Heart Health

What is angiotensin?

Angiotensin is a naturally produced hormone that forms part of a complex interaction of hormones, known as the renin-angiotensin hormone system that regulates blood volume, body fluid levels and blood pressure.  Angiotensin is produced by the liver as angiotensinogen, which is converted to angiotensin I by the action of renin, released by the kidney when blood pressure and volume is low.  Angiotensin I is the inactive precursor for Angiotensin II, which is produced by the action of Angiotensin Converting Enzyme (ACE) mainly in the lungs, but also in the kidney and endothelial cells lining the blood vessels. 

Angiotensin II is a highly vasoactive hormone that has potent effects on blood pressure and fluid balance.  It stimulates vascular smooth muscle to contract, which causes blood vessels to constrict (narrow).  This increases blood volume while at the same time reducing blood vessel volume, which increases blood pressure.  Angiotensin II also stimulates the production of the hormone aldosterone from the adrenal gland.  Aldosterone stimulates the tubule cells of the kidney to reabsorb salt (sodium and potassium) and water from the blood, which also increase blood volume and pressure.

ACE also degrades the enzyme bradykinin, which is a potent vasoldilator, and this action of ACE further increases blood pressure.  

ACE inhibitors for hypertension and heart failure

If the renin-angiotensin is out of balance, then blood pressure will remain too high and can result in hypertension, heart failure and kidney failure.  This is why angiotensin is the target of several drugs for cardiovascular disease, including ACE inhibitors that prevent the formation of angiotensin II from Angiotensin I.

ACE inhibitors are used to treat hypertension and congestive heart failure and work by inhibiting the action of Angiotensin Converting Enzyme and this action reduces blood volume, widens blood vessels and lowers blood pressure.  They also reduce the production of aldosterone, which reduces uptake of salt and water by the kidneys and reduces blood volume and fluid retention in the tissues.  ACE inhibitors also prevent the degradation of bradykinin, which further lowers blood pressure. 

The combined actions of ACE inhibitors reduces the force needed for the heart to pump blood around the body and helps weakened heart muscle to work more efficiently, also reducing excess water that is retained in body tissues causing swelling (oedema), as a result of congestive heart failure. 

Blood clots 

Haemostasis is the process of preventing bleeding from a damaged blood vessel to keep blood flowing through the artery or vein.  Injury or damage to a blood vessel wall initiates the formation of a blood clot or thrombus to block the site of the damage and prevent bleeding, which if severe can cause haemorrhage or severe bleeding from a ruptured blood vessel.  However a thrombus can form even if the vessel wall is not ruptured as a result of damage by cholesterol deposits; smoking; high blood pressure; or from blood pooling due to atrial fibrillation.  If the thrombus grows into the lumen of the blood vessel it can cause a blockage resulting restriction of blood flow to the heart or brain and this can result in stroke or heart attack. 

Platelet aggregation and thrombus formation 

Blood platelets (thrombocytes), which are the smallest cell type of the blood and are not true cells as they lack a nucleus, play an important role in haemostasis by initiating thrombus formation.  Thrombosis formation is a complex process that begins with platelet aggregation (or clumping).  Platelets are normally prevented from aggregating by factors produced by the endothelial cells that line the blood vessel walls.  When the vessel wall is damaged, this exposes collagen in the vessel wall, which triggers platelets to begin clumping and then they release their own aggregating factors to amplify the process.  One of these factors called adenosine diphosphate (ADP) binds to a specific receptor on the platelet surface.  Platelet aggregation is also triggered by thrombin a protein in the blood that forms part of the coagulation cascade.  A common cause of vessel injury in cardiovascular disease is when an artery wall, hardened by build-up of cholesterol, ruptures exposing an atherosclerotic plaque and this triggers platelet aggregation.

Blood coagulation

The coagulation cascade is activated at the same time as platelet aggregation by the exposure of collagen and tissue factor and involves a series of reactions in which inactive blood enzymes are converted to their active form.  The end product of the coagulation cascade is the conversion of the soluble protein fibrinogen to an insoluble fibrous protein called fibrin, which mixes with the clumps of aggregated plates to form the thrombus.  Several of the coagulation proteins are synthesised in the liver and are dependent on Vitamin K as a cofactor for their production.  The anticoagulants that target vitamin K dependent coagulation factors work by depleting the body’s supply of vitamin K and thereby, preventing the synthesis of these coagulation factors.

Anti-platelet drugs and anticoagulants

Anti-clotting and anticoagulant medications (antithrombotic) are used to prevent the formation of a blood clot or thrombosis in conditions where it could be life threatening, such as cardiovascular disease, congestive heart failure, atrial fibrillation and reduced blood flow due to immobility. 

Antiplatelet drugs like clopidogrel work by binding to the ADP receptor on the platelet surface and inhibiting the activation of platelet aggregation.

Anticoagulants like warfarin work by inhibiting an enzyme that recycles used vitamin K after it has participated in the coagulation cascade and thereby depletes the supply of vitamin K.  This action inhibits the synthesis of Vitamin K dependent coagulation factors, which blocks the coagulation cascade and prevents the final stage of clot formation.

What is angiotensin?

