Peripheral transmission L5 Flashcards
non-selective AR agonists
give an examople
4 things it does to help in life saving situations
Adrenaline
- stimulates heart in acute cardiac failure (via b1)
- relieves bronchospasm (via b2) ® helps in acute asthma, anaphylactic shock
- induces vasoconstriction (via a1) -> helps in anaphylactic shock
- reduces secretions from mast cells (via b2) ® helps in anaphylactic shock
why is adrenaline used along side some anaesthetics
produces vasoconstriction at the site of injection ® limits systemic availability of the local anaesthetics
give a non selective alphaR agonist?
topical decongestants (e.g. xylometazoline)
directly stimulates α receptors on blood vessels supplying the nasal mucosa and conjunctiva
vasoconstriction
reduces congestion
selective α1-AR agonists include…..
phenylephrine and oxymetazoline
what do phenylephrine and oxymetazoline do?
selective a1 AR agonists
useful nasal decongestants
- Phenylephrine can also be used to ….
- Phenylephrine can also be used to produce mydriasis
- and also to treat acute hypotension such as that arising from septic shock.
selective α2 -AR agonists include ….
selective α2 -AR agonists include clonidine and α-methylNA
uses of Clonidine and α-methyldopa?
Clonidine and α-methyldopa (converts into α-methylNA (false transmitter) within the nerve terminal as mentioned before) are useful as anti-hypertensive drugs.
They reduce blood pressure, partly by inhibiting NA release from peripheral nerve endings but also by acting on central neurons that reduces sympathetic discharge towards the periphery.
(activation of pre-synaptic α2-ARs in the periphery)
as well as a2 AR, what other receptor does clonidine bind?
imidazoline I1 receptors?
give a nonselective B-AR agonist
- Isoprenaline (ISO) was used in asthma to relax bronchi through actions on β2 ARs but the increase in heart rate from β1-AR stimulation was a major problem; it has therefore been replaced by selective β2-AR agonists.
β1-AR selective agonists….
an exmaple, and a use
β1-AR selective agonist (e.g. dobutamine) ® in septic/cardiogenic shock to promote cardiac contraction but they can also potentially cause cardiac dysrhythmias
Short acting β2 -AR selective agonists…. an exmaple?
(SABA)
salbutamol and terbutaline
max. effect <=30min, action lasts for 3-5hrs
bronchodilators
. Long acting (8-12 hours) β2-AR agonists
exmaples and use?
- salmeterol and formoterol are used prophylactically in chronic asthma.
- Clenbuterol is a LABA used for horse.
- Long acting β2-AR agonists are also used in treating chronic obstructive pulmonary disease (COPD), especially the very-long-acting β2-AR agonist indacaterol is used for this.
B3 AR selective agonist? and use
- Mirabegron is a β3-AR agonist that relaxes the detrusor smooth muscle and increases bladder capacity. It is used for patients with overactive bladder.
nonselective a-AR antagonists
examples and use
Phentolamine and phenoxybenzamine
Their use as anti-hypertensive drugs is obsolete (and largely replaced by a1-AR antagonists) as they may reduce blood pressure so much that it triggers reflex tachycardia.
Phenoxybenzamine, unlike phentolamine, covalently binds to the receptor and causes long lasting inhibition. For this reason, it retains a specific clinical use …..
Phenoxybenzamine, unlike phentolamine, covalently binds to the receptor and causes long lasting inhibition. For this reason, it retains a specific clinical use in preparing patients with phaeochromocytoma for surgery since surgical manipulation tend to cause a massive release of catecholamine in the circulation.
a1 AR antagonists
examples and use
prazosin
decrease peripheral vascular resistance, lower blood pressure by causing relaxation of both arterial and venous smooth muscle.
to treat hypertension without causing the same degree of reflex tachycardia observed with the non-selective α-AR antagonists
problems with a1 AR antagonists?
- The undesired effects of α1-AR antagonists include postural hypotension and incontinence, the latter occurring because α1-ARs mediate contraction of the smooth muscle of the bladder, which is now inhibited.
what does tamsulosin do?
