Explore Intermediate Pharmacology at UCL with a focus on the Cardiovascular Pharmacology chapter. Navigate the intricacies of anticoagulants, fibrinolytics, lipid-lowering drugs, and more. Please note that these materials are intended for personal use only and should be used in accordance with acad...
Cardiovascular Pharmacology – Summary
Smooth Muscle Pharmacology
Smooth Muscle Contraction
Smooth muscle
o Contains two major proteins – actin + myosin – arranged randomly
o No troponin – found in skeletal and cardiac muscle – actin and myosin are highly organised
Stimulation of smooth muscle
o Autonomic / enteric nervous system + hormones + autocoids + pacemaker cells + stretch
Smooth muscle types
o Single unit
Only some cells are innervated
Depolarisation leading to contraction spreads through gap junctions
May contain pacemaker cells – have spontaneous depolarisation – spreads throughout cell
o Multi-unit
Each cell is individually innervated + little communication between cells
2+
Ca dependent smooth muscle contraction
o Ca2+ is released from intracellular stores in the
sarcoplasmic reticulum phasic rise in Ca2+
influx of extracellular Ca2+ through Ca2+ channels
on the cell membrane sustained rise
o Ca2+ binds to Ca2+ binding protein = calmodulin
(CaM) producing Ca-CaM complex
o Calcium-calmodulin complex binds to and
activates myosin light chain kinase myosin
light chain kinase phosphorylated myosin light
chains producing myosin head ATPase
activity allowing actin-myosin crossbridge
formation to occur contraction
o Myosin light chains are dephosphorylated by myosin light chain phosphatase inhibiting
contraction
Voltage-gated Ca2+ channels
o In smooth muscle -Ca2+ influx through L-type voltage gated Ca 2+ channels
o Mechanisms to open voltage-gated Ca2+ channels
Gq-GPCRs
Produce contraction by stimulating depolarisation + opening L-type voltage gated
Ca2+ channels
P2x purinoceptors
Ligand gated non-selective cation channels stimulated by ATP
Allows influx of Ca2+ + Na+ producing depolarisation opening L-type Ca2+
channels
Non-selective cation channels
Stimulated by stretch
Allows influx of Ca2+ + Na2+ producing depolarisation
o In single unit smooth muscle
Cells are depolarised by a wave of depolarisation depolarises other cells through Ca2+
influx through voltage-gated Ca2+ channels
Gq-GCPRs – which mediate smooth muscle contraction
o Agonist | receptor
Noradrenaline / adrenaline | α1-AR
Acetylcholine | M3
Histamine | H1
,Cardiovascular Pharmacology – Summary
5HT | 5-HT2
Prostaglandins | DP, EP, FP
Angiotensin II | AT1
Vasopressin | V1
Endothelin | ET1
Substance P / neurokinin A | NK1NK2
o Stimulation of Gq-GPCRs stimulation of phospholipase-C (PLC) acts on PIP2 release IP3 into
cytosol + DAG in the membrane
IP3 – stimulates IP3 receptors on intracellular Ca2+ stores to release Ca2+ contraction
DAG – activates PKC phosphorylates + inhibits different K+ channels in smooth muscle
causes smooth muscle to depolarise Ca2+ influx through voltage-gated Ca2+ channels
contraction
o In some smooth muscle – depletion of intracellular Ca 2+ stores by IP3 causes signal to store-
operated non-selective cation channels (NSCC) in membrane stimulating opening allows influx
of Ca2+ + Na+ opening voltage-gated Ca2+ channels contraction
o Ca2+-activated chloride channel
Ca2+ can stimulate opening of Ca2+ activated Cl- channels efflux of Cl- in smooth muscle
due to high intracellular Cl- concentration depolarisation opening voltage-gated Ca2+
channels
Calcium sensitisation
o Mechanism in smooth muscle – results in greater contraction produced by a rise in intracellular Ca 2+
Contractile state of smooth muscle – depends on activity of myosin light chain kinase +
myosin light chain phosphatase
o Activity of myosin light hain phosphatase is reduced myosin light chain kinase activity
predominates greater contraction
o Can be stimulated by Rho kinase
Gq-GPCRs couple to G12./13 alpha subunit of G-proteins activation of Rho-GEF exchanges
GDP or GTP bound to GTPase Rho-A activates Rho-A stimulates Rho-K
phosphorylates and inhibits myosin light chain phosphatase
o Can be stimulated by PKC
PKC is activated by Gq-GPCR pathway phosphorylates protein CPI-17 binds to and
inhibits myosin light chain phosphatase
Gi-GPCRs and smooth muscle contraction
o α2-AR with α1-AR in arterioles
Directly stimulate contraction on vascular smooth muscle
o M2 receptors with M3 in G.I. tract and bladder
Have a potentiating effect on M3 mediated contractions
o Giα – reduced cAMP?
o Giβγ – other mechanisms?
