels beds
What degrades acetylcholine?
acetylcholinesterase in the synapse, pseudocholinesterase in the blood (degrades extrasynaptic ACh).
What receptor is found in the ganglia of all sympathetic and parasympathetic postganglionic neurons?
The nicotinic cholinergic receptor. Ionotropic - when ACh binds, a nonselective cation channel opens and excites postganglionic cell. ALSO found at neuromuscular junction
What’s the deal with the adrenal medulla?
The adrenal medulla functions like a post-ganglionic SYMPATHETIC neuron. Nicotinic receptors on the adrenal medulla are activated by acetylcholine, causing the release of epinephrine and norepinephrine into the blood.
What are muscarinic cholinergic receptors?
Found in effector tissue at parasympathetic synapses. M1, M2, and M3, but mainly M2 and M3 are found in ANS.
What is M2?
expressed mainly in heart atria, inhibits adenylyl cyclase and hyperpolarizes the membrane.
What is M3?
expressed mainly in smooth muscle, couples to Gq. Activates PLC to increase Ca via IP3, which stimulates protein kinase C.
What is the alpha1 adrenergic receptor?
couples to Gq–PLC-IP3 and DAG–PKC.
contracts smooth muscle in many tissues (arterioles in skin, viscera, salivary glands. also pupillary constriction/mydriasis).
What are beta adrenergic receptors?
All couple to Gs and increase cAMP. Only concerned about beta1 and 2.
Where is beta1 > beta2?
Heart
Juxtaglomerular cells of the kidney
Where is beta 2> beta 1?
Skeletal and coronary arterioles and some veins
Bronchial smooth muscle
Mediate vasodilation and bronchodilation
What do dopamine receptors do?
Mainly concerned with D1, which couple to Gs. Prominent on renal vasculature and mediate vasodilation.
When is renin released? What does it do?
In response to low renal BP and sympathetic activity. It triggers the production of angiotensin II, which is a powerful vasoconstrictor.
Are blood vessels parasympathetically innervated?
For the most part, NO! PS/vagal activity does not affect peripheral vascular resistance or diastolic BP. BUT there are muscarinic receptors widely expressed on vascular endothelium.
Where does NO come from? What does it do?
released from vascular endothelial cells when activated by a cholinergic agonist. Diffuses to vascular smooth muscle and activate guanylyl cyclase —muscle relaxation and vasodilation.
What does PS stimulation do to the AV node?
Gi activated which reduces cAMP-dependent phosphorylation of LTCC. P-R interval lengthens.
AV-block can occur from excessive PS stimulation.
What does PS stimulation do the atria?
reduces contractility and shortens AP. Reduced phosphorylation of LTCCs and phospholamban (which inhibits SERCA) leads to smaller rise in Ca during AP.
What does pyridostigmine do?
Anticholinesterase so we see exaggerated response to nl PS activity - doesn’t affect vasculature bc there is no normal PS activity there.
Use for treatment of myasthenia gravis in which nAChRs of neuromuscular junctions are targets of autoimmune destruction.
Direct effect on vasculature: none
Direct effect on heart: slows HR
Reflex effect on heart: none - no change in vascular tone or ventricular contractions - baroreceptors have nothing to respond to.
-can get SA or AV block
What’s an AV block?
Under normal conditions, SA node in the atria sets the pace for the heart, and these impulses travel down to the ventricles. In an AV block, this message does not reach the ventricles or is impaired along the way.
What’s weird about sweat glands?
Sweat gland innervation is sympathetic, but postganglionic fibers release ACh - increased secretion, use muscarinic receptors.
Anticholinesterase toxidrome?
- they’re found in pesticides, nerve gas (ex: Sarin).
Mnemonics:
SLUDGE (salivation, lacrimation, urination, defecation, GI upset, emesis)
KILLER B’s (bradycardia, bronchospasm, bronchorrhea-excessive mucous discharge)
DUMBELS (defecation, urination, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, lacrimation, salivation).
What does Atropine do?
- reduces resp. secretions during surgery
- reverses effects of anticholinesterases, acts as antagonist on muscarinic receptors.