- α1-AR antagonists also cause relaxation of the prostate capsule and inhibit prostate hypertrophy, which has lead to the development of drugs like tamsulosin.
- These are selective α1A-AR antagonists that allow better bladder emptying and thus reducing urinary retention associated with benign prostatic hypertrophy.
- Since α1B-ARs largely mediate vasoconstriction, these α1A-AR antagonists produce much less postural hypotension which is a common problem with non-selective and a1-selective AR antagonists.
α2-AR selective antagonist example?
clinical use?
Yohimbine – a naturally occurring alkaloid, is a selective α2-AR selective antagonist, but it has no clinical use for the humans, being only a useful experimental tool to determine α-AR subtype response in a given tissue.
which AR antagonist is useful for BPH
α1A-selective antagonist (e.g. tamsulosin)
-> less hypotension than prazosin that acts
on α1B to control vascular tone -> useful in BPH
T or F
there are no clinically useful β2 -AR antagonists
T
Although all β-blockers lower blood pressure, they do not induce postural hypotension, because…
Although all β-blockers lower blood pressure, they do not induce postural hypotension, because the α ARs remain unaffected
All β-blockers block …..
All β-blockers block the positive chronotropic and inotropic actions of endogenous catecholamines at β1-ARs, resulting in decreased heart rate and myocardial contractility.
Beta blockers are primarily indicated in?
They are primarily indicated in hypertension and angina but can be useful in cardiac arrhythmias, myocardial infarction, heart failure, hyperthyroidism, and glaucoma
beta blockersnaming conventions?
The names of all β-blockers end in “-olol” except for labetalol and carvedilol.]
describe propanolol
- non-selective among β-AR subtypes, and has been effectively used in the treatment of hypertension since its development in the 1960s.
- It lowers blood pressure in hypertension by several different mechanisms of action.
- Decreased cardiac output is the primary mechanism, but inhibition of renin release from the kidney, decrease in total peripheral resistance with long-term use,
- and decreased sympathetic outflow from the CNS also contribute to the antihypertensive effects.
*
bad effecsts of propanolol?
- Propranolol and similar non-selective b-blockers have some undesirable actions that largely stem from their action on b2-ARs.
- For example, they are contraindicated in patients with COPD or asthma as blockade of b2-ARs in the bronchial smooth muscle can exacerbate condition and lead to a serious crisis.
- Blockade of b2-ARs causes a loss of vasodilation in cutaneous blood vessels that leads to coldness in the extremities.
whats meant by sceond generation beta blockers?
selective b1-AR antagonists (the 2nd generation or cardioselective b blockers) such as atenolol, has largely replaced the non-selective b blockers for avoiding the above mentioned issues associated with their use.
- have fewer/no effects on lungs
- less effect on peripheral vascular beta2 AR
- receptors -> less frequent coldness of extremities
- have fewer/no effects on carbohydrate metabolism
what are 3rd generation beta blockers?
Nebivolol
Carvedilol
NANc transmitters include…
they include small molecules (purines: ATP and its derivatives), neuropeptides and volatile substances (e.g. NO).
T or F
NANC can be co-released with the classical transmitters or be released separately
T
2 main peptides implicated with the
ANS?
Vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) seem to be the ones mostly implicated in the autonomic nervous system
do peptides act on GPCRs?
yep
ATP as an NANC transmitter can directly act on ….
ATP as an NANC transmitter can directly act on ligand-gated ion channels and thus mediate neurotransmission
can NANC effects last longer?
yes - the transmitter may be removed more slowly from the cleft - longer effects
whats suramin
ATP antagonist
also blocks some P2Y subtypes
Co-transmission enables…..
Co-transmission enables greater complexity of signalling; the time courses of actions of the transmitters may be different, allowing different types of responses to be elicited in the postsynaptic cell
Transmitters are often released independently of one another; e.g. …..
Transmitters are often released independently of one another; e.g. higher concentrations of Ca2+ are required to elicit release of peptide transmitters , so they are preferentially released at high rates of neural stimulation (i.e depolarisation).
is STP a neurotransmitter
yep
ATP and other purines act as transmitters within the central and peripheral nervous systems via interacting with …..