Gq-GPCR agonists – stimulate smooth muscle contraction
o α1-Adrenoceptor agonists
Adrenaline – used for anaphylactic shock
Noradrenaline – used for septic shock
Phenylephrine – nasal decongestant
o Muscarinic agonists
Pilocarpine – used for glaucoma
Bethanechol – used for urinary retention
o Oxytocin
o Used to induce labour
,Cardiovascular Pharmacology – Summary
Smooth Muscle Relaxation
Smooth muscle relaxation types – caused by reduced Ca 2+ repolarisation of smooth muscle relaxation
o Passive relaxation
Slow – occurs following contraction
Relaxes smooth muscle following removal of contractile stimulus
o Active relaxation
Faster – stimulated by a rise in cyclic nucleotides
Gs-GPCRs – cause rise in cAMP
Nitric oxide – cause rise in cGMP
Passive smooth muscle relaxation
o Sarcolemma Ca2+ ATPase pumps Ca2+ into intracellular stores + plasmalemma Ca 2+ ATPase pumps Ca2+
out of cell reducing intracellular Ca2+ concentration
o Rise in Ca2+
Stimulates Na+/Ca2+ exchanger
Removes 1 Ca2+ out of cell in exchange for 3 Na+
Stimulates opening of Bk channel
Causes hyperpolarisation of cell closing voltage gated Ca2+ channel
o Depolarisation stimulates opening of voltage gated K + channels (Kv channels) hyperpolarising cell
closing voltage gated Ca2+ channels
Active smooth muscle relaxation stimulated by rise in cAMP (G s-GPCRs)
o Stimulation of Gs-GPCRs stimulates adenylate cyclase activity converting ATP into cAMP
cAMP stimulates PKA PKA phosphorylates and stimulates the opening of K ATP channels + BKCa
channels hyperpolarising smooth muscle cell closing voltage gated Ca2+ channels reducing
Ca2+ influx relaxation
PKA also inhibits myosin light chain kinase activity inhibiting contraction
o Signal for relaxation is terminated by metabolism of cAMP by PDE (phosphodiesterase enzymes)
into AMP
Active smooth muscle relaxation stimulated by rise in cGMP (nitric oxide)
o Endothelium dependent vasorelaxation
Acetylcholine stimulates release of endothelium derived relaxing factor (EDRF) from
endothelium causing relaxation of smooth muscle
o Stimulation of eNOS in endothelial cells – production of nitric oxide
Release of nitric oxide from endothelial cells by endothelial dependent vasodilators – which
stimulate endothelial nitric oxide synthase (eNOS)
Acetylcholine stimulates muscarinic M3 Gq-GPCR receptor on endothelial cells stimulates
phospholipase C stimulating release of IP3 IP3 causes release of intracellular Ca2+ from
intracellular stores causing phasic rise in intracellular Ca2+
Depletion of stores sends signal to plasma membrane store operated Ca2+ channels
open influx of Ca2+ sustained rise in intracellular Ca2+
Ca2+ binds to calmodulin Ca-CaM complex binds to and stimulates nitric oxide synthase
(NOS) catalyses conversion of L-arginine + oxygen into L-citrulline + nitric oxide
released from cell
o Mechanism of smooth muscle relaxation by nitric oxide
Nitric oxide diffuses out of endothelial cell into vascular smooth muscle cell binds to and
stimulates enzyme soluble guanylate cyclase catalyses conversion of GTP to cGMP
cGMP binds to and stimulates protein kinase G (PKG) phosphorylates and stimulates
myosin light hain phosphatase dephosphorylates myosin light chains relaxation
cGMP – broken down by phosphodiesterase terminating signal
PKG functions
o Phosphorylates and inhibits phospholipase C inhibiting contraction
stimulated by Gq-GPCRs preventing rise in Ca2+
, Cardiovascular Pharmacology – Summary
o Phosphorylates and stimulates sarcoplasmic endoplasmic reticulum Ca 2+
pump increasing Ca2+ uptake into intracellular stores
o Phosphorylates and stimulates plasmolemma Ca 2+-ATPase pump
increasing removal of Ca2+ from cell
o Stimulates opening of BKCa channels causes cell hyperpolarisation
inhibits Ca2+ influx through voltage-gated Ca2+ channels
o Directly inhibits L-type Ca2+ channels preventing Ca2+ influx
Mediators which stimulate endothelium dependent vasodilation
o Endothelial mediators
Act in an autocrine way
ATP
Acetylcholine
o Inflammatory mediators
From basophils or mast cells – responsible for increased blood flow at sites of inflammation
Histamine
Bradykinin
Substance P
o Platelet mediators
Thrombin
5-HT
ADP
o Hormones, growth factors
VEGF
Insulin
Endothelium dependent vasodilators
o Agonist | endothelial receptor
Acetylcholine | M3
Histamine | H1
ADP/ATP | P2Y
Bradykinin | BK2
Substance P | NK1
GCRP | CGRP1
o Shear stress of endothelial cells – caused by flow of blood = also stimulates nitric oxide release
Endothelial derived relaxing factors
o Nitric oxide
Small + lipid soluble
o Prostacyclin
Produced by arachidonic acid released from endothelial cells stimulates IP prostacyclin
receptors on smooth muscle Gs-GPCRs) rise in cAMP relaxation
o EDHF – endothelium derived hyperpolarising factor
Produced hyperpolarisation of smooth muscle
More important in resistance arterioles – involves gap junctions + other factors
Particulate guanylate cyclase receptors
o Single transmembrane enzyme linked receptors – natriuretic peptide receptors
o Natriuretic peptides Stimulate NPR-A and NPR-G receptors (particulate guanylate cyclase receptors)
causes guanylate cyclase activity converts GTP into cGMP stimulates PKG relaxation
Smooth muscle relaxing drugs
o β2-adrenoceptor agonists
o Prostacyclin analogues
o Receptor antagonists
o Calcium channel blockers
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