Regulation of CV system

Question 1

Stroke volume is regulated by what 3 things?

Answer 1

1. Inotropy (contractility) +
2. Preload +
3. Afterload -

Question 2

what is the most prevalent category of drug target?

Answer 2

GPCRs

Question 3

Describe PKA tetramer

Answer 3

2 Regulatory and 2 catalytic subunits.

Binding of 4 cAMP molecules causes dissociation

Free catalytic subunit can phosphorylate target proteins

Question 4

What does phospho of PLB do?

Answer 4

Relieves inhibition of SERCA
Leads to faster Ca2+ reuptake into SR
–> may enhance the rate of cardiac myocyte relaxation.

(When phospholamban is phosphorylated by PKA its ability to inhibit (SERCA) is lost.)

Question 5

Phospho of RyR?

Answer 5

Increase Ca2+ sensitivity so less is needed to evoke Ca2+ release

Question 6

Phospho of DHPR?

Answer 6

Slows inactivation
Increases entry of trigger Ca2+
Increase Ca2+ induced Ca2+ release = increases inotropy

Question 7

Phospho of troponin I?

Answer 7

Decreases Ca2+ sensitivity of troponin C
Allows faster dissociation of Ca2+ so faster filling = increased lusitropy

Counterintuitive!

Question 8

Sympathetic stimulation ___ HR

Parasympathetic stimulation ____ HR

Answer 8

Symp = increase
Parasymp = decrease

Question 9

cAMP binding stimulates HCN channels, this does what to inward current and AP generation?

Answer 9

Increases inward current and increasing spontaneous AP generation

Question 10

What is primary mechanism for parasympathetic control of HR? Secondary mechanisms?

Answer 10

Primary is activation of IKACh current via GIRK (inwardly rectifying K+) channels –> lets current in at (-) potentials
hyperpolarization-activated K+ channel responsible for resting potential in ventricular myocytes

Secondary are the binding to M2 muscarinic Ach receptors, ↓ing cAMP

Question 11

Striated muscle contraction = ___ filament regulation

Answer 11

Thin

Question 12

Do VSMCs have sarcomeres?

Answer 12

No
(myofilaments of SM, unlike skeletal and cardiac are not arranged in sarcomeres)

They also have no troponin!

Question 13

Describe the molecular steps involved in Ca2+ regulation of vascular smooth muscle contraction.

What permits cross-bridge cycling in VSMC?

Answer 13

1. Contraction is triggered by mechanical, chemical, or electrical stimuli.
2. Ca2+ enters cytoplasm from SR and/or PM Ca2+ channels
3. Ca2+ binds calmodulin
4. Ca2+-Calmodulin binds to myosin light chain kinase (MLCK) to activate it
5. Activated MLCK phosphorylates the myosin head - permits cross bridge cycling
6. MLC dephosphorylated by myosin light chain phosphatase (MLCP); stops contraction
7. cAMP inhibits MLCK - causes VSMC relaxation

Phophorylation of myosin head

Question 14

cAMP inhibits MLCK which does what for VSMC and Cardiac cells?

Answer 14

causes VSMC relaxation!!! This is different from contraction in cardiac cells (contraction).

Question 15

Is baroreceptor reflex an intracellular signaling pathway?

Answer 15

No, baroreceptors are pressure sensitive neurons, that provide short term and rapid negative feedback mechanism for sudden changes in blood pressure.

They don’t contract. They respond to stretch.

Question 16

4 vasoactive metabolites

Answer 16

Primary mechanism to match blood flow to capillaries to metabolic demand

1. PO2
2. PCO2
3. Increased extracellular K+
4. Increased adenosine (by product of HPV analysis)

Question 17

Myogenic response (autoregulation)

Answer 17

Independent of metabolism, maintains constant flow despite changes in pressure (ie postural changes)

When you stretch isolated blood vessel, it constricts

Question 18

Myogenic response can be overcome by what?

Answer 18

the vasoactive metabolites

Question 19

NO signaling

• what is it?
• what is it produced by?

Answer 19

Potent gaseous vasodilator with short half-life (10-60s) so has local effects

Produced by vascular endothelium

Question 20

Decreased NO is associated with increased risk for what condition?

Answer 20

Atherosclerosis

Question 21

What is the NO synthase sensitive to?

Answer 21

Components of cigarette smoke such that NO production can be compromised by CV disease risk factors

ie smoke cigarettes, get atherosclerosis (b/c NOS doesn’t work and you don’t get enough NO)

Question 22

NO action in VSMCs?

Answer 22

○ Humoral regulators activate GPCRs on endothelium that increase intracellular Ca levels.
○ Increase intracellular Ca activates NO synthetase.
○ Free NO diffuses into VSMCs and activates guanylate cyclase
○ cGMP is increased and activates PRG, which activates SERCA and inhibits the L-type Ca channel.
○ Resultant decreased Ca causes relaxation (vasodilation)

Question 23

Endothelin

Answer 23

Potent peptide vasoconstrictor produced by vascular endothelium

Endothelin Converting Enzyme (ECE) is the rate-limiting converting enzyme

Binds to GPCR on VSMC which are Gq coupled receptors, produces IP3 and increases Ca within VSMC and leads to vasoconstriction

Question 24

What is the primary system for long-term control of blood pressure?

Answer 24

RAAS

Question 25

ACE does what?

what is it used to treat?

Answer 25

Converts Angiotensin I to Angiotensin II which is a vasoconstrictor.

Used to treat hypertension and heart failure

Question 26

How does Angiotensin II work?

Answer 26

Binds to GPCRs on VSMCs - Gq linked to induce systemic vasoconstriction

Also stimulates sympathetic activity and release aldosterone, endothelin, and ADH

Question 27

What is the role of aldosterone?

Answer 27

Increase blood volume and BP by promoting Na and water reabsorption

Question 28

What is the role of ADH

Answer 28

Increases water reabsorption in kidney = increases blood volume and BP

Can also bind to receptors in vasculature to cause vasoconstriction