Mechanism of catecholamines (NE or epinephrine)

in SA and AV nodes (slow response):

Sympathetic adrenergic

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non-selective cation channel: (HCN) Hyperpolarization-activated Cyclic Nucleotide gated ion channel

Mechanism of catecholamine (NE and epinephrine) in atrial and ventricular muscles:

Sympathetic adrenergic

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phosphorylation of (1) Ryanodine receptors (RYR): increase sensitivity to cytoplasmic Ca²⁺ allows more Ca²⁺ release by SR, (2) Ca²⁺ L-type channels permits more Ca²⁺ influx, (3) inhibiting phospholamban, allowing more Ca²⁺ reuptake to SR, (4) Troponin I - destabilizes the actin-myosin cross-bridge, (5) Enhance SR Ca⁺ ATPase activity, leads to faster muscle relaxation (lusitropic effect)

 (3) in SA/AV nodes, ↑Na⁺ influx through HCN (I_f) channels, increasing steepness of phase 4 pacemaker potential

Mechanism of ACh in SA and AV nodes (slow response)

Parasympathetic Muscarinic 

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ACh binds muscarinic receptor -> G_βγ-> adenyl cyclase -> ↑ K⁺ conductance (via opening K⁺ ion channel) and ↓Ca²⁺ conductance via reducing cAMP

Duchenne muscular dystrophy

complete absense (<5%) of expression of dystrophin

Sex-Linked (X-chromosome)

milder form is called

Reflex Sympathetic Dystrophy Syndrome or

Complex Regional Pain Dynrome

ANS disorder: sympathetic

injury to nerve or soft tissue does not following normal healing pathway

injury->pain impulse (via sensory nerves) -> CNS -> sympathetic nerve-> inflammatory response at original site of injury ->spasm of vessels -> swelling -> pain -> ad infinitum

Frey's Syndrome

ANS disorder: parasympathetic

regeneration of parotid gland parasympathetic secretomotor fibers, attach to great auricular nerve -> saliva production -> flushing/sweating

Horner's syndrome

ANS syndrome: sympathetic

damage of blockage to sympathetic nerve (chain)

Symptoms: Horny PAMELa

Ptosis, Anhidrosis, Miosis, Enophthalmos and Loss of ciliospinal reflex.

Atropine

reversible ACh muscarinic blocker

antidote to SLUDGE in (ANS)

Mushroom poisoning

"Crocodile tears"

Atrial fibrillation (arrhythmias)

uncoordinated atrial depolarization

Etiology: sick sinus syndrome, enlarged atria size, and pressure in heart failure ,hypertension, coronary heart disease -> latent pacemakers

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First degree heart block

Lengthening of PR interval > 0.2 sec.

could result in a failure to activate the ventricles

Etiology: increased vagal tone, drugs that depress conduction through the AV node (digitalis, β blockers) ischemia, or infarction

Bundle Branch block

wide QRS complex (> .12 s)

Etiology: action potentioals through bundle branches can be blocked by ischemic or infracted Bundle of His fibers

Long QT

prolonged action potential duration (long QT interval) and delay in repolarization: can result in ventricular arrhythmias

Etiology: Na+ channel can't inactivate, or K+ channel can't repolarize

What diseases lead to decreased contractility in the heart?

Systolic Dysfunction

(1) MI

(2) Transient Myocardial ischemia

(3) Chronic volume overload: mitral regurgitation, aortic regurgitation

(4) Dilated cardiomyopathy

What diseases lead to an increased afterload?

Systolic Dysfunction

(1) Aortic stenosis

(2) Uncontrolled hypertension

Systolic dysfunction leads to what?

Systolic Dysfunction -> L. heart failure -> decreased C.O.

What diseases lead to impaired ventricular relaxation?

Diastolic Dysfunction

(1) LV hypertrophy

(2) Hypertrophic cardiomyopathy

(3) Restrictive cardiomyopathy

(4) Transient myocardial ischemia

What diseases lead to an obstruction of LV filling?

Diastolic Dysfunction

(1) Mitral Stenosis

(2) Pericardial constriction or tamponade

Diastolic dysfunction leads to what?

Dystolic dysfunction -> decreased preload -> decreased stroke volume -> decreased cardiac output

What conditions can cause right-sided heart failure?

(1) Left sided heart failure: blood backs up to the lungs and RV
(2) Pulmonic valve stenosis: ↑RV workload => RV hypertrophy
(3) RV infarction: ↓RV contractility, impaired RV relaxation
(4) Parenchymal pulmonary disease: Hypoxia will increase PA pressure => ↑RV workload => RV hypertrophy

(5) Pulmonary vascular disease (PE, pulm HTN)
– ↑RV workload => RV hypertrophy

Explain the mechanism of ↑ATP utilization and local reduction in blood flow (ischemia) => vasodilation

Metabolic control of blood flow:

- Mismatch bet. ATP use and ATP demand => ↑ATP breakdown => ↑Adenosine => Vasodilation

- ↑PCO₂ ↑lactic acid ↑ H⁺ => ↓pH => vasodilation

-> ↑K⁺ extracellular or ↑osmolality => vasodilation

Explain the mechanism of ↓ATP and Ca²⁺ and vasodilation

Metabolic control of blood flow

↓ATP => K_ATP channels open => ↑K⁺ efflux => VSMC (vascular smooth muscle cell) hyperpolarization => VSMC Ca²⁺ channels close => ↓Ca²⁺ influx => vasodilation

Myogenic Mechanism of control of blood flow

Myogenic mechanism is dep. on Ca²⁺, but not the presence of endothelium. Leads to vasoconstriction, as opp. to vasodilation (metabolic control).

