Term
| What can hypertension lead to you? |
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Definition
• cerebrovascular accident – ‘stroke’.
• kidney failure
• myocardial infarction – ‘heart attack’. |
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Term
| What are the 2 types of hypertension? |
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Definition
1. Systemic hypertension.
2. Pulmonary hypertension. |
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Term
| Define systemic hypertension |
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Definition
| Systemic hypertension is a chronic medical condition in which the blood pressure in the arteries is elevated. |
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Term
| What pressures would give systemic BP? |
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Definition
Textbook systemic blood pressure=120/80 mm Hg
NICE define systemic Stage 1 hypertension as ≥ 140/90 mmHg
NB: Blood pressure changes with age so cannot be defined strictly in terms of absolute values of pressure (in 95th percentile or greater) |
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Term
| What specific cases cause systemic hypertension? |
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Definition
• Renal artery stenosis: an abnormal narrowing of the renal artery. The kidneys are heavily involved in blood pressure control.
• Phaeochromocytoma: a catecholamine-secreting neuroendocrine tumour of chromaffin tissue of the adrenal medulla, which causes episodes of severe hypertension. |
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Term
| Define primary 'essential' hypertension |
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Definition
it is the form that has no identifiable cause – it is idiopathic. Most common.
systemic |
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Term
| Define pulmonary hypertension |
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Definition
| Pulmonary hypertension is characterised by an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, leg swelling and other symptoms. |
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Term
| Is pulmonary or systemic pressure higher? |
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Definition
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Term
| When does pulmonary hypertension occur? |
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Definition
| Occurs when arteries that carry blood from the heart to the lungs become narrowed. Can occur at any age - much more common in young adults (and twice as common in women as in men). |
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Term
| What pressures would give pulmonary BP? |
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Definition
Textbook pulmonary blood pressure = 25/10 mm Hg
Normal mean pulmonary artery pressure (PAP) ≈ 14 mm Hg
Pulmonary hypertension is defined as mean PAP ≥25 mmHg |
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Term
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Definition
PAP = (CO x PVR) + PVP
CO = cardiac output; PVR = pulmonary vascular resistance;
PVP = pulmonary venous pressure. PVP equates to left atrial pressure. |
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Term
| What specific cases cause pulmonary hypertension? |
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Definition
• Cirrhosis: the replacement of liver tissue by scar tissue leading to loss
of function. This can lead to a serious complication known as portopulmonary hypertension: the coexistence of portal and pulmonary hypertension.
Congenital (at or before birth) abnormalities. |
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Term
| What is pulmonary hypertension classed as? |
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Definition
| secondary hypertension: it is caused by an identifiable, underlying cause, which the hypertension is secondary to. Idiopathic forms of secondary hypertension are rare, by definition. |
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Term
| How is hypertension treated? |
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Definition
It is possible to correct hypertension without using drugs (life-style changes)
But drug treatment often recommended
Around 15% of people are not responsive to current drug treatments |
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Term
| List the major biological mechanism controlling BP (7) |
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Definition
1. Fluid volume control (sodium retention) at the renal distal tubules
2. The renin-angiotensin system (RAS)
3. Voltage-gated calcium channels (in vascular smooth muscle)
4. Sympathetic nervous system (α- and β-adrenoceptors)
5. Nitric oxide and cyclic GMP
6. Endothelin-1
7. Prostanoids |
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Term
| How much higher is systemic stystolic BP than pulmonary systemic BP? |
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Definition
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Term
| Which demographic is more likely to have pulmonary hypertension? |
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Definition
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Term
| Which equation is key in controlling BP? |
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Definition
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Term
| What is BP determined by? |
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Definition
CO (therefore the heart)
TPR (which is determined by the small muscular arteries and arterioles) |
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Term
| How do the kidneys control BP? |
