Vascular contribution to muscular health

Question 1

Why is blood flow important?

Answer 1

o The circulatory system (that blood flow is part of) is an organ system driven by the heart, to provide a constant supply of blood to the body through the blood vessels (3 different circuits)
o Circulation of blood plays a very important role in whole body health as it transports red & white blood cells, hormones, oxygen and nutrients
o At the micro-circulatory (capillary) level, blood flow is responsible for the movement of nutrients into the cells of the body
o It is also responsible for the removal of cellular by-products (e.g. carbon dioxide and metabolic acids (i.e. lactate))
o Inadequate tissue perfusion has numerous detrimental effects dependent upon the tissue in question (e.g. syncope, organ failure)

Question 2

What is Poiseuille’s Law?

Answer 2

o Poiseuille’s law tells us that resistance is inversely proportional to the (fourth power of the) radius
o A 19% increase in radius will double the flow rate (vasodilation)
o A 16% reduction in radius will halve the flow rate (vasoconstriction)

Question 3

What is the role of adrenaline?

Answer 3

o Released from the adrenal medulla in response to lowered BP
o Two mechanisms of action:
 Speeds heart rate and force of ventricular contraction.
 Dilates the skeletal muscle vascular beds and constricts the splanchnic (mesenteric) vascular beds.
o Therefore, increases cardiac output and systolic BP but often has little effect on mean arterial BP

Question 4

What is ADH?

Answer 4

o Also known as vasopressin
o Released from the posterior part of the pituitary (near optic cytoplasm) in response to lowered BP and increased plasma osmolality to maintain blood volume
o Release is slowed by Alcohol (part of the reason for a hangover)
o Two mechanisms of action:
 Promotes reabsorption of water in the kidney
 Constricts blood vessels if present at a high enough concentration
o Thus, ADH increases SV and TPR, keeping BP up

Question 5

What is ANP?

Answer 5

o Released from the atria in response to stretch by increased blood volume
o Three mechanisms of action:
 Promotes sodium (and thus water) excretion in the kidney
 Can inhibit ADH and aldosterone secretion
 Acts as a vasodilator
o Thus, ANP lowers SV and TPR, keeping BP down

Question 6

How does blood flow to tissues?

Answer 6

o ‘Basal’ flow varies by tissue (e.g. high in kidneys, low in skeletal muscle)
o When cells become more active this increases circulation to the region, at the expense of other tissues.
o Examples are exercise and splanchnic or peripheral ‘nutritive flow’ in postprandial periods
o Goal to ensure blood flow changes occur at an appropriate time and in the right area
o The regulation of local flow is mediated by:
 Neural factors (sympathetic nervous system)
 Endocrine factors (hormones)
 Local factors (bi-products signalling metabolic demand)

Question 7

How does changing the resistance of arterioles change things?

Answer 7

o Varying resistance of the arterioles is primarily used to control:
 flow to a particular organ (or organs)
 whole-body perfusion pressure
o Flow = change in pressure/resistance
 Pressure = 10 mmHg; Resistance = 2 mmHg/ml/min; FLOW = 5 ml/min
 Pressure = 5 mmHg; Resistance = 8 mmHg/ml/min; FLOW = 0.63 ml/min

Question 8

What impacts blood flow the most?

Answer 8

o Viscosity and length don’t change much usually so for simplicity we will ignore those parameters in the following examples
o RADIUS IMPACTS BLOOD FLOW THE MOST

Question 9

How does sympathetic input affect blood flow?

Answer 9

o Local conditions and input from the nervous system help to regulate local blood flow
o Neural input comes via the sympathetic nervous system (controls the tone of vascular smooth muscle), which releases noradrenaline to cause vasoconstriction via α1 adrenoreceptors on vascular smooth muscle
o These effects are strongest in the skin, kidney, skeletal muscle and digestive tract vessels

Question 10

What functions do autoregulation/metabolic vasodilation have?

Answer 10

o Flow regulation is most important in organs that require constant perfusion or where local metabolic conditions may change rapidly and markedly
o Local mechanisms have two primary functions:
 They adjust local resistance in response over a large range of arterial pressures (50-170 mmHg) to provide constant local flow - This is autoregulation e.g kidney
 They cause upregulation of flow when local metabolic demands increase. This is achieved by dilating muscular vessels and therefore decreases resistance - This is metabolic vasodilation e.g skeletal muscle

Question 11

How does autoregulation work?

Answer 11

o Flow regulation is achieved by dilating an artery (to reduce pressure) or constricting it (to increase pressure)
o Stretch receptors (mechanically gated ion channels) mediate part of this response and lead to constriction as they open and allow influx of Na+ and Ca2+
o Vasodilating metabolites (adenosine, K+ ions) act on smooth muscle cells to cause relaxation

Question 12

What is nitric oxide?

