VASCULAR: REGULATION OF VASCULAR SMOOTH MUSCLE Flashcards
Describe frequency dependent contraction
Greater frequency of action potentials we get summation of force
- Happens in the GI tract
Describe slowly depolarizing waves and how that leads to contraction
Produce spiking behavior of action potentials leading to an oscillating waveform
Example: uterine smooth muscle and small arterioles
Describe how tonic depolarization leads to contraction
- Changing membrane potential results in change of force. No action potentials!
- Example: occurs in multi-unit smooth muscle contraction
Describe how pharmacomechanical coupling leads to contraction
- no change in membrane potential (no depolarization) but change in force; most common and diverse stimulation of vascular smooth muscle
- Caused by different agents
- Mediators: drugs, hormones, neurotransmitters, local environmental changes
- Second messengers altering Ca2+: - e.g. IP3, cGMP, cAMP
What are the different ways membranes can be depolarized?
- Pacemaker channels
- Inhibition of Na/K-ATPase leading to slow depolarization
- Changes in K+ channels
- Non-selective cation channels
Describe the 3 mechanisms for contraction in vascular smooth muscle
ATP signaling pathway
- ATP from synaptic vesicle binds to P2x receptor on smooth muscle cell
- P2x receptors are non-selective cation channels that allow sodium and calcium ions to enter and depolarize the smooth muscle cell
- Calcium channels open in response to increase in Ca2+ in smooth muscle cell
- Produces rapid contraction of the smooth muscle
Norepinephrine signaling pathway
- Norepinephrine from synaptic vesicle binds to adrenergic receptor, G protein activates PLC converting PIP2 to IP3, IP3 acts on IP3 receptors which release calcium from stores
- Produces a slightly slower response than ATP signalling pathway but is important for prolonged stimulation
Neuropeptide pathway
- Neuropeptides are released from synaptic vesicles and bind to Y1 receptors which causes increase in calcium
- Slowest response
Describe how EDRF works!
EDRF: endothelium derived relaxing factor; AKA nitric oxide (NO)
- Produced in the endothelium by eNOS (endothelial nitric oxide synthase)
- Converts L-arginine
- High levels of calcium lead to nitric oxide production
- Blood flow can also raise levels of calcium leading to nitric oxide production
- Nitric oxide diffuses freely into vascular smooth muscle and activates guanylyl cyclase
- Guanlyl cyclase converts GTP to cGMP
- cGMP activates PKG and - PKG phosphorylates phospholamban which causes it to move away from SERCA leading to an increase in Ca2+ uptake from the cytoplasm into the SR. This results in faster relaxation and thus vasodilation
- PKG also phosphorylates MLCK which inhibits it and reduces the force of contraction
Define: nitroprusside or glycerol trinitrate (GTN)
direct nitric oxide donor which causes vasodilation. Important for restoring blood flow in the coronary arteries
Define: sildenafil
Sildenafil: drug name for viagra. Inhibits PDE5 activity leading to lots more PKG and way more relaxation.
Define: phosphodiesterase E5 (PDE5)
Phosphodiesterase E5 (PDE5): enzyme that breaks down cGMP into GMP
How does endothelin (ET) work?
released from the endothelium and acts on endothelium A receptors in the vascular smooth muscle cells. Gq acts on PLC which converts PIP to IP3. IP3 acts on IP3 receptor leading to increased release of Ca2+ from SR. This leads to vasoconstriction
- Hypoxia promotes the release of endothelin
- Occurs in high pressure vessels
Describe ETB receptors
In low pressure vessels: ETB receptors on endothelial cells stimulate eNOS leading to vasodilation
Describe EDHF - endothelium derived hyperpolarizing factor
Acts on potassium channels leading to more potassium efflux leading to hyperpolarization of the VSM cells. Calcium channels are less likely to open and Ca2+ is less likely to flow inwards
Explain how mast cells regulate VSM contraction
produce histamine, histamine binds H1 receptors on endothelium and activates NOS → vasodilation
Explain how the kidney regulates VSM contraction
- Produces renin
- Renin: converts angiotensinogen to angiotensin I
- Angiotensin I is converted to angiotensin II by ACE
- Angiotensin II binds AT1 receptors, which activates the Gq, PLC, IP3, Ca2+ release pathway leading to very potent vasoconstriction and cardiac hypertrophy
Explain how the pituitary and hypothalamus regulates VSM
Produces antidiuretic hormone (ADH) AKA vasopressin which prevents water loss at the kidney and causes vasoconstriction
Explain how surrounding tissue regulates VSM
- Produces metabolites
- adenosine, increased K+, increased CO2, decreased O2, decreased pH
- Generally causes vasodilation
MAP (mean arterial pressure) is homeostatically regulated by the ___________
baroreceptors
State the location and function of: B1 (Gs)
Location: cardiac
Functions
- Increase heart rate
- Increase contractility
State the function of: B2 (Gs) at the bronchioles
Function: bronchodilation
State the function of: B2 (Gs) at the large skeletal muscle vasculature and coronary arteries
- Vasodilation (adrenaline has a much greater affect than noradrenaline)
- Increase blood supply during exercise
- Distinct from metabolic vasodilation
- Little effect on blood pressure regulation
State the location and function of: a1 (PLC)
- Location: vascular smooth muscle
Function - Profound vasoconstriction
- Increase blood pressure
State the location and function of: a2 (Gi)
- Location: vascular smooth muscle/sympathetic nerve endings
Function - Modify response to a1 stimulation
- Autoregulate (reduce) noradrenaline release from sympathetic nerves
