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55 Cards in this Set

  • Front
  • Back

what are autocoids

substances that produce an effect in tissues in which they are releasedwhat

what do autocoids act on

act on cells which release them (autocrine)


act on cells in close vicinity (paracrine)

examples of autacoids

bradykinin


histamjne


5-HT- serotonin

what is bradykinin

inflammatory mediator. it is a peptide that causes blood vessels to dilate


9 amino acid peptide chain

kininogens are the precursors to what

kinins

what are kinins formed by

cleavage of kinogens by the enzyme kallikerin.

kallidin (KD) is often referred to as what

as lys- bradykinin is a decapeptide


can be converted to BK BY aminopeptidase enzymes

what are the bradykinin receptors

B1 and B2


B3-B5 less known

what is the rank order potency of kinins at B1 receptor

des-arg9 BK> lysBK>>BK


preferentially activated by kinins lacking the C-term arg residue

rank order potency of kinins at the B2 receptor

Lys-BK>>> des-arg9 BK


HIGH affinity for BK and Lys-BK(kallidin)

where does a lot of sucessful medication come from

using GPCR as a target


looking at the way they work for therapeutic value

what are bradykinin agonists

peptide ligands


B1: R-838 (modifyed to create side chains so better specificity)


B2: labradimil

bradykinin antagonists

substituted peptides


B1- leu-des-arg BK OR Lys-leu- des -arg BK


B2- D-arg-BK

antagonist of bradykinin is by doing what

modifying amino acids in the 9 amino acid sequence

what is a peptidominetic ligand for bradykinin

b2= firazyr for hereditary angiodemia (HEA)

typical signalling cascades Of BK/kinins

releases of intracellular Ca2+


activates PLA2


release of PGI2 and/or NO

what happens when kinins bind to B2 receptors

kinin binds to B2 promotes Gq coupling pathway which triggers a rise in intracellular calcium levels that promotes PLA2 dependent release of arachidonic acid and prostacyclin synthesis

what is the full pathway of kinin binding( coupling mechanism)

kinin bind to B2 receptor, Gi coupling pathway, stimulates phospholipase C, calcium mobslisation, phospholipase A2 and then esterification of arachidonic acid

what are other outcomes in actions of BK/kinins

vascular leakage


pain


contraction/relaxation of smooth muscle


transport of water and ions

explain BK AND inflammation

inflammation causes extravasation and activayion of kininogenases (kallikerins) produces more bradykinin


increase kallikerins increase bradykinis


release of inflammatory PG mediators

what happens during inflammation with BK

up-regulation of b1 receptor(upregulated receptor- more opportunity to bind)


release of B1 receptor agonists


-vasodilation


-odemea


-increased vascular leakage

physiological and pathophysiological roles for BK


- vasodilation

anti hypertensive


septic shock


pancreatitis

physiological and pathophysiological roles for BK


increase in vascular permeability

pancreatitis


hepatorenal syndrome


edema


rhinitis

physiological and pathophysiological roles for BK


release of inflammatory mediators

rhinitis


asthma


colitis


arthritis

physiological and pathophysiological roles for BK


stimulation of sensory nerves

pain


arthritis

physiological and pathophysiological roles for BK


contact activation

Alzheimer’s disease

physiological and pathophysiological roles for BK


GLUT 4 translocation

improvement in insulin sensitivity

physiological and pathophysiological roles for BK


ischemic preconditioning

prevention of


infarction


remodelling


arehythmias

physiological and pathophysiological roles for BK


release of NO, PGI2 and t-PA

anti


hypertrophic


proliferative


aggregationally


atherosclerotic

histamine formed by

decarboxylation of L-histidine, by histidine decarboxylase

what are histamine synthesis and inactivation

all tissues can synthesise histamine


rate of synthesis increased in inflamed tissues


metabolised by histamine N-methyltransferase (HNMT)and diamine oxidase (DAO) to give methyl imidazole acetic acid

explain histamine release


and what its triggered by

generated in granules of mast cells and WBCs


histamine release is triggered by allergens binding to mast-cell-bound IgE antibodies causing degranulation

other triggers of histamine release

release from mast cells via sensory pain receptors


anaphylatocins


tissue damage, heat mechanical injury

histamine is release by what

exocytosis that can lead to inflammation and further cellular damage

what are histamine receptors

GPCRs- H1-H4

what are histamine receptors

GPCRs- H1-H4

what do histamine receptors couple to

H1 couple to Gaq


H2 couple to Gas


H3 and H4 couple to Gai

what happens when histamine binds to H1 receptors

increased ca2+ leads to smooth muscle contraction


increased capillary permeability


vasodilation

what happens when histamine binds to H2 receptors

increased cAMP


Leads to increased gastric acid secretion- blood vessels:


vasodilation


increased capillary permeability

what happens when histamine binds to H3 receptors

decrease in cAMP


leads to


decrease in histamine release


decrease in secretion


and vasodilation

give an example of a H1 antagonist and their functions

mepyramine, promethazine


used for allergic conditions- skin reactions and hay fever

give and example of H2 antagonist and their functions

Ranitidine/cimetidine


treatment of peptic ulcers/stomach acid production


what is cinetidine

selective H2 antagonist for gastric ulcers

what is 5-HT

it is a monoamine neurotransmittee

how do you get synthesis of 5-HT

L-tryptophan is taken up into cell


converted into 5-HTP


5-HTP is then converted into 5-HT

enzymes involved with the synthesis of 5-HT

tryptophan hydroxylase


5-HTP decarboxylase

where are 5-HT Stored and when they are released

intestine- enterochromaffin cells- released during stimulation of gut


blood- platelets-released during clotting


brain- neurones- released during nerve stimulation

what does 5-HT DO to the intestine

mediates motility by activating enteric neurones which regulates contraction and relaxation

what does 5-HT DO to the intestine

mediates motility by activating enteric neurones which regulates contraction and relaxation

what does 5-HT DO in platelets

causes aggregation, also causes vasoconstriction (prevents blood loss)

what does 5-HT DO to the intestine

mediates motility by activating enteric neurones which regulates contraction and relaxation

what does 5-HT DO in platelets

causes aggregation, also causes vasoconstriction (prevents blood loss)

what does 5-HT DO to the brain

regulation of mood, sleep patterns

whats an example of a selectin serotonin reuptake inhibitor and function

fluxoeine


inhibits serotonin reuptake via sert


higher levels of 5-HT In the synaptic cleft to activate the receptor

why is mediator biology an extensive subject

insight into functions of molecules released in body that produces pharmacological effects


mediators that trigger disease and subsequently exploit for developing new therapies