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Definition
| control fluid balance and therefore amount of fluid in circulatory system and vascular tone by releasing certain chemicals |
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Term
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Definition
| moving from the capillary into the tubular cells and tubular fluid. If a substance is secreted, chances are it will be eliminated as a general rule for the direction it is going. |
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Term
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Definition
| moving from the tubular fluid into the capillaries. If a substance is moving in this direction, chances are the body will keep it, as it is moving back into the blood. |
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Term
| What happens to blood at the kidney? |
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Definition
1. blood arriving at the kidney is filtered at the glomerulus
2. large proteins like albumin are filtered out
3. small ions pass into the fluid in the renal tubules
4. some are reabsorbed |
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Term
| What is the effect of sodium reabsorption in the distal tubule? |
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Definition
increases fluid retention and BP
As reabsorption proceeds, the solute concentration of tubular fluid decreases and that of the peritubular fluid and adjacent capillaries increases. Osmosis then pulls water out of the tubular fluid and into the peritubular fluid. |
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Term
| How is sodium reabsorbed? (2) |
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Definition
1. Na+-Cl- co transporter
2. Na+ channels (aldosterone from adrenal glands increases expression of these channels) |
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Term
| Describe the Na+-Cl- co/sym transporter |
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Definition
one sodium and one chloride ion into the epithelial cell
sodium is then transported into the interstitial space via a Na+-K+ ATPase transporter |
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Term
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Definition
enters epithelial cell and sodium is then transported into the interstitial space via a Na+-K+ ATPase transporter
mediated by aldosterone which binds to its A receptor (transcription factor) |
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Term
| What else does aldosterone affect? |
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Definition
| expression of Na+-K+ ATPase transporter |
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Term
| Describe the RAAS when blood volume is low |
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Definition
1. juxtaglomerular cells in the kidneys activate their prorenin and secrete renin directly into circulation
2. Plasma renin then carries out the conversion of angiotensinogen released by the liver to angiotensin I
3. Angiotensin I is subsequently converted to angiotensin II by the angiotensin converting enzyme (ACE) found in the lungs. |
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Term
| Describe the events of angiotensin II |
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Definition
| Angiotensin II is a potent vasoactive peptide that causes blood vessels to constrict, resulting in increased blood pressure. Angiotensin II binds to the AT1-receptor in the smooth muscle of blood vessels. This increases the resistance to blood flow and hence increases the pressure of the blood. |
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Term
| Describe the AT1 receptor |
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Definition
| AT1 is a G-protein-coupled receptor, coupled to Gq |
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Term
| Therefore what does binding to AT1 cause? |
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Definition
| . It thus activates phospholipase C and increases the cytosolic [Ca2+], which in turn triggers cellular responses such as activation of protein kinase C. Protein kinase C controls the function of other proteins through phosphorylation (of their -OH groups). |
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Term
| What else does angiotensin II stimulate? |
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Definition
| the secretion of the hormone aldosterone from the zona glomerulosa of the adrenal cortex. |
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Term
| What does aldosterone cause? |
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Definition
| the tubules of the kidneys to increase the reabsorption of Na+ and water into the blood; it controls the Na+ channels and the Na+/K+ exchange pump. This increases the volume of fluid in the body, which also increases blood pressure. |
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Term
| What is Na+ conversion associated with? |
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Definition
| K+ loss (because of the action of the exchange pump) |
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Term
| Therefore, what can prolonged aldosterone secretion cause? |
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Definition
hypokalaemia
a dangerous reduction in the plasma [K+]. |
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Term
| How does calcium lead to vasoconstriction? |
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Definition
1. Ca2+ forms complex with calmodulin
2. this complex activates MLCK
3. MLCK phosphorylates smooth muscle myosin
