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