0721 - Local control of blood flow - RM Flashcards
What is the role of smooth muscle cells in determining vessel diameter?
This one’s pretty obvious. Contraction is slow compared to skeletal muscle - revolves around Ca-calmodulin activating MLCK, which phosphorylates MLC, allowing cross-bridge cycling and contraction - MLC-P relaxes the muscle. MLCK sensitivity to [Ca] is dependent on Ca-calmodulin (increase) or cAMP/cGMP (decrease activity). To save energy, contraction can be kept latched.
Describe the processes of electro- and pharmacomechanical coupling in smooth muscle
Common pathway - sympathetic varicosities possess varicosities with vesicles containing NA and ATP - there is a very low probability of release for each stimulation, however when released it evokes an excitatory junction potential (ATP = fast one, NA slow one) - together they produce force which generates an AP.
Voltage-dependent mainly in small arteries/arterioles - NA acts on 1 receptors, activating second messengers (Gq, then phospholipase C-ß, PIP2, then IP3 and diacyl-glycerol). IP3 activates receptors, releasing Ca from SR to open CLCa (more Ca coming in). DAG opens TRP-channels, allowing lots of Na and some more Ca in. Together, this partially depolarises the membrane (slow EJP), enough to reach a threshold (~-35mV) to open L-type Ca channels, which activate MLCK and contract. A slow process (0.1-1s), blocked by nifedipine.
Pharmacomechanical - large arteries - have fewer L-type VDCCs and ClCa. Similar process except no EJP, and DAG activates TRP and PKC. PKC inhibits MLC-P, increasing contractility.
What is the myogenic response in blood vessels?
Myogenic (Bayliss) response acts to maintain constant perfusion in the presence of increased arterial pressure. Stretch-activated Ca++ channels increase cytosolic Ca++, leading to constriction and reducing flow.
What is basal vascular tone?
Basal vascular tone relates to the small constitutive Ca++ influx into smooth muscle cells via voltage-gated calcium channels, keeping a minimum (basal) level of contraction.
What is neurogenic tone? How can it be altered?
Neurogenic tone controlled by neural (alpha-1 receptors on vessels, ß1 in heart) vascular innervation (vasoconstrictor fibres), and humoural (adrenaline causing forearm vasodilation due to ß2 receptors). Adrenaline causes vasodilation in most vessels except alpha-1-dominant tissues such as skin and intestines. Vasopressin and Angiotensin II activate Gq leading to constriction, and ANP leads to vasodilation.
What are some substances involved in local metabolic control?
Most cause vasodilation:
Extracellular K activates K(ir) and Na/K-ATPase, hyperpolarising the cell, reducing [Ca], thus relaxing.
Acidosis (H+, lactate) relaxes brain vessels
Histamine and serotonin activate Gq, causing constriction
COX-enzymes - Prostaglandins dilate and thromboxane constricts
Leukotrienes can either dilate or constrict.
How is flow determined by endothelial cell-dependent mechanisms?
ECs secrete many substances, mostly dilate. They are linked to VSMCs via myo-endothelial gap junctions (MEGJs). Shear stress activates eNOS, releasing NO, and there are also receptors that release ACh, bradykinin, and histamine in the presense of increased [Ca]:
NO diffuses to VSMC, increasing cGMP and relaxing, directly and by activating K+.
PGl2 binds to receptors on VSMCs, increasing cAMP, and relaxing.
If the cell is hyperpolarised (hyperpolarisation-activated endothelial factor), it opens KCa, it spreads through MEGJs, closing VDCCs (voltage-dependent calcium channels), and relaxing, spreading relaxation up and downstream via gap junctions.
How does adrenaline cause vasodilation?
Adrenaline activates ß2 receptors, activating Gs, activating adenylyl cyclase, increasing cAMP, which Activates PKA. PKA stimulates Ca extrusion and K+ efflux, which hyperpolarises the cell, closing VDCCs. PKA also inhibits MLCK, reducing sensitivity. Together, these lead to the passive process of vessel relaxation and lower contractility.