4. leads to cross-bridge formation between the myosin heads and the actin filaments, and hence, smooth muscle contraction
5. contractions leads to vasoconstriction |
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Term
| How are Ca2+ 'switched off'? |
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Definition
| Opening of K+ channels will ‘switch off’ Ca2+ channels because K+ will leave the cell down its concentration gradient, repolarising/hyperpolarising the cell therefore setting the membrane voltage too negative for Ca2+ channels to open |
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Term
| What does activation of the sympathetic NS do? |
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Definition
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Term
| What are α-adrenoceptors activated by in vascular SMC? what are the effects? |
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Definition
| noradrenaline from sympathetic nerve terminals causes vasoconstriction |
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Term
| What are β-adrenoceptors activated by in cardiac muscle and juxtaglomerular cells? what are the effects? |
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Definition
| noradrenaline (nerve terminals) and adrenaline (adrenal glands) act on the heart to increase CO, JGA to increase renin release |
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Term
| What are the effects of adrenaline these receptors? |
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Definition
| Adrenaline is an agonist at the receptors and its action is associated with excitement and exercise. |
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Term
| Where is NO produced and released? |
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Definition
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Term
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Definition
| the enzyme guanylate cyclase to produce cGMP. This cGMP then activates protein kinase G |
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Term
| What are the effects of PKG? |
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Definition
1. reuptake of Ca2+
2. opening and Ca2+-activated K+ channels: K+ will diffuse down its concentration gradient out of the cell causing repolarisation/hyperpolarisation, which causes inhibition following stimuli that have increased intercellular Ca2+ |
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Term
| What does the fall in ca2+ ensure? |
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Definition
| myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the cross-bridge cycle and leading to relaxation of the smooth muscle cell – vasodilation. |
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Term
| What is the fate of cGMP? |
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Definition
| The cGMP is degraded by the action of the phosphodiesterase enzyme. |
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Term
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Definition
| Endothelins are peptides produced by endothelial cells (name similarity) in response to trauma or inflammation, which are responsible for the constriction of blood vessels and hence the raising of blood pressure. |
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Term
| What kind of factors are endothelins? |
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Definition
| paracrine factors; they diffuse over a relatively short distance, having a local action (on nearby cells). |
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Term
| What does endothelin-1 bind to? |
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Definition
ET-1 binds to the ETA receptor, a G-protein-coupled receptor found in the smooth muscle of blood vessel
Gq |
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Term
| What are the effects of ET-1 binding to ETA? |
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Definition
1. Gq activates PLC
2. PLC hydrolyses PIP2 to DAG and IP3
3. DAG activates PKC
4. IP3 binds to IP3 receptors on the sarcoplasmic reticulum, liberating intracellular Ca2+ stores. |
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Term
| Therefore, what are the overall effects of ET-1 binding to ETA? |
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Definition
| Binding of ET-1 to ETA increases vasoconstriction and the retention of Na+, which itself leads to increased water retention and therefore increased blood pressure. |
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Term
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Definition
Prostanoids are a subclass of eicosanoids consisting of:
1. prostaglandins (mediators of inflammatory and anaphylactic reactions)
2. thromboxanes (mediators of vasoconstriction)
3. prostacyclins (active in the resolution phase of inflammation.) |
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Term
| How are prostanoids made? |
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Definition
1. phospholipids in the cell membrane are acted on by enzymes called phospholipase A2
2. this produces arachidonic acid
3. COX enzymes act on AA to make many signalling molecules e.g. prostaglandin I2 (prostacyclin) |
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Term
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Definition
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Term
| What are the effects of IP receptor activation? |
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Definition
The IP receptors are G-protein-coupled receptors coupled to Gs. Gs activates adenylate cyclase, which as a result increases the level of cAMP. cAMP activates protein kinase A (PKA).
