0721- Local control of blood flow- CG Flashcards
Define basal vascular tone
background vasoconstriction- at basal conditions, all vessels have background smooth muscle contraction that determines its diameter
Varies between organs- ie high vasodilatory capacity (myocardium) have high tone
smooth muscle cells (as well as endothelium) have a central role in determining vessel diameter
describe the processes of electro- and pharmacomechanical coupling in vascular smooth muscle cells (VSMC)
VSMC contraction slower compared to skeletal muscle,
Multiple synpases
Excitation- SYMPATHETIC ONLY- SNS fibres innervate arterioles. Terminal axons form ‘pearl strings’ containing varicosities with vesicles (instead of skeletal muscles’ single synapse). QUANTAL RELEASE OF NA+ATP WITH LOW RELEASE PROB BUT LARGE CAPACITY (exercise). Evokes fast and slow EJPs. ‘effector’ VSMC has 2 receptor types: a1 (NA) and P2X (ATP). ATP for fast EJPs, NA has slow EJP AND can evoke depolarisation independent contraction- ca2+ sensitisation).
In the cell, Gq initiated
Contraction- EJPs summate to produce calcium-based APs. (Ca2+ influx thru VGCC- calmodulin, MLC-K pathway)
Relaxation- via Myosin Light Chain Phosphorylase
Describe vascular smooth muscle cell (VSMC) structure
Important components- contractile proteins cross hatching, anchored by dense bodies Connected via gap junctions, and have calveolae instead of t-tubules
What is the mechanism of voltage dependent VSMC contraction in the cell
a1
- Calcium influx from extracellular fluid and sarcoplasmic reticulum [Ca] binds to calmodulin
- = ca-modulin complex, which activates MLC-K (myosin light chain kinase), which adds phosphate onto myosin head to activate cross bridge cycling
Opposite action by MLC-P (phosphatase), MLC proteins control sensitivity to calcium cAMP and cGMP inhibits contraction Adrenaline causes Ca sensitisation, (increased contraction force for a given [Ca]). KCl desensitizes.
How are action potentials generated from EJPs
Calcium influx APs (via L type voltage gated channels) can occur with enough summation (RMP -40- -60mV, more depolarized than neurons) A2 and b2 can be also activated if very strong stimulation Resting state= muscle cell in in half contracted state (?) Smaller amplitude compared to neuronal APs
What are the differences between voltage dependent and independent depolarisation (APs). Compare
Voltage dependent- small arteries/arterioles, NA activate a1 receptor (Gq –> IP3 + DAG, which produce slow EJPs- via TRPC, Cl channels, increasing downstream Ca –> activate L type Ca = calcium AP) Membrane depolarisation (through summation) activate L type VDCC (DAG- Na influx helps open Ca channels (voltage gated), calmodulin, MLC-K, etc)
Voltage independent- large arteries (less L type VDCC and Cl channels). No slow EJP since no Clca channels. Similar to voltage dependent, except DAG also activates PKC –> Ca sensitisation = increased contractility
Both has IP3- sensitive Ca2+ release from SR
What is neurogenic tone and how can it be altered? Describe the hierarchy of vascular control
Vascular tone regulated by three tier hierarchy •Bottom tier (intrinsic) : autoregulation by myogenic response (resistance vessels). •Middle tier (intrinsic): mostly relaxation. autoregulation can be modulated by locally produced vasoactive agents. – Metabolic vasodilators: adenosine (ATP breakdown), K, CO2 (hypoxia), lactate, H+ (acidosis) , hyperosmolarity, H2O2 – Endothelial secretions: NO, EDHF, prostacyclin, endothelin. – Autacoids: histamine, bradykinin, PAF, leukotrienes. – Vasospasm: serotonin, thromboxane. • Top tier (extrinsic) regulation by nerves and circulating hormones (adrenaline, angiotensin II, vasopressin).
