Lecture 30 - Pharmacology Of Smooth Muscle In Relation To Cardiovascular Function Flashcards
What constitutes most of the tunica media in blood vessels
Vascular smooth muscle (VSM)
What does vascular smooth muscle play an important role in
The control of vascular tone
What is a major regulator in the contraction in VSM
Calcium
How is calcium in vascular smooth muscle regulated
By an intricate system of calcium mobilisation and calcium homeostatic mechanisms
The interaction of a physiological agonist with its plasma membrane receptor stimulates
The hydrolysis of membrane phospholipids
Where is calcium released from
The sarcoplasmic reticulum
Where do agonists stimulate calcium release from
Extracellular space
What has to be stimulated by agonist to allow calcium release from the extracellular space
Voltage-gated, receptor-operated and store-operated channels
Calcium homeostatic mechanisms tend to
Decrease the intracellular free calcium concentration by activating calcium extrusion via the plasmental calcium pumps and the Na+/Ca2+ exchanger and the uptake of excess calcium by he sarcoplasmic reticulum and possibly the mitochondria
A threshold increase in the intracellular calcium concentration
Activates calcium-dependent myosin light chain phosphorylation, stimulates the actin-myosin interaction and initiates VSM contraction
What is nitric oxide (NO)
An endothelium-dependent vasodilator of the underlying smooth muscle
What does NO play a major role in
The maintenance of basal vasodilator tone of the blood vessels
How is NO formed
Under the influence of the enzyme nitric oxide synthase (NOS)
What is the action of NOS
It converts the amino acid L-arginine to NO
What produces NO in the vasculature
Endothelial NOS (eNOS)
What is inactive eNOS bound to
Caveolin
Where is inactive eNOS located
In the small invaginations in the cell membrane called caveolae
What happens to eNOS when intracellular levels of calcium rise
eNOS becomes detached from caveolin and is activated
NO agonists can influence
The detachment of eNOS from caveolin by releasing calcium from the endoplasmic reticulum
Examples of NO agonists
Bradykinin, acetylcholine, adenosine triphosphate, adenosine diphosphate, substance P and thrombin
Once intracellular calcium stores are depleted what happens
A signal is sent to the membrane receptors to open calcium channels allowing extracellular calcium into the cell
What is store-operated calcium entry of capacitive calcium entry
Once intracellular calcium stores are depleted a signal is sent to the membrane receptors to open calcium channels allowing extracellular calcium into the cell
What protein does calcium attach to
Calmodulin
Where is calmodulin found
In the cytoplasm of the cell
What happens after calcium is bound to calmodulin
It undergoes structural changes which allow it to eNOS
Once calcium is bound to eNOS what happens
eNOS converts L-arginine into NO
What does a reduction in calcium cause
The calcium-calmodulin complex to dissociate from eNOS, which in turn binds to caveolin and becomes inactive
What is the short term increase of NO dependent upon
The intracellular calcium
What is a mechanism to regulate NO production
Phosphorylation of eNOS
How does phosphorylation of eNOS occur
By the actions of protein kinases such as protein kinase A and cyclic guanosine-3’,5’-monophosphate (cGMP) protein kinase dependent II
What initiates eNOS phosphorylation
Sheer stress
The actions of what initiate eNOS phosphorylation through sheer stress
Protein kinase B (Akt)
What does sheer stress result from
Increased blood flow in the vessel
In what way can sheer stress induce NO production
eNOS phosphorylation and baby stimulating endothelial cell receptors by allowing the transfer of blood-borne agonist to attach to endothelial cell receptors and increase intracellular calcium
What does sheer stress activate in particular
Specialised calcium-activated potassium channels on the endothelial cell surfaces
What does the activation of calcium-activated post assign channels cause
An efflux of potassium and an influx of calcium
Once synthesised what happens to NO
It diffuses across the endothelial cell into the adjacent smooth muscle where it binds to the enzyme soluble guanyly cyclase (sGC)
Once the enzyme sCG is activated what does it do
It increases the conversion rate of guanosine triphosphate to cGMP
What does the present of cGMP do
It decreases smooth muscle tension, reduces calcium release from the sarcoplasmic reticulum and helps to restore calcium to the sarcoplasmic reticulum
What do organic nitrate do
Relax all types of smooth muscle
