CV & Vascular Signaling (complete) Flashcards Preview

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Flashcards in CV & Vascular Signaling (complete) Deck (24):

Describe the mechanisms by which PKA-mediated phosphorylation of L-type Ca++ channels affect inotropy and lusitropy

- L-type Ca++ channels are activated by depolarization
- Influx of Ca++ through these trigger RyR2 opening (SR Ca++ release)
- Sympathetic stimulation => ^ cAMP and ^ PKA
- PKA phosphorylates L-type channels => slowed inactivation
- Increases magnitude of Ca++ influx => inotropy


Describe the mechanisms by which PKA-mediated phosphorylation of RyR2 affect inotropy and lusitropy

- Sympathetic stimulation => PKA phosphorylates RyRs
- This increases RyR sensitivity to Ca++ (less Ca++ needed to evoke SR Ca++ release)
- Increases inotropy


Describe the mechanisms by which PKA-mediated phosphorylation of phospholamban (PLB) affect inotropy and lusitropy

- PLB inhibits SERCA
- PKA phosphorylates PLB => PLB dissociation from SERCA
- Increases Ca++ reuptake into SR
- Faster Ca++ reuptake => ^ lusitropy and ^ inotropy by increasing SR Ca++ load


Describe the mechanisms by which PKA-mediated phosphorylation of troponin I (TnI) affect inotropy and lusitropy

- TnI inhibits troponin complex (inhibits actin-myosin interaction w/o Ca++)
- PKA (and other kinases) phosphorylate TnI => decreases Ca++ sensitivity of complex and ^ dissociation of Ca++ from complex
- This increases lusitropy => allows heart to fill more quickly


Describe how hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to autonomic control of heart rate

- HCNs produce I(f) (an inward, depolarizing current)
- Sympathetic stimulation of the SA node cells => ^ cAMP => cAMP binds to HCNs
- HCNs now more likely to open => speeds rate of diastolic depolarization
- Parasympathetic stimulation (ACh) activates M2 muscarinic ACh receptor (coupled w/ Gi/o)
- This has opposite effect as sympathetic => decreases cAMP => less binding to HCNs => decrease I(f) through HCNs => slows HR


Describe how L-type Ca++ channels contribute to autonomic control of heart rate

- ß-adrenergic stimulation increases L-type current => contributes to the sympathetic increase in HR
- Symp stimulation increase SR Ca++ load via PKA mediated phosphorylation of L-type channels and RyRs
- Parasymp stimulation via ACh activates M2 muscarinic Ach receptors => activates G(i) => slowing HR due to relaxation


Describe how GIRK channels contribute to autonomic control of heart rate

- Gbg subunit binds to GIRK channels => activates IKACh current (K+) => hyperpolarizes cell
- This drives membrane potential to K+ equilibrium => slows spontaneous firing frequency

***This is the primary mechanism for parasympathetic regulation of HR


Describe vascular smooth muscle cells (so that you can compare them with cardiac myocytes)

- Small, mononucleated cells
- Electrically coupled via gap junctions
- Not striated
- Not arranged in sarcomere
- SR Ca++ release not essential for contraction
- Contraction rate slows, sustained, and tonic
- Can be initiated by mechanical, electrical, or chemical stimuli
- Do NOT have troponin


Describe cardiac myocytes (so that you can compare them with vascular SM cells)

- Striated
- Arranged in sarcomeres
- SR Ca++ release essential for contraction
- Contraction rate faster and unsustained


Describe Ca++ regulation of vascular SM contraction

- Ca++ enters cytoplasm from SR & voltage-gated Ca++ channels
- Ca++ binds to calmodulin (CaM)
- Ca++-CaM binds to myosin light chain kinase (MLCK) => activates
- MLCK-activates phosphorylates MLC => cross bridge cycling
- Contraction halted by dephosphorylation of MLC by MLC phosphotase
- cAMP causes relaxation of VSMCs


Describe the mechanisms by which sympathetic stimulation (via alpha1- adrenergic receptors) alters vascular tone

- These are GPCRs coupled to G(q)
- Gaq activates phospholipase C (PLC) => activates DAG and IP3
- IP3 activates IP3Rs (intracellular Ca++ release channels) on SR of VSMCs
- ^ Ca++ => VSMC contraction and vasoconstriction
- PKC phosphorylates targets in VSMCs (e.g. L-type Ca++ channels)


What are arterial baroreceptors?

- Pressure sensitive neurons in aortic arch and carotid sinus
- Na+ channels open in response to mechanical stimulation (stretched by high BP) => Na+ depolarization => APs
- Baroreceptor neurons project to sensory area of CV control center in brainstem
- Distinct output areas control symp and parasymp output to heart and vasculature


Describe the arterial baroreceptor reflex arc

- when stimulated by ^ BP => ^ baroreceptor firing rate => decreased sympathetic output and ^ parasymp
- This decreases HR, inotropy, and vascular tone => vasodilation and decreased BP


What are the 4 tissue metabolites that control local flow to a capillary bed?

1) Decreased PO2
2) ^ PCO2/decreased pH
3) ^ K+
4) ^ Adenosine


Describe the myogenic response

- Feedback mechanism designed to maintain constant flow despite pressure changes
- Intrinsic in VSMCs --- Stretch causes VSMC contraction by opening stretch-activated ion channels => depolarize VSMC
- This ^ intracellular Ca++ via L-type


Describe how nitric oxide regulates vascular smooth muscle tone

- NO increased vasodilation
- Mechanism: NO activates guanylate cyclase => ^ cGMP => activates PKG => decreases intracellular Ca++ via activation of SERCA & inhibition of L-type => Decreased Ca++ => relaxation and vasodilation


Describe how endothelin regulates vascular smooth muscle tone

- Endothelin increases vasocontriction
- Produced by vascular endothelium
- mechanism: binds to ET receptors => GPCRs coupled to G(q) => similar to alpha-adrenergic response


Describe the origin and effects of atrial natriuretic peptide on blood pressure

- ANP is a vasodilator => released by atria after mechanical stretch
- Involved in long-term Na regulation and H2O balance, blood volume, arterial pressure
- Acts on ANPRs (receptor guanylate cyclases) throughout body => produce cGMP => activates SERCA


Describe the renin-angiotensin-aldosterone system

System for blood volume regulation

mediated by kidney


Describe renin in the renin-angiotensin-aldosterone system

- released into circulation by juxtoglomerular cells when stimulated by JG cells, decreased BP in renal a., or decreased Na reabsorption in kidney
- Renin cleaves angiotensinogen to angiotensin I (AI)
- AI then cleaved by ACE to AII


Describe the direct effects of angiotensin II

AII is a potent systemic vasocontrictor

Binds to GPCRs on VSMCs


Describe the indirect effects of angiotensin II

1) Stimulates sympathetic activity => ^ vasocontriction
2) ^ aldosterone release from adrenal cortex
3) Stimulates endothelin release from vascular endothelium => ^ vasocontriction
4) stimulates ADH release from pituitary


Describe aldosterone

- promotes Na and H2O reabsorption in the kidney
- This ^ blood volume => ^ BP


Describe anti-diuretic hormone

- formed in hypothalamus
- released by pituitary
- ^ H2O reabsorption in kidney
- ^ peripheral vasoconstriction during systemic shock