In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of the myosin light chain of myosin. The smooth muscle relaxation leads to vasodilation. |
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Term
| What drugs modulate mechanisms controlling BP? |
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Definition
| 1. thiazide diuretics and aldosterone antagonists |
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Term
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Definition
| works by inhibiting Na+ reabsorption – it blocks the Na+/Cl- symporter – at the beginning of the DCT. More water is lost as a result of more Na+ reaching the collecting ducts. |
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Term
| How do aldosterone antagonists work? |
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Definition
| block Na+ channel synthesis |
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Term
| What are the effects of thiazide diuretics and aldosterone antagonists? |
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Definition
| reduce Na+ reabsorption and fluid retention leading to a decrease in BP |
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Term
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Definition
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Term
| Name an aldosterone antagonists and give its effects |
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Definition
| Spironolactone is a potent antagonist, a blocker, of the androgen receptor as well as an inhibitor of androgen production. Ultimately this blocks the effects of aldosterone. |
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Term
| What are the effects of AT1 Receptor Antagonists and ACE Inhibitors? |
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Definition
Reduce:
• Vasoconstriction
• Vascular hypertrophy
• Sodium retention |
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Term
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Definition
| Captopril is an ACE inhibitor, therefore it will block the actions of the enzyme so it cannot convert angiotensin I into angiotensin II. |
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Term
| Name an AT1 Receptor Antagonist |
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Definition
| Candesartan is an AT1 receptor blocker, preventing the binding and therefore downstream actions (via the G-protein-coupled receptor) of angiotensin II. |
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Term
| What are the effects of Ca2+ Channel Antagonists and K+ Channel Agonists? |
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Definition
| Ca channel blockers and K channel openers promote vasodilation by reducing Ca influx into the vascular smooth muscle cell |
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Term
| Name a Ca2+ Channel Antagonists and give its effects |
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Definition
Amlodipine
an L-type Ca2+ channel blocker, thus reducing the amount of intracellular Ca2+ and thus the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the cross-bridge cycle and leading to relaxation of the smooth muscle cell – vasodilation. |
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Term
| Name a K+ Channel Agonists and give its effects |
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Definition
Minoxidil
causes the K+ channels to open, thus causing repolarisation/hyperpolarisation of cell membranes because K+ will leave the cell down its concentration gradient. This prevents voltage-gated Ca2+ channels opening because the membrane potential is too negative due to it being repolarised/hyperpolarised. This again reduces intracellular Ca2+ levels, myosin light-chain kinase can no longer phosphorylate the myosin molecule, thereby stopping the cross-bridge cycle and leading to relaxation of the smooth muscle. |
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Term
| How do α-blockers work? give an example |
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Definition
Doxazosin
This inhibits the binding of noradrenaline (released from sympathetic nerve terminals) and therefore blocks vasodilation and hence reduced blood pressure. |
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Term
| How do β-blockers work? give an example |
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Definition
Propranolol
b-blockers reduce CO and renin release mediated by noradrenaline/adrenaline |
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Term
| How do NO donors work? give an example |
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Definition
Sodium nitroprusside is an NO-releasing drug. It mimics the actions of the endothelial cells releasing NO, causing vasodilation of the smooth muscle.
NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP activates protein kinase G which activates phosphatases which inactivate myosin light chains. Myosin light chains are involved in muscle contraction. The end result is vascular smooth muscle relaxation, which allow vessels to dilate. |
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Term
| How do phosphodiesterase inhibitors work? give an example |
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Definition
Sildenafil (Viagra)
It acts by inhibiting the cGMP-specific phosphodiesterase enzyme and thus prevents degradation of cGMP. Prolonged cGMP levels lead to prolonged inactivation of the myosin light chains, which in turn leads to a sustained period of vasodilation. |
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Term
| How do endothelin synthesis blockers work? give an example |
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Definition
| Phosphoramidon is an endothelin converting enzyme (ECE) inhibitor, thus reducing the amount of endothelin synthesised in endothelial cells. A reduction in ET synthesis constitutes a reduction in ET binding at ET receptors. This decreases vascular resistance and Na+/water retention. |
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Term
| How do prostacyclin receptor agonists work? give an example |
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Definition
Iloprost is a synthetic analogue of prostacyclin PGI2. Prostacyclins cause vasodilation upon binding to the prostacyclin receptors (IP).
The IP receptors are G-protein-coupled receptors coupled to Gs. Gs activates adenylate cyclase, which as a result increases the level of cAMP. cAMP activates protein kinase A (PKA).
In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of the myosin light chain of myosin. The smooth muscle relaxation leads to vasodilation.
Prostacyclin (IP) receptor agonists promote vascular smooth muscle cell relaxation and vasodilation mediated via IP receptors. |
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Term
| What is the most common form of hypertension? |
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Definition
| essential systemic hypertension |
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Term
| What do antihypertensives aim to reduce? |
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Definition
- Total peripheral resistance (vessel tone)
- Fluid load
- Cardiac output (heart rate, stroke volume) |
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