Increased flow/perfusion pressure => vascular smooth muscle “stretched” => stretch opens stretch sensitive cation channels (Na⁺) => cations enter cell => membrane depolarizes => voltage gated Ca²⁺ channels open =>  Ca²⁺enters cell and triggers
contraction => vessel diameter decreases => blood flow/perfusion reduced

Mechanism of Endothelial cells neural/hormonal control of blood flow

shear stress, ACh (M) , or bradykinin (β₂) => ↑Ca²⁺ => ↑endothilial NO synthase activity => ↑NO (from L-arginine) => diffusion of NO to VSMC => ↑sGC activity (receptor of NO) => ↑cGMP => ↑PKG activity =>

(1) ↑phosphorylation of MLCK, which inhibits MLCK => ↓ MLCK activity => ↓phosphorylation of MLC => ↓actin-myosin interaction

(2) ↑phosphorylation of SR Ca++ ATPase (SERCA) activity => ↓ [Ca++]i
 

=> VASODILATION

5 Vasodilators released by Endothelium

PRO-PRO-EDHF = VASODILATION

Prostacyclin 
Prostaglandin E₁
EDHF

(Endothelium-derived hyperpolarizing factor)

Histamine (allergies, tissue damage)

Bradykinin (tissue injury, immune reactions)

CC: injury to endothelium is primary event => atherosclerosis (atherogenesis)

3 Vasoconstrictors released by endothelium

Endothelin
Thromboxane A₂
Prostaglandin F_2α

CC: injury to endothelium is primary event => atherosclerosis (atherogenesis)

Systemic Neural and hormonal control of blood flow:

Mechanism of NE in VSMC

Sympathetic activation releases NE => NE binds to α-1 adrenergic receptor in VSMC plasma membrane => G_q =>↑IP₃/binds to an IP₃ receptor in SR membrane leading to the opening of Ca²⁺ channels=> ↑ Ca²⁺ intracellular=> vasoconstriction

Activators: endothelin, angiotensin II, serotonin, arginine vasopressin =>

Systemic Neural and hormonal control of blood flow:

Mechanism of Epinephrine (Epi) in VSMC

Epi => β2 adrenergic receptors => Gs =>↑ adenyl cyclase activity => ↑cyclic AMP => ↑PKA activity => ↓Ca²⁺ intercellular => vasodilation

Mechanism of PKA: (first two are similar to PKG)

(1) ↑phosphorylation of MLCK, which inhibits MLCK => ↓ MLCK activity => ↓ phosphorylation of MLC => ↓actin-myosin interaction
(2) ↑Phosphorylate SERCA pumps => ↓Ca²⁺ intercellular
(3) ↑Phosphorylates K channels => hyperpolarization

Generally, parasympathetic innervation is not found in blood vessels. What are the two exceptions?

What are the similarities and differences bet. control of arteriole tone and venous tone?

Similarity: Veins have vascular smooth muscle cells that are affected by the same factors as arterioles such as α1 adrenergic vasoconstriction and other hormonal
influences

Differences: While arterioles are the inflow valves that control the rate of capillary/nutritive blood flow, veins regulate the distribution of available blood between peripheral and central venous compartment

Veins have little basal tone and are usually in
a dilated state; therefore metabolites that accumulate in the interstitial space have no effect on veins

When is venous pressure in the foot highest? What causes change in venous pressure?

CC: What can happen when valves in vein fail to close?

Varicose veins: incompetence of the valves of superficial veins

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α₁ receptor: Type, Location and Mechanism

Adrenoreceptor

Location:

Vascular smooth muscle, skin, renal, and splanchnic

GI tract: sphincter

Bladder: sphincter

Radial Muscle: iris

Mechanism

IP₃ => ↑intracellular [Ca²⁺]

α₂ receptor: Type, Location and Mechanism

Adrenoreceptor

Location

GI tract: wall

Presynaptic adrenergic neurons

Mechanism:

Inhibition of adenylyl cyclase => ↓cAMP

β₁ receptor: Type, Location and Mechanism

Adrenoreceptor

Location:

Heart

Salivary glands

Adipose tissue

Kidney

Mechanism:

Stimulation of adenylyl cyclase => ↑cAMP

β₂ receptor: Type, Location and Mechanism

Adrenoreceptor

Location:

Vascular smooth muscle of skeletal muscle

GI tract: wall

Bladder: wall

Bronchioles

Mechanism:

Stimulation of adenylyl cyclase => ↑cAMP

Nicotinic receptor: Type, Location, Mechanism

Cholinoreceptor

Location:

Skeletal muscle: motor end plate

Postganglionic neurons: SNS and PNS

Adrenal medulla

Mechanism:

Opening Na⁺ and K⁺ channels -> depolarization

Muscarinic receptor: Type, Location, Mechanism

Cholinoreceptor

Location

All effector organs: PNS

Sweat glands: SNS

Mechanism

IP₃ => ↑Ca²⁺ intracellular