CVS: Vascular Tone and Endothelium

Question 1

What are vasodilator nerves?

Answer 1

A few specialised tissues contain vasodilator nerves, as well as vasoconstrictor nerves

Hay Parasympathetic, Sympathetic and Sensory (nociceptive C fibres) vasodilator nerves

Question 2

Describe parasympathetic vasodilator nerves

Answer 2

Parasympathetic nerves release Ach/VIP. These act on endothelium to release NO. This causes vasodilatation. Examples inc:
Male genitalia: Release of NO by parasympathetic nerves causes production of cGMP which leads to vasodilatation
Salivary glands – release Ach / VIP
Pancreas & intestinal mucosa – release VIP

Question 3

Describe sympathetic vasodilator nerves

Answer 3

Some symp nerves produce vasodilatation e.g. Skin (sudomotor fibres) – release Ach, VIP. Vasodilatation needed in e.g. hot weather, exercise

Vasodilatation of head, face, upper chest areas occurs w sympathetic-mediated stress response, e.g. blushing

Question 4

Describe sensory (nociceptive C fibres) vasodilator fibres

Answer 4

Trauma or infection stimulates sensory C-fibre nerves
The nociceptive fibres release Sub P, CGRP
These act on Mast cells to release histamine, which in turn acts on endothelium and vsm
Both produce vasodilatation called ‘’Flare’’ in skin
Flare is part of the Lewis triple response: 1) Local redness 2) Wheal/swelling 3) Flare

Question 5

How does NO relax the endothelium?

Answer 5

Blood flow, inflammation, vasodilator nerves (Sub P, histamine, bradykinin, Ach, VIP) create shear stress on endothelium. This activates eNOS enzyme which produces NO
NO diffuses into the media layer and activates GC, which activates GMP–> cGMP–> PKG. This causes vasodilation

Blood flow causes constant NO release which controlls vascular tone, alongside tonic symp activity

Question 6

How does Prostacyclin relax the endothelium?

Answer 6

Shear stress, Inflammation, Ach etc produces PGI2 via COX enzyme. PGI2 acts on Prostanoid receptor on vsm. This activates the Gs pathway: (AC - cAMP – PKA) to produce vasodilation.

This mostly occurs in the kidney:
Tonic PGI2 production maintains blood flow in renal arterioles
Needed to maintain GFR and kidney function
COX inhibition (NSAIDs), reducing PGI2, is potentially dangerous in kidney failure

Question 7

Why do PKG and PKA produce vasodilatation?

Answer 7

Question 8

Explain how K+ causes endothelium derived hyperpolarisation

Answer 8

Shear stress from blood flow, Inflammatory factors (Sub P, histamine, bradykinin, Ach) activates K+ channels in the endothelium.
Lots of K+ comes out of the cell, increasing local external K+ conc. This switches on K+ channels and increases Na/K-ATPase.
Both lead to hyperpolarisation of VSMCs -> decrease VGCCs and Ca entry–> Vasodilation

Question 9

Describe another type of Endothelium derived hyperpolarisation

Answer 9

Activation of K+ channels causing hyperpolarisation in endothelial cells can spread across Gap junctions between endothelium and VSMCs.

The vsmc also gets hyperpolarised, decreasing vgccs and Ca entry–> vasodilation

Question 10

What happens if you use adrenaline to stimulate b2-adrenoceptors on vascular smooth muscle?

Answer 10

B2 adrenoreceptors in blood vessels/ airways are Gs protein coupled. They activate the AC pathway to form PKA. PKA stimulates 3 things:

• SERCA/ Ca ATPase: increase uptake into SR
• K+ activity: increases­ K channel activity, hyperpolarisation, decreases VGCCs
• Switches off MLCK: fall in Ca2+ sensitivity, causing relaxation

ALL of these factors cause vsm relaxation

Question 11

What is the clinical importance of the endothelium and if it got damaged?

Answer 11

Endothelium dysfunction can be caused by hypertension, diabetes, cigarette smoking, which profoundly affects vascular tone: e.g. reduce NO/PGI2 production, less vasodilation so more vasoconstriction–> CVD

This also explains why systemic infection/inflammation (e.g. Sepsis) is v difficult to treat- it activates SO many different vasodilator pathways

Question 12

In which clinical condition would we need to increase vasodilatation?

Answer 12

Hypertension reduces important tonic vasodilatation (e.g. NO, PGI2), causing poor end organ perfusion
It increases afterload, causing poor CO.
Heart has to work much harder- greater 02 demand
Raised bp= due to an imbalance of vasoconstrictor and vasodilator mechanisms

Raised bp does not mean greater drive and blood flow. It means a greater pa drop across arterioles- higher pa upstream, lower pa/blood flow downstream of excessive constriction

Question 13

Describe and explain Gq receptors blocker vasodilator agents

Answer 13

AT1 antagonists e.g. Losartan: block AT1 receptors to reduce vasoconstriction
ACEi e.g. Enalapril: reduce Ang II levels. Both of these used in hypertension, heart failure
a1 antagonists e.g. Prazosin. These are competitive receptor antagonists for drug-resistance hypertension
ETA receptor antagonist e.g. Bosentan: block ETA receptors which are upregulated in pulmonary artery hypertension

Question 14

Describe Ca blockers and K channel openers as vasodilator agents

Answer 14

CCB e.g. Amlodipine: vascular selective, block influx of Ca2+ to reduce vasoconstriction. Used in hypertension, angina

K Channel Openers e.g. Nicorandil: causes hyperpolarisation, less VGCC activation/Ca influx, so causes vasodilatation. Used in angina

Question 15

Describe Contractile mechanism relaxants

Answer 15

Nitrates e.g. Glyceryl trinitrate (GTN): NO donors, PKG-mediated vasorelaxations. Used in angina, pulmonary oedema

PDE5 inhibitors e.g. Sildenafil: cGMP breakdown, PKG-mediated vasodilatation. Used in erectile dysfunction