CR2.9 Autonomic and local control of the CVS

Question 1

Describe neural, humoral and local factors related to control of the cardiovascular system.

Answer 1

1. Systemic
   
   1. Neural
      
      1. NA –> SNS
      2. Ach –> PNS
   2. Humoral
      
      1. Adrenaline –> Adrenal medulla (short term, fast acting)
      2. Vasoactive peptides –> RAAS (long term, slow acting)
2. Local vascular control (i.e. on-site regulation) Local factors within specific blood vessels influence VSMC contraction and relaxation –> perfusion. These can be influenced by flow / shear stress, pH, NO, ATP, adenosine, CO₂, O₂, endothelins

Question 2

Describe the two different contractile activities observed in VSMVs.

Answer 2

VSMC can be classified on the basis of contractile activity. Fast versus slow contratile gene programs give rise to phasic and tonic smooth muscle phenotypes.

• Tonic contractile activity is slow and found in the aorta and vena cava
• Phasic contractile activity is fast and can be found in resistance arteries and systemic microvasculature

Question 3

Briefly describe how VSMC can be classified on the basis of innervation.

Answer 3

Multiunit VSMCs: composed of seperate fibers with few gap junctions and richly innervated –> stretching DOES NOT produce a contactile response

Unitary VSMCs: composed of bundles or sheets of fibers and highly enriched with gap junctions. Limited innervation is required and DOES respond to stretch, local and humoral factors

Question 4

Explain the mechanism of VSMC contraction and relaxation.

Answer 4

Contraction –> increase intracellular Ca²⁺

1. Neural (e.g. NA) and/or humoral (e.g. ATII, ADH, endothelin-1) factors act on transmembrane signalling proteins
2. Intracellular signalling triggers opening of Ca²⁺ entry via L-type voltage-gated channels
3. Ca²⁺ release from the SR via IP₃ binding to the IP₃R
4. Ca²⁺ entry cia voltage-independent channels (e.g. stretch due to blood flow –> myogenic)
5. Increased intracellular Ca²⁺ activates calmodulin (CM) and forms Ca²⁺-CM complex
6. The Ca²⁺-CM complex activates myosin light chain kinase (MLCK)
7. Phosphorylation of MLC by MLCK allows myosin to interact with actin, producing contraction

N.B. No troponin-C such as found in cardiomyocytes.

Relaxation –> remove intracellular Ca²⁺

1. Ca²⁺ uptake by SERCA increased
2. Extrusion to ECF via Ca²⁺ ATPase pump
3. Extrusion to ECF via Na⁺/Ca²⁺ exchanger

Relaxation occurs when myosin light chain phosphatase dephosphorylates the MLC.

Question 5

Describe the regulation of VSMC contraction and relaxation.

Answer 5

Neuronal and humoral agonists of VSMC G-protein coupled receptors (GPCRs). There are several G-proteins and different biological agonists act on different G-proteins to illicit different effects.

Examples:

• Epinephrine, adenosine, prostacyclin act on ß₂ receptors to activate Gs to increase cAMP and cause vasodilation by regulation of MLC phosphorylation
• NA/Epinephrine act on alpha₁ receptors to activate Gq to increase Ca2+ release from the SR and cause vasoconstriction

Question 6

List some of the most prominent chemical factors of local vascular smooth muscle (VSMCs) tone and breifly describe the effect on systemic and pulmonary circulation.

Answer 6

• PO₂
• PCO₂ (i.e. major metabolic waste products)
• pH

These chemical mediators change in response to changes in metabolic demand. E.g. in exercise, reductions in PO_2, pH and increases in PCO₂ cause vasodilation in the systemic circulation and vasoconstriction in the pulmonary circulation (i.e. to avoid perfusing a part of the lung with impaired gas exchange).

Question 7

List three vasoactive compounds induced by ligand-reecptor interactions on endothelial cells.

Answer 7

The endothelium of capillary beds are the source of several vasoactive compounds.

1. Nitric oxide (NO) –> potent vasodilator response to shear stress
2. Prostacyclin (PGl₂) –> vasodilator implicated in inflammation –> reduces activity of MLCK
3. Endothelins (ETs) –> peptides that cause potent and long-lasting vasoconstriction –> implicated in CV pathology such as systemic and pulomary hypertension and HF

Question 8

Describe the process of autoregulation.

Answer 8

N.B. Flow = change in pressure / resistance

• Increased pressure leads to increased resistance
• Reduced pressure leads to reduced resistance

This is regulated by local myogenic, metabolic and endothelial factors rather than neural and endocrine factors. e.g. stretch-activated channels increase calcium entry into VSMCs

Very important in organs sensitive to low PO₂ –> renal, cerebral, coronary circulation.

Question 9

Describe three types of blood pressure (MAP) regulatory mechanisms.

Answer 9

Short term:

• The arterial baroreceptor reflex (neural)
• Secondary neural regulation of arterial blood pressure depends on chemoreceptors

Intermediate-term:

• Transcapillary volume shifts (e.g. drinking water, exercise, sepsis)
• Stress relaxation (i.e. sustained increased intravascular pressure –> VSMC relaxation and dialtion –> increased volume capacity and reduction in BP

Long-term (see CR3)

Question 10

Define the clinical syndrome shock. Explain the physiological mechanisms underpinning this clinical presentation, with reference to Frank Starlings Law of the Heart.

Answer 10

Shock –> Hypovolaemic shock is a large reduction in mean arterial pressure (MAP).

This activates circulatory control mechanisms to restore MAP and CO quickly. This triggers the chemoreceptor and baroreceptor reflexes. Also activated hormonal mechanisms to retain fluid (see CR3).