- No effect at vasculature
- Increase HR and atrial contraction.
- No effect at ventricles
- No real change in BP
Toxidrome effects essentially opposite of anticholinesterase toxidrome.
What does acetylcholine do?
- Full agonist at muscarinic and nicotinic receptors but MUCH more potent at muscarinic.
- if administered IV, rapidly degraded by pseudocholinesterase.
in LOW doses, BP drops (from direct dilation of vasculature), reflex tachycardia, doesn’t get to SA node.
in HIGH doses, BP drops big time but SA nodes are affected so bradycardia occurs, sympathetic reflex to increase HR is overpowered.
What does hexamethonium do?
- Antagonist at nicotinic neuronal receptors (not at neuromusc. jxns).
- Used for hypertension bc it blocks sympathetic innervation of vasculature (predominant tone).
- causes orthostatic hypotension because baroreceptors can’t activate sympathetic tone for compensatory vasoconstriction when someone stands up.
What does nicotine do?
- Agonist at Nn and Nm nicotinic receptors - increases primary tone of organs.
- Increases BP
- increases HR (due to epi released by adrenals)
- initial contraction at skeletal muscles due to Nm nicotinic receptors, followed by paralysis.
Cholinergic drugs
pyridostigmine, atropine, acetylcholine, hexamethonium, nicotine
What sympathetic receptors are found in the vasculature?
- alpha1 throughout. Beta2 also found, particularly high in coronary and skeletal muscle arteries.
- sympathetic activity causes a net increase in vasc. resistance, which increases diastolic BP. This is caused both by synaptically released norepi and circulating epi
- blood flow can be redistributed to areas with high beta2 and away from high alpha1 from sympathetic stimulation
- renal blood flow preserved through D1 receptors.
What does phenylephrine do?
acts on alpha receptors - constricts SM.
Direct effect on vasc: increased peripheral vasc. resistance, increase in diastolic BP
Direct effect heart: none, no alpha receptors in heart
Reflex: decreased HR
What does epinephrine do?
Activates alpha and both beta receptors
At high dose (usual), alpha receptor mediated vasoconstriction dominates over beta2 vasodilation. Vascular beds, cutaneous (alpha only) very constricted.
HR INCREASED because of direct effect of Epi on beta1 receptors, overwhelms reflex response.
At LOW doses, diastolic BP decreases because EPI IS MORE POTENT AT BETA2. This is why we see transient decrease in BP at beginning of Epi IV infusion. Still raises HR
Why do dentists inject epi?
Because it constricts the vasculature, which reduces the systemic distribution of local anesthetic
What does norepinephrine do?
Agonist at alpha and beta1 (NOT beta2!)
Increases BP more than epi because its lacks beta2 activity.
Such a strong BP effect that the baroreceptor reflex effect is very strong so we see decreased HR (direct effect increased HR).
What does isoproterenol do?
beta receptor agonist
potent vasodilator from beta2
HR and contractility both increased from beta1
Reflex and direct effects in same direction
What does phentolamine do?
blocks alpha1 which decreases diastolic BP
Reflex increases HR and contractility
Risk of orthostatic hypotension because reflex vasoconstriction is blocked
Alpha blockers are often used for enlarged prostate which can result in orthostatic hypotension and tachycardia.
What does propranolol do?
nonselective beta antagonist
At HIGH doses Increased diastolic BP and vasoconstriction because of unopposed alpha receptors.
At LOW doses, propranolol is used to treat hypertension, not understood why
HR decreased due to block of beta1
Airway constricts due to loss of beta2 dilation
What does albuterol do?
beta2 selective agonist used as a bronchodilator.
adverse side effects: hypotension (direct effect), tachycardia (reflex).
What does Tyramine do?
releases norepi
found in aged cheese, wine, chocolate
metabolized in liver by monoamineoxidase (MAO) which is inhibited by some antidepressants
high tyramine food can induce hypertension in people taking MAO inhibitors - sustained release of norepi causes vasoconstriction
What is compliance?
volume/pressure. low compliance is stiff and difficult to fill
