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