ATP and other purines act as transmitters within the central and peripheral nervous systems via interacting with purinergic receptors (purinoceptors)
what are the three subfamilies for the purinoceptors:
- Adenosine receptors – A1, A2A, A2B and A3 (all are GPCRs)
- Ionotropic P2X1-7 receptors – all are homo/heterotrimeric ATP-gated cation channels
- Metabotropic P2Y1-14 receptors: GPCRs, some are primarily activated by ATP whilst some others by ADP, UTP, GTP, UDP, UDP- glucose
ATP is packed into vesciels by
packed into vesicles by Vesicular Nucleotide Transporter (VNUT)
how can ATP be released?
released by exocytosis in Ca2+-dependent way or through large membrane channels called the pannexins or via the nucleotide transporters (NtT)
can ATP be borken down outside the cell?
Once released into the extracellular space, ATP can be converted to ADP, AMP and to adenosine by the action of ecto-nucleotidases. This leads to termination of transmission at the P2X and P2Y family of purinoceptors
after hydrolysis - what happens to adenosine in the cleft?
, adenosine – the final end product of ATP degradation, is present in the cytosol of all cells and is taken up and released via a specific membrane-bound nucleoside transporter(s) (NsT). Adenosine itself can be hydrolysed to inosine by the enzyme adenosine deaminase (see in Figure).
released ATP converted by ectonucleotidases to ADP which activates ….
converted by ectonucleotidases to ADP which activates P2Y receptors
describe P2X channels?
P2X receptors are non-selective cation channels - equally permeable to Na+ and K+ and with significant Ca2+ permeability. They open within milliseconds of the binding of extracellular ATP.
distribution of P2X channels?
They have a widespread tissue distribution, being expressed on both central and peripheral neurons, where they are involved in synaptic and/or neuromuscular transmission.
P2X_, P2X_ and P2X_ are the predominant receptor subtypes expressed in neurons.
P2X_ predominates in smooth muscle.
P2X2, P2X4 and P2X6 are the predominant receptor subtypes expressed in neurons. P2X1 predominates in smooth muscle.
what happens in mice lacking P2X1?
In sympathetically- innervated tissues, such as the vas deferens or blood vessels, ATP produces fast responses mediated by P2X1 receptors, followed by a slower component mediated by G protein-coupled a-ARs.
Male mice lacking the P2X1 receptor gene have a drastically reduced fertility because of much reduced sperm count in the ejaculate. It has been suggested this receptor might be a target for a male contraceptive.
Adenosine is an atypical transmitter - why?
Adenosine is an atypical transmitter - it is neither stored in vesicles nor released by a Ca2+-dependent process. It is found in the cytosol as well as in the extracellular fluid throughout the
what does dipyridamole do?
ATP is then taken up by cells through a nucleoside transporter (NsT). This transporter can be blocked by certain drugs such as dipyridamole which thus indirectly increase the concentration of extracellular adenosine
T or F\
Such ‘adenosine-boosting’ role of methotrexate is believed to contribute to its immunosuppressive action significantly.
T
why in pathological condition is extracellular adenosine raised?
- large amount of ATP released from stressed cells (ischaemia and hypoxia)
- from large pores pannexins, connexins
- converted to adenosine by ecto-nucleases
- also reports suggesting larger intracellular production as well as increased direct leak of adenosine from the cytosol of metabolically-stressed cells.
There are four distinct adenosine receptors
what are they
- There are four distinct adenosine receptors, all of which are G-protein coupled, either Gs or Gi and signal primarily through the activation (A2A and A2B) or inhibition (A1 and A3) of adenylyl cyclase and thus cAMP signalling.
- Some, if not all, of these receptors have also been reported to activate phospholipase C (and thereby trigger intracellular Ca2+ release) and mitogen-activated protein kinase (MAPK).
- Adenosine receptors can also modulate function of voltage-gated Ca2+ channels (via influencing their level of phosphorylation) and K+ channels (via βγ subunit and/or altering phosphorylation states).