Outline the differential control of arteries/arterioles
Conduit artery Proximal feed arteries- flow induced dilation ( middle) Proximal resistance vessels- top = sympathetic) Arteriole resistance vessels- myogenic response, bottom Terminal arterioles- metabolic vasodilation, middle
What is the myogenic response and its function
Purpose is to maintain of constant perfusion, autoregulation of perfusion in specific vascular bed (organ specific constant perfusion) If vessel is dilated, stretch activated channels = TRPM/C channels open, causing Ca influx, causing contraction (flow constricted)
In more detail:
pressure → PLC, DAG –> stretch-activated TRPM/C channels → smooth muscle depolarization and opening of L-type Ca++ channels that increase cytosolic [Ca++]i and muscle tone (vasoconstriction)
List some at least 5 substances involved in metabolic control
- metabolic vasodilator: adenosine, K, lactate
- endothelial secretions: NO, prostacyclin
- Autacoids: histamine, bradykinin, leukotrienes
- Vasospasm: serotonin, thromboxane Vasoactive metabolites: most cause relaxation
–Accumulation of K+ in extracellular space: activates Kir and Na/K-ATPase →hyperpolarisation →[Ca2+]↓→relaxation.
– Acidosis(H+, lactate): relaxation in brain vessels.
–Hypoxia: vasodilation via KATP and Kir in resistance vessels, but constricts pulmonary vessels and large systemic arteries (Ca- sensitivity ↓).
–ATP breakdown of in extracellular space: adenosine via A2A receptors (Gs) →relaxation. –HPO42- and osmolarity ↑: released into muscle ISF →relaxation. –H2O2 ↑ from mitochondrial ATP production → relaxation. • Local hormones (autacoids): – Histamine (H1), serotonin (5-HT 2A) via Gq activation on VSMCs: constriction.
– Prostaglandins (dilation) and thromboxane (constriction) produced by COX.
– Leukotrienes: can cause dilation or constriction .
Explain the components of extrinsic vessel control (top tier)
Sympathetic control - Neural: vasomotor nerves- Neural: vascular innervation (α1 receptors on vessels; β1 in heart) • Mostly via vasoconstrictor fibres.
- Humoral vasoactive hormones- adrenaline, angiotension 2, vasopressin
Parasympathetic only on specialised vascular beds, ie saliva
What are the actions of adrenaline, in the body What about vasopressin, angiontensin 2, ANP
Stress hormone, stimulated by exercise, hypotension In heart: activate B1 = increase contractility, HR, SV Vessels- dilation (B2) of myocardium, skeletal muscle Constriction in vessels with predominant a1 expression- skin, intestines Vasopressin, ang 2 = Gq vasoconstriction ANP= vasodilation
What mechanism does adrenaline relax vessels?
B2 (Gs activation)- adenylate cyclase increase cAMP, activate PKA Which stimulates Ca extrusion, hyperpolarisation, reduce Ca sensitivity by inhibiting MLC-K = vessel relaxation Unlike B1, no funny channels so no Ca APs. pka does different things, ie sequests Ca in the sarcoplasmic reticulum instead of release
How is flow determined by endothelial cell dependent mechanisms
•Endothelial shear-stress causes relaxation via VSMC hyperpolarisation which spreads upstream to increase flow. (essentially myogenic response)
Stricker summary
Take-Home Messages •Central to VSMC contraction is [Ca2+]↑ and MLC-K activity↑. •Sensitivity to [Ca2+]modulated by 2nd messenger systems. •NA / ATP are secreted at varicosities in quanta causing EJP. •Contraction arises from voltage-dependent and –independent mechanisms. •VSMC typically contain α1, α2 andβ2 receptors; response dependent on receptor density & neural or humoral activation. •Vascular control is established via a 3-tiered system •Vascular control varies for different vascular beds. •Myogenic contraction allows for autoregulation of perfusion. •Endothelial shear-stress causes relaxation via VSMC hyperpolarisation which spreads upstream to increase flow. • Metabolic products mostly cause vasodilation.
