Potential antihypertensives Flashcards
How can blood pressure be calculated?
How can cardiac output be calculated?
Blood pressure= cardiac output x systemic resistance
Cardiac output= stroke volume x heart rate
what is a synthetic compound that can increase our heart rate?
Isoprenaline- a beta adrenoceptor agonist
our heart rate rate goes up as there are beta adrenoceptors in our heart
what is a natural compound that can agonistically acts on the adrenoceptors?
Noradrenaline= alpha1,2 and beta adrenoceptor agonist
Mean arterial pressure is going up a lot yet heart rate is going down= baroreceptor reflex to the change in peripheral resistance
the major determinant at resting normal conditions is total peripheral resistance for BP at physiological, normal conditions.
ALSO: TO LOWER BP: alpha adrenoceptor blocker put in =
• Normally vessel is kept partially narrow by sympathetic nerves releasing NA and binding to alpha adrenoceptors= some vasoconstriction/ promoting contraction
• THUS, if put a blocker= drop in BP as removing tonic influence
why should we bother treating hypertension?
- Increased risk of stroke, heart failure and coronary artery disease
- 29% of global deaths = Cardiovascular disease
- In 2008 CVD = 50, 000 premature deaths
- =£30 Billion financial burden
outline NICE’s guideline for treating hypertension
•STEP 1. ACE inhibitor or low cost ARB
(systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg):
•STEP 2. ACEi + Calcium channel blocker
(systolic BP >160 mm Hg or diastolic BP >100 mm Hg):
- STEP 3. ACEi + CCB + thiazide diuretic
- STEP 4. Resistant hypertension
Changes depending on ethnic group
describe the role of angiotensin2
a potent vasoconstrictor that increases the release of NA from sympathetic nerves = more vasoconstriction.
Angiotensin 2 also activates the release of aldosterone from adrenal medulla= more water reabsorption= expand circulating volume
how does a rise in [ca2+]i induce contraction of vascular smooth muscle cells?
increased[Ca2+]I –> Formation of Ca2+ - calmodulin complexes–> Activation of myosin light chain kinase (MLCK) –> Phosphorylation of myosin light chain ‘heads’ –> Crossbridge formation between phosphorylated ‘heads’ of myosin light chains and actin filaments –> Crossbridges ‘row’ myosin light chain along actin to produce shortening and tension
name some newer smooth muscle targets that are in development whilst some are hypothesised
- K+ channels
- Cl channels
- Na /Ca2+ exchange blockers
- Rho Kinase
- Endothelin antagonists
- Remodelling
what usually happens in a SMC when an agonist binds to GPCR? THEREFORE, what do we aim to do with these newer smooth muscle targets?
Agonist binds to GPCR (most vasoconstrictors are coupled to Gq) = activation of PLC= breakdown of PIP2–> IP3 and DAG= IP3 interacts with its receptors in SR= releases calcium
- DAG activates protein kinase C
- Lots of calcium released and lots of calcium influx through VGCCs (open by membrane depolarisation)
-SMC: lots of ways to raise calcium and tends to vary in different arteries–> how the cell modulates the different pathways to keep intracellular calcium low
how can potassium channels brake cellular excitability?
- If potassium channel is open in VSMC= potassium ions leave the cell= membrane potential hyperpolarises (goes more negative) = Likelihood of VGCCs to be open is less likely= relaxed/ vasodilation= reduces contraction
- If K+ channels blocked or malfunctioned= closed/ underperforming= membrane potential becomes more depolarised= likelihood of VGCCs to be more open= calcium ions build up= contract= vessels vasoconstrict
name and describe what the KCNQ genes are associated with
•Family of 5 genes (KCNQ1-5)
•Encode voltage dependent K+ channels (Kv7.1-7.5)
(7.1 found a lot in the heart)
Hereditary disorders:
•Arrhythmia (KCNQ1)
•Epilepsy (KCNQ2/3)
•Deafness (KCNQ4)
- Kv7.1 mainly in cardiac muscle and inner ear
- Kv7.4 in the inner cells too
- Kv7.2, 3 and 5 in neurones
what are 2 pieces of evidence that shown Kv7 channel activators having a potential therapeutic benefit?
1) Human mesenteric arteries
•These are resistance arteries
•Measuring force
•Added alpha adrenoceptor agonist= contraction= prototype anti-epileptic drug that enhance Kv7 channels= blood vessels are no longer constricted
•If put blocker of these kV7 Channels= effects are reversed
2) KCNQ channel blockers increase cerebral vasospasm, KCNQ channel openers prevent cerebral vasospasm.
When you block Kv7 channels= cerebral arteries have lost its myogenic response= blood flow to brain reduces
If Kv7 channel activator is added= good blood flow to the brain
do Kv7 channel activators offer therapeutic benefit?
Based on expression profile: Kv7.4 can be targeted–> has all the vasorelaxant properties but none of the neuronal or cardiac side effects.
would kv7.4 target be greater than VDCC blockers?
would be beneficial:
- Get a very strong reflex, increase in HR with calcium channel blockers
- Get an aggressive vasodilation
- Baroreceptor reflex= increase HR
- There are calcium channels in cardiomyocytes= if they’re blocked= can get conduction problems in the cardiomyocytes
give a summary on KCNQ genes
- Aorta and conduit arteries express KCNQ genes
- Protein
- KCNQ blockers that do NOT differentiate different KCNQ isoforms = spasmogenic
- KCNQ1 selective blockers = non-spasmogenic
- Kv7 activators are vasorelaxant and hypotensive
- Anti-hypertensives
Discovered in 2001: kv7.4 channel activity is downregulated in animals with primary and secondary hypertension–> have to find out how its downregulated= may have found a mechanism that underlies hypertension
