Block 2: Autocoids

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Many autocoids act through the production of which gas?: NO
What are NO three main functions?: 1. neurotransmitter in PNS and CNS
2. mediates vasodilation (= endothelium-derived relaxing factor, EDRF)
3. in lg quantities it can kill or inhibit growth of microorganisms, tumor cells, or lymphocytes
Which two nitric oxide synthase (NOS) isoforms are constitutively expressed?: endothelial NOS (eNOS)
neuronal NOS (nNOS)
What activates eNOS and nNOS?: calcium/calmodulin binding
(from ACh, serotonin, Histamine, bradykinin...) to make small amounts of NO
Which NOS isoform is expressed only after stimulation of cells with cytokines, microbes, or microbial products?: inducible NOS (iNOS)
What happens once it iNOS is expressed?: it is constitutively active and makes large amounts of NO
Where is iNOS made?: variety of cell types-
cells of immune system,
vascular sm mm cells
pancreatic islet cells,
etc.
How is NO transported?: it's not, its a gas-- it diffuses through membranes to act on surrounding cells
What is the t1/2 of NO?: short- a few seconds
How is NO inactivated?: interaction with O2 --> converted to nitrite or nitrate
What happens when NO binds Fe in heme group?: activates guanylate cyclase --> inc cGMP --> activates cGMP dependent protein kinase --> relaxes sm mm --> vasodilation
What is the reaction catalyzed by NOS?: L-arginine + NADPH + O2 --> L-citrulline + NADP + NO
What may be involved in processes ranging from excitotoxic cell death to memory?: Ca entry through NMDA receptors --> activates nNOS --> glutamate inc
Which NOS is involved with NonAdrenergic NonCholinergic (NANC) in GI, urogenital, and vascular systems?: nNOS
What do children get when they have deficient nNOS myenteric nerves at the pylorus?: pyloric stenosis
What may account for some forms of erectile dysfunction?: NO (via nNOS)
What are three actions of eNO: 1. vasodilator
2. prevents platelet adherence and aggregation and neutrophil aggregation
3. prevents sm mm proliferation
Which NO is part of an adaptive response during inflammation and injury?: iNO- it kills foreign bodies through formation of damaging radicals and peroxynitrite ions
When would inhibition of NOS be beneficial?: When large amounts of NO are causing damage during septic shock
Are thre any isoform specific inhibitors of NOS?: no
When is inhaled NO used to produce selective pulmonary vasodilation and improved oxygenation?: persistent pulmonary hypertension of newborn
and
ARDS
What are prostaglandins?: eicosanoids derived from arachidonic acid
Where are prostaglandins stored?: they're not stored- synthesized in response to stimuli and released in bursts into extracellular space
Where do prostaglandins act?: through specific G protein linked cell surface receptors; act locally
Mechanism of prostaglandin synthesis?: membrane phospholipids --> (phospholipase A2) --> arachidonic acid --> (cyclooxygenase) --> PGG2 --> prostaglandins
Where do NSAIDS work?: inhibit cyclooxygenase
analogue of PGE2 used for abortion: dinoprostone
analogue of 15-methyl-PGF2a used for postpartum hemorrhage: carboprost
analogue of PGE1 used for erectile dysfunction: alprostadil (Caverject)
analogue of PGE2a derivative used for gastric ulcers/abortion: misoprostol
(mye-so-prah'-stole)
analogue of PGE2a derivative used for abortion: gemeprost
analogue of prostacyclin used for Raynaud's disease: Iloprost
infused to keep ductus arteriosus in neonate awaiting surgery: PGE1 (alprostadil)
What is used when there is delayed closure of ductus arteriosus?: NSAIDS
Even though several prostaglandins are potential vasodilators, why are they rarely used?: hypotension
headache
flushing
Name four effects of prostaglandins on female reproductive system?: 1. contraction of uterine sm mm
2. used with anti-progestins to prematurely terminate preg
3. used to induce cervical ripening to aid labor
4. responsible for menstrual cramps (--> use NSAIDS)
Does VIP vasoconstrict or vasodilate?: potent vasodilator
Where is VIP expressed?: CNS
PNS
enteric nervous system
How does VIP act?: through G protein linked receptors
Name three roles of VIP?: immunomodulation
circadian rhythms
growth factor
Where is VIP often co-localized with NOS?: in PNS neurons- may help with neurotransmission
relate VIP to pancreatic D cell tumors?: overexpressed in these tumors --> pancreatic cholera --> watery diarrhea, hypokalemia, acidosis
How is a pancreatic D cell tumor managed?: surgically or with the drug streptozocin
What is the rate limiting step in the development of an erection?: ability to achieve sm mm relaxation --> allowing increased blood flow into corporal sinusoids
What is the mechanism of action of all drugs available for treatment of erectile dysfunction?: relaxation of sm mm of corpora cavernosa through increases in cyclic nucelotids cAMP or cGMP; some also have uses as vasodilators
What are three main routes of administration of drugs used to tx erectile dysfunciton?: intracavernous injection
transurethral suppositories
orally
oral administration cGMP phophodiesterase inhibitor inc cGMP: sildenafil = Viagra
oral and injected alpha1/alpha2 antagonist inc cAMP: phentolamine
urethral suppository and injection PGE1 inc cAMP: alprostadil
injection cAMP phosphodiesterase inhibitor inc cAMP: papaverine
(pa-pav'-ah-reen)
injection parasympathetic neurotransmitter and al/a2 antagonist inc cAMP not yet FDA approved: VIP and
phentolamine
Name two newer drugs of the same class as viagra?: tadalafil (cialis)
vardenafil (levitra)
When is sildenafil ABSOLUTELY CONTRAINDICATED?: all pt's taking nitrate drugs --> systemic vasodilation and visual impairment
What causes the visual impairment in pt's on nitrates who take viagra?: inhibition of cGMP phosphodiesterase type 6 found in the retina
What is t1/2 of bradykinin?: short - about 15 sec
Name five roles of bradykinin?: 1. produces pain
2. marked vasodilation (10x that of HA)
3. inc vascular permeability (--> hypotension)
4. induces prostaglandin E's (through activation of phospholipase A2)
5. stimulates production of HA and serotonin
What bradykinin receptor is upregulated during inflammation and may be important in the inflammatory response?: B1
Which bradykinin receptor is constitutively expressed and activation leads to release of NO and consequent vasodilation, hypotension, permeability and pain?: B2
Kininase II is identical to which molecule?: ACE
What does ACE have to do with bradykinin?: some of the effects of ACE-inhibitors are due to enhanced effects of bradykinin
Work through the steps of prekallikrein all the way to inactive fragments: prekallikrein ->(HFa or trypsin)-> kallikrein

kininogen ->(kallikrein)-> bradykinin ->(kininase I and II)-> inactive fragments
This neuropeptide found in the CNS, PNS, and ENS is a potent arteriolar relaxant: substance P
What is substance P made from and what receptors does it act on?: made from preprotachykinin
acts through tachykinin receptors
What may substance P be involved in ?: migraines
How is calcitonin gene related peptide (CGRP) made?: by alternative splicing of the calcitonin gene
Where is CGRP expressed: CNS
PNS
ENS
CV system and Urogenital system
What does CGRP have in common with substance P?: it may also be involved in migraines

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