Answer 12

o Nitric oxide (NO) is a potent vasodilator produced by the vascular endothelium
o NO is synthesised from L-arginine and oxygen by the nitric oxide synthase (NOS) enzyme in response to increased intracellular Ca2+
o There are two forms of NOS; eNOS (endothelial) and iNOS (inducible)
o NO quickly diffuses out of the endothelium and into vascular smooth muscle where it increases cyclic GMP levels, leading to relaxation
o A number of drugs act on the NO signalling pathway including sildenafil citrate (viagra) which enhances NO signalling
o Nitric oxide itself is useful in angina (nitro-glycerine)

Question 13

How does blood flow occur in skeletal muscle?

Answer 13

• INSULIN
• NO DEPENDENT VASODILATION
• INCREASED FLOW IN LARGE & SMALL VESSELS
• INCREASED ACCESS FOR INSULIN & NUTRIENTS TO INTERSTITIUM & MUSCLE CELLS (even in the absence of increased bulk flow – nonnutritive to nutritive switch)
• IMPROVED MPS DUE TO INCREASED AA DELIVERY???

Question 14

What is the relationship between muscle/health and locomotion?

Answer 14

“Lack of activity destroys the good condition of every human being, while movement and methodical physical exercise save and preserve it” ---Plato ~400 B.C
	Locomotion 
	Metabolism 
	Endocrinology 
	Homeostasis 
	Fuel Store 
	40% body mass 
	Energy Transfer 
	“Myokines” 
	Thermoregulation 
	Substrate 
	Efflux

Question 15

What is the relationship between muscle mass and health/age/disease?

Answer 15

Skeletal muscle has essential locomotory and metabolic functions, a decrease of:
 1-2% Muscle mass/year
 Muscle Function
 Metabolic Function
 Quality of life
 Exacerbated by a multitude of ageing-associated diseases***

Question 16

What is the relationship between medicine and life expectancy?

Answer 16

Medicine has extended our life expectancy

Question 17

How do life expectancy and ‘health span’ differ?

Answer 17

o Life expectancy continues to rise

o Parameters of healthspan have stagnated for at least a decade

Question 18

How is low muscle mass associated with mortality?

Answer 18

Low muscle mass is associated with mortality (the more severe the sarcopenia, the faster survival rate drops)

Question 19

What is the relationship between muscle quantity/quality with advancing age?

Answer 19

Dynapenia at a greater rate than sarcopenia primarily due to reduced central activation

Question 20

How does nutrition regulate MPS?

Answer 20

The EAA Leucine has a unique signalling capacity in terms of modulating mTORc1-signalling- via leucyl-tRNA pathways

Question 21

How does resistance exercise training restore leg blood flow?

Answer 21

RESISTANCE EXERCISE TRAINING DID RESTORE LEG BLOOD FLOW BUT ONLY AT THE LEVEL OF THE LARGE ARTERIES…

Question 22

Blood flow and muscle metabolism: a focus on insulin action (Clark et al., 2003)

Answer 22

New methods have shown that a major hemodynamic effect of insulin is to increase nutritive capillary blood flow in muscle. Current evidence suggests that this effect is independent of an increase in bulk flow to muscle that often accompanies insulin’s action. Insulin-mediated capillary recruitment may have similar beneficial effects to those of exercise relating to hormone and substrate delivery to the muscle cells. Interventions that impair capillary recruitment give rise to insulin resistance with decreased insulin-mediated glucose uptake in muscle. Conversely, exercise training enhances both insulin-mediated capillary recruitment and muscle glucose uptake.

Question 23

Regulation of Blood Flow in the Microcirculation. Microcirculation (Segal, 2005)

Answer 23

The regulation of blood flow has rich history of investigation and is exemplified in exercising skeletal muscle by a concerted interaction between striated muscle fibers and their microvascular supply. This review considers blood flow control in light of the regulation of capillary perfusion by and among terminal arterioles, the distribution of blood flow in arteriolar networks according to metabolic and hemodynamic feedback from active muscle fibers, and the balance between peak muscle blood flow and arterial blood pressure by sympathetic nerve activity. As metabolic demand increases, the locus of regulating oxygen delivery to muscle fibers “ascends” from terminal arterioles, through intermediate distributing arterioles, and into the proximal arterioles and feed arteries, which govern total flow into a muscle. At multiple levels, venules are positioned to provide feedback to nearby arterioles regarding the metabolic state of the tissue through the convection and production of vasodilator stimuli. Electrical signals initiated on smooth muscle and endothelial cells can travel rapidly for millimeters through cell‐to‐cell conduction via gap junction channels, rapidly coordinating vasodilator responses that govern the distribution and magnitude of blood flow to active muscle fibers. Sympathetic constriction of proximal arterioles and feed arteries can restrict functional hyperemia while dilation prevails in distal arterioles to promote oxygen extraction. With vasomotor tone reflecting myogenic contraction of smooth muscle cells modulated by flow‐induced vasodilator production by endothelium, the initiation of functional vasodilation and its modulation by shear stress and sympathetic innervation dictate how and where blood flow is distributed in microvascular networks. A remarkable ensemble of signaling pathways underlie the integration of smooth muscle and endothelial cell function in microvascular networks. These pathways are being defined with new insight as novel approaches are applied to understanding the cellular and molecular mechanisms of blood flow control.