much oxygen it needs? How is muscle blood flow regulated? What do - - PowerPoint PPT Presentation

VASODILATOR MECHANISMS IN

SKELETAL MUSCLE

Ylva Hellsten, Department of Nutrition, Exercise and Sports, University of Copenhagen

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

SKELETAL MUSCLE BLOOD FLOW CHARACTERISTICS

• WIDE RANGE OF FLOWS
• PRECISE MATCHING OF FLOW TO OXYGEN DEMAND
• RAPID RISE WITH ONSET OF EXERCISE

Saltin et al. 1998 Leg blood flow

0.2-0.4 l/min 7-10 l/min

Rådegran & Saltin 1998

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

WITHOUT A FALL IN BLOOD PRESSURE

Tight coupling between flow and muscle metabolism- but how does the muscle know how much oxygen it needs? How is muscle blood flow regulated? What do we know about mechanisms?

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Overall regulation of skeletal muscle blood flow

• Sympathetic activity

Vasoconstrictors

+

Vasodilators Functional Sympatholysis

What happens with sympathetic activity during exercise?

Smooth muscle cells integrate the constrictive and dilatory signals

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

To achieve an increase in flow during exercise, vasodilators must be formed locally in the active muscle to an extent that well overcomes the vasoconstrictive effect of the increased sympathetic activity

KEY POINT

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Endothelial cells Erythrocytes Smooth muscle cells Skeletal muscle cells

Cellular sources of vasodilators in skeletal muscle

ARTERIOLE CAPILLARY

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Endothelial cells Erythrocytes Skeletal muscle cells

Which vasodilators are formed in the muscle?

ARTERIOLE CAPILLARY

ATP Nitric oxide Prostacyclin Adenosine ATP Nitric oxide ATP Nitric oxide

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Nitric oxide and prostacyclin are central vasodilators in skeletal muscle

KEY POINT

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Shear stress Oxygen desaturation

• f the

hemoglobin molecule Skeletal muscle contraction Conducted/ retrograde vasodilation

Coupling to oxygen need

Mechanisms which lead to the formation of vasodilators

Endothelial cells Smooth muscle cells Erythrocyte

Endothelial independent Endothelial dependent

ENDOTHELIAL DEPENDENT AND INDEPENDENT VASODILATION

MECHANOTRANSDUCTION- SHEAR STRESS

MECHANICALLY MEDIATED

Vasodilation

Glycocalyx

VEGFR2

SHEAR STRESS

PECAM-1

ERK 1/2 MAPK PKA NO

Prostaglandins

Endothelial cell

Mechanisms of vasodilation

O2

ERYTHROCYTE MEDIATED VASODILATION

P2Y

ATP

Endothelial cell

NO PGs Sympatholysis

NO Vasodilation

O2

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Mechanisms of vasodilation

Conducted or retrograde vasodilation: How vasodilation can be conveyed from the site of capillaries and arterioles upstream

Bagher & Segal Acta Physiol. 2011

Fast electromechanical signalling and slow calcium waves convey vasodilation upstream ATP

?

Mechanisms of vasodilation

eNOS →Nitric oxide COX → Prostacyclin

Physiological role of vasodilators: Change in exercise flow in response to arterial infusion of inhibitors of vasodilator systems

Endothelial cell Reduced exercise hyperemia?

INFUSION OF INHIBITOR

Femoral artery

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

L-NMMA Indomethacin

PHARMACOLOGICAL INHIBITION OF NO AND PG FORMATION: EFFECT ON EXERCISE INDUCED VASODILATION

5 10 15 20 25 30 Rest 60 90 240

Vascular conductance (ml/min/ mmHg)

Time (s)

Control NOS+ COX Blockade

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

PHARMACOLOGICAL INHIBITION OF EITHER NO OR PG FORMATION: EFFECT ON EXERCISE INDUCED VASODILATION

Time (s)

Control NOS Block COX Block

5 10 15 20 25 30 Rest 60 90 240

Vascular conductance (ml/min/ mmHg)

VASODILATOR REDUNDANCY: One vasodilator system compensates

for the reduced function of another

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Interaction between vasodilator systems is an important feauture in muscle blood flow control

KEY POINT

NO Prostaglandins EDHF

Vascular function-vasodilator capacity: Vasodilation in response to arterial infusion of vasodilators

ATP Ado Ach

R Endothelial cell Vasodilation

INFUSION OF COMPOUND

Femoral artery

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Nitric oxide Epoprostenol (PGI2)

Type II diabetics have reduced vasodilator respons to infusion

• f ATP and adenosine

Thaning et al. 2010 ; 2011 1 2 3 4 Baseline ATP Adenosine Control T2D

Leg blood flow (L/Min) in relation to infused conc

* *

Baseline ATP Adenosine

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

ATP and adeno nosin sine

COPENHAGEN WOMEN STUDY Pre and post menopausal women The effect of 3 months of intense cycle training on the responsiveness to prostacyclin

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS

Pre Menopause Post Menopause Age 49+/_ 1 yrs 53+/_ 1 yrs BMI 23+/_ 0.5 23+/_ 0.6

Pre training comparison Change with training

Prosta stacycli lin

Several vasodilator mechanisms allow for rapid and precise adjustment according to oxygen demand and for coordination of flow Several vasodilators interact and allow for optimal regulation and compensatory mechanisms (Redundancy) Nitric oxide and prostaglandins are two central vasodilators Oxygen is highly likely to be key in the precise control of blood flow in relation to metabolic demand

UNIVERSITY OF COPENHAGEN DEPARTMENT OF NUTRITION, EXERCISE AND SPORTS