How to organic nitrates relax smooth muscle
By their metabolism to nitric oxide
In small doses what effect do organic nitrates have on the body
They cause venorelaxation which decreases CVP, reduce SV, increased heart rate and there is no change in arterial pressure
What effect do higher doses of organic nitrates have
They can cause arteriolar dilation which decreases arterial pressure, reducing the afterload
What effect do organic nitrates have on coronary blood flow in normal subjects
The cause an increase in coronary blood flow
What effect do organic nitrates have on angina patients
Blood is redirected towards the ischaemic zone
What are the benefits of use in angine
Decreased myocardial oxygen requirements via decreased preload, decreased afterload and improved perfusion of the ischaemic zone
What are the main types of organic nitrates used in angina
Glycerltrinitrate (GTN) and isosorbide mononitrate (ISMN)
What are GNT and ISMN metabolised to
Nitric oxide
Characteristics of GTN
It is short acting and undergoes first-pass metabolism
How is GTN administered in stable angina
Sublingually or as a spray
How is GTN administered in unstable angina
By IV
How is GTN administered for a more sustained effect
By a transdermal patch
Characteristics of ISMN
It is longer acting than GTN and is resistant to first-pass metabolism
How is ISMN administered
Orally
What is ISMN administered for
Prophylaxis and a more sustained effect
What are adverse effects of organic nitrates
Headaches, hypotension, fainting, reflex tachycardia and formation of methaemoglobin
How can reflex tachycardia be prevented
By the co-administration of a beta-blocker
What do calcium antagonists block/prevent
The opening of L-type channels in excitable tissue in response depolarisation
What does the blockage of L-type channels cause
A limit on the increase of the concentration of intracellular calcium
What do L-type channels mediate
The upstroke of the AP in the SA and AV nodes and phase two of the ventricular AP
What effect can calcium antagonists have on the AV node
They can reduce the rate and conduction through the node
What effect do calcium antagonist have on contraction
They reduce the force of contraction
What are the three main type of calcium channel antagonists
Verapamil, amplodipine and ditiazem
What are the characteristics of verapamil
Relatively selective for cardiac L-type channels and blocks the pore
Characteristics of amlodipine
It is a dihydropyridine compound which is relatively selective for smooth muscle L-type channels and acts allosterically to prevent channel opening
When used to treat angina what effects do verapamil and diltiazem have
Negative inotropic effects
What offsets the negative inotropic effects of verapamil and diltiazem
The baroreceptor reflex
What are calcium antagonists used to treat
Hypertension
What are the effects of calcium antagonists in hypertension
Reduce calcium entry into vascular smooth muscle which causes generalised arteriolar dilation causing a reduced TPR and MABP
Example of a drug that is selective for smooth muscle L-type channels
Amloplipine
What are adverse effects of calcium antagonists
Hypotension, dizziness, flushing and swollen ankles
What is a dysthymia
An irregular heartbeat
How is the ventricular rate in rapid atrial fibrillation reduced
By suppressing the conductance through the AV node
What is normally used in rapid atrial fibrillation
Verapamil particularly in combination with beta-blockers
Potassium channel openers open
ATP-modulated potassium (Katp) channels
How do potassium channel openers act
By antagonising intracellular ATP which closes the Katp channel and causes hyperpolarisation which switches off L-type calcium channels
What drug is used as a last resort in hypertension
Minoxidil
What are the side effects of minoxidil
Reflex tachycardia and salt and water retention
What is used in begins refactory
Nicorandil
What are adrenoceptors
G-protein-coupled receptors (GPCRs)
How are GPCRs activated
By the sympathetic transmitter noradrenaline and hormone adrenaline
What do alpha1-adrenoceptors receptor antagonists cause
Vasodilation by blocking the vascular alpha1-adrenoceptor which causes a reduced sympathetic transmission which results in a decreased MABP
What are the most frequency alpha1-adrenoceptor receptor antagonists
Prazosin and doxazosin
What provide symptomatic relief in benign prostatic hyperplasia
Alpha1-adrenoceptor receptor antagonists
What is benign prostatic hyperplasia
An abnormally enlarged prostate compressing the urethra
What is the main adverse effect of alpha1-adrenoceptor receptor antagonists
Postural hypotension