- These receptors are widely expressed and have been implicated in several biological functions, both physiological and pathological.
describe adenosines affect on the heart
reduces (via A1 receptors) rate and force of cardiac contraction ® given as an i.v. bolus injection to terminate supraventricular tachycardia, safer than other agents because of its ultrashort duration of action
describe adenosines affect on vascular smooth muscle/
- Acting through A2A and A2B receptors that are Gs coupled, adenosine causes relaxation of vascular smooth muscle cells.
(by increasing cAMP)
describe adenosines effects on the CNS
and an antagonist
- Acting primarily through the presynaptic A1 autoreceptors, adenosine exerts pre-synaptic inhibitory effects on the release of excitatory transmitters in the CNS and periphery.
The stimulation experienced after consumption of methylxanthines such as caffeine occurs partly as a result of blocking this action. Caffeine is a competitive antagonist of A1 receptors.
what is Regadenoson
Regadenoson (Lexiscan or Rapiscan) is an adenosine derivative and selective A2A adenosine receptor agonist with coronary vasodilating activity.
It has been approved by the FDA for diagnostic purpose only in a type of heart scan called ‘radionuclide myocardial perfusion imaging’ to see the blood flow in the heart muscle.
Regadenoson is used as a ‘stress agent’ that has a similar effect on the heart as exercise.
describe how neuropeptide transmitters are produced?
Neuropeptides usually activate _____ and thus are more appropriately described as neuromodulators rather than neurotransmitters.
Neuropeptides usually activate GPCRs and thus are more appropriately described as neuromodulators rather than neurotransmitters.
T or F
For a given neuropeptide, there can be several receptor isoforms
T
Neuropeptides tend to produce a prolonged response because they are not rapidly removed from the extracellular fluid. Their response is terminated …… by?
Neuropeptides tend to produce a prolonged response because they are not rapidly removed from the extracellular fluid. Their response is terminated either by diffusion or by extracellular peptidases
neuropeptides have much _____ affinity for their target GPCRs they are active at concentrations ____ than the small molecule neurotransmitters
neuropeptides have much higher affinity for their target GPCRs ® they are active at concentrations lower than the small molecule neurotransmitters
describe NO
a gaseous inorganic free radical, which plays a role in physiological regulation
describe NO synthesis
not synthesized or stored in vesicles or released by exocytosis
requires activation of nitric oxide synthase (NOS) which converts L-arginine to NO and L-citrulline
3 isoforms of NOS
- neuronal NOS (nNOS, or NOS I) expressed in the CNS and NANC nerves
- inducible NOS (iNOS, or NOS II) is usually absent but its expression is induced in macrophages and other cells (fibroblasts, vascular smooth muscle cells, endothelial cells, Kupffer cells, neutrophils etc.) by bacterial lipopolysaccharide and/or inflammatory cytokines, notably interferon-γ.
- endothelial NOS (eNOS, or NOS III) expressed in platelets as well as endothelial cells
NO activates….
NO activates soluble guanylyl cyclase
NO activates sGC through interacting with the ____ moiety of the enzyme.
NO activates sGC through interacting with the haem moiety of the enzyme.
how does NO lead t osmooth muscle relaxation?
NO stim sGC = cGMP production
Upon production, cGMP can act directly on effector proteins such as ion channels but more commonly through the activation of protein kinase G (PKG). The latter phosphorylates various proteins and leads to relaxation of smooth muscle, particularly in the blood vessels and this accounts for the term endothelium-derived relaxation factor (EDRF) that is used to denote NO.
where is NO released in the ANS?
Innervations with nitrergic (i.e. NO releasing) postganglionic nerves are present in several peripheral tissues that notably include upper airways, gastrointestinal tract (the enteric neurons) and male sexual organs.
t or F
• neuropeptides typically orginiate from their larger precursors that undergo complex pre-processing to produce the active neuropeptides. They are stored and released in a manner distinct from the small molecule neurotransmitters.
T
how is NO involved in arousal?
Nitrergic nerves
release of NO during arousal
activation of soluble GC
cGMP
PKG
vasodilation
penile erection (viagra/sildenafil inhibits PDE5 that breaks cGMP)
fat
mamba
