Blood Pressure Control Flashcards
What is the BP equation?
What effects Stroke volume?
BP = CO * TPR
CO = HR*SV
SV = volume of blood expelled by left heart to systemic arteries…
= determined by venous return…. venodilatation decreases SV….
How do blood vessels act as functional syncytium?
Intecellular gap junctions couple cells within each layer.
Myoendothelial gap junctions couple smooth muscle and endothelial cells.
Release of local mediators (NO/Prostaglandins) + neuromediators by sympathetic NS..
What agonists and receptors trigger SM contraction?
Noradrenaline acts on A1/A2 adrenoceptors.
= A1 is Gq/11 coupled.
= A2 is Gi/Go coupled…
Ang II acts on AT1 receptors.
ADH acts on V1 receptors.
Thromboxane A2 acts on TP.
ATP acts on P2Y…
Except a2-adrenoceptors, these receptors are all Gq/11 coupled…. causing PLC activity = IP3 + DAG = release of Ca2+ from SR via IP3 receptors.
What L-VACC’s are present in vascular SM?
Cav1.2b = L-VACC’s are activated by depolarisation as opposed to agonist-induced contraction.
BUT
CCBs block opening…
How does Ca2+ lead to SM contraction.
Intracellular Ca2+ interacts with calmodulin.
Ca2+/Calmodulin is active kinase which phosphorylates Myosin Light Chain Kinase (MLCK)….
Phosphorylated MLCK can interact with troponin C and induce myofilament contraction.
How can calcium sensitisation lead to enhanced contraction?
MLCP = Myosin Light Chain Phosphatase removes activating phosphate group from Myosin Light Chain…. inducing relaxation.
Agonists of Gq/11 receptors = NA(a1), ATP(P2Y), Thromboxane A2 (TP), ADH (V1), Ang II (AT1) can couple with phosphorylation of CPI-17 = an endogenous inhibitor of MLCP.
Also, Gq/11 can couple with RhoA and activate ROCK - which can also inhibit MLCP…
What agonists can mediate SM relaxation?
Adrenaline/NA acts on B2 adrenoceptors.
Prostaglandin I2 acts on IP receptors.
Adenosine = A2 receptors.
Histamine = H2 receptors.
= Gs coupled receptors….
ANP/BNP can act on NPR-A and CNP can act on NPR-B…
= Gc coupled = activate protein Kinase G.
Potassium channel activators - like Minoxidil, Diazoxide…
= hyperpolarisation = inhibits L-VACCs…
How do these agonists mediate SM relaxation?
Adrenaline/NA on B2 adrenoceptors - maybe in the coronary arteries, near the skin, muscles during exercise…
Prostaglandin (IP), Adenosine (A2), Histamine (H2) are all Gs coupled receptors.
= Activate AC = Increase cAMP….
cAMP activates PKA = PKA inhibits Myosin Light Chain Kinase = reduced phosphorylation of Myosin Light Chain = Inhibit SM contraction….
ANP/BNP/CNP (NPR-A and NPR-B) are all Gc coupled = activated Guanylate Cyclase.
= Increasing cGMP.
= cGMP activates Protein Kinase G = which activates Myosin Light Chain Phosphatase…. = which inhibits Myosin Light Chain….
How does Ca2+ removal from vascular SM compared to cardiomyoctes?
SERCA2a is main mechanism in vascular SM, like with cardiomyocytes.
BUT in healthy blood vessels, NCX plays a little role in Ca2+ extrusion compared to cardiomyocytes…
Phospholambin also plays no role in controlling SERCA2A. (Which gets phosphorylated + activated to speed up Ca2+ removal in cardiomyocytes..)
Overview of SM relaxation in blood vessels?
Agonist induced activation of Gs-coupled receptors activates PKA = phosphorylation of MLCK…
Activation of MLCP via CNP/BNP/ANP activation of Gc coupled NPR-A and NPR-B receptors which activates GC and Protein Kinase G…
Aswell as endothelial derived endogenous vasodilators like NO and Prostaglandin I2….
How is NO produced in endothelial cells?
eNOS is constitutively active.
BUT enhanced activity by increase Ca2+ (Ca2+/Calmodulin) as well as phosphorylation (from Gq/11 coupled agonists).
eNOS synthesises NO from L-Arginine and O2.
NO diffuses into SM cells.
What is the effect of NO on SM cells?
NO activates soluble Guanylate Cyclase (GC).
soluble GC converts GTP to cGMP.
cGMP activates MLCP and also activates Protein Kinase G, which also activates MLCP.
= Less phosphorylation of Myosin Light Chain = less contraction.
How are the effects of NO inhibited?
PDE5 degrades cGMP into 5’GMP….
= so cGMP can no longer activate PKG or MLCP…
What is the endogenous NOS inhibitor?
ADMA = competitive NOS inhibitor naturally in the body.
Plasma ADMA levels are raises in endothelial disorders like atherosclerosis, Familial Hypercholesterolemia, hypertension…
= ADMA is a risk factor for CV diseases.
What is Sildenafil?
How do NO donors work?
PDE5 selective inhibitor = Viagra.
Prevents the degradation of cGMP by PDE5…
= cGMP can act as vasodilator for SM relaxation.
Glyceryl trinitrate (GTN) and SNP are NO donors …. increase NO for vasodilation.
= used for Angina but can build tolerance = used short-term relief.