Angiotensin is a naturally produced hormone that forms part of a complex interaction of hormones, known as the renin-angiotensin hormone system that regulates blood volume, body fluid levels and blood pressure.  Angiotensin is produced by the liver as angiotensinogen, which is converted to angiotensin I by the action of renin, released by the kidney when blood pressure and volume is low.  Angiotensin I is the inactive precursor for Angiotensin II, which is produced by the action of Angiotensin Converting Enzyme (ACE) mainly in the lungs, but also in the kidney and endothelial cells lining the blood vessels. 

Angiotensin II is a highly vasoactive hormone that has potent effects on blood pressure and fluid balance.  It stimulates vascular smooth muscle to contract, which causes blood vessels to constrict (narrow).  This increases blood volume while at the same time reducing blood vessel volume, which increases blood pressure.  Angiotensin II also stimulates the production of the hormone aldosterone from the adrenal gland.  Aldosterone stimulates the tubule cells of the kidney to reabsorb salt (sodium and potassium) and water from the blood, which also increase blood volume and pressure.

ACE also degrades the enzyme bradykinin, which is a potent vasoldilator, and this action of ACE further increases blood pressure.  

Angiotensin II receptor

The binding of Angiotensin II to the Angiotensin receptor (AR) activates the receptor and this mediates all the actions of Angiotensin II via a series of trans-membrane and intracellular signal transduction systems, including activation or inhibition of enzymes (activation of phospholipases C and A2 and tyrosine kinases, inhibition of adenylate cyclase) and opening of calcium channels.

The Angiotensin II receptor is widely distributed and is found on the cells of many organs and tissues of the body, including the heart, blood vessel walls, kidney, adrenal gland, lung and brain.  The consequences of activating the AR depend on which tissue the receptor is located in.  In the cortex of the adrenal gland, activation of the AR by Angiotensin II stimulates the release of aldosterone, which in turn stimulates the reuptake of salt and water in the kidney.  In the heart muscle, it causes cardiac hypertrophy or growth, which is a pathological condition associated with high blood pressure.  In the vascular smooth muscle of blood vessel walls it causes vasoconstriction and narrowing of the blood vessels, which contributes to increased blood pressure. 

Angiotensin II receptor blockers for hypertension and heart failure

The angiotensin receptor (AR) is a target for antihypertensive drugs since blocking the receptor also blocks all the actions of Angiotensin II that happen as a result of activation of the AR.  Angiotensin receptor blockers (ARBs) cause vasodilation or widening of the blood vessels, which reduces blood pressure.  They also reduce the production of aldosterone, which reduces uptake of salt and water by the kidneys, blood volume and fluid retention in the tissues, and therefore, ARBs are suitable for treating congestive heart failure. 

Unlike ACE inhibitors, ARBs do not prevent the degradation of bradykinin, which further lowers blood pressure but also causes persistent dry cough as a side effect due to bradykinin.  Therefore, ARBs are often used for those intolerant to ACE inhibitors.  

Hypertension

Beta blockers are used to treat and manage hypertension to lower high blood pressure. Blood pressure is the force needed to pump blood around the body. Blood pressure measurements are divided into systolic pressure, which is when the heart contracts forcing blood out into the arteries, and diastolic when the heart rests and fills with blood. Hypertension is high blood pressure at rest and causes reduced blood flow, increases the force needed to pump blood around the body, increases workload on the heart and increases oxygen demand. This can cause damage to blood vessels as well as end organ tissue damage to the kidneys, eyes and nerves. Hypertension also increases risk of cardiovascular disease, including stroke and heart attack.

Heart conditions

Beta blockers are used to treat and manage several cardiovascular conditions, including:

• Angina, which is caused by narrowing of the arteries that supply the heart (coronary arteries) reducing blood flow to the heart and causing symptoms like discomfort or pain in the chest and breathlessness on exertion.


• Heart failure, which is inefficient pumping of the heart so that it cannot maintain an adequate circulation of blood and is due to weakened heart muscle caused by a previous heart attack, high blood pressure or an enlarged heart (cardiomyopathy). Symptoms include oedema (fluid in the tissues) and breathlessness.


• Irregular heart beat also known as dysrhythmia or arrhythmia, which is due to abnormal electrical activity to the heart resulting in a heart beat that is too fast or slow or irregular. It has several known causes, including high blood pressure or heart disease, with symptoms including heart palpitations and shortness of breath.


• Heart attack (myocardial infarction), which is when blood flow to the heart is blocked and the heart muscle does not get enough oxygen so that cells begin to die. Beta blockers can help prevent serious damage to the heart during early stages of acute myocardial infarction and can help with prevention of further heart attacks.

How do beta blockers work?

Beta blockers work by binding to beta adrenergic receptors in the heart blocking the action of chemicals like adrenaline that are released by the adrenal glands in response to nerve stimulation during physical and mental stress. Adrenaline stimulates increased heart rate and constriction (narrowing) of blood vessels and beta blockers reverse this action to slow heart rate, dilate (widen) blood vessels, lower blood pressure, and increase blood flow and oxygen to the heart. Several beta blockers are available, including the cardioselective beta 1 receptor blockers atenolol, metoprolol, carvedilol; also nadolol, which is non-selective and also binds to beta 2 receptors in the bronchial smooth muscle in the lungs and vascular smooth muscle.

What are calcium channels?

Calcium channels are openings in the membrane of electrically excitable cells such as nerve cells and muscle cells.  They lead directly from the inside to the outside of a cell and regulate the amount of calcium that enters and leaves a cell.  The concentration of calcium is normally much higher outside the cell, but when triggered by certain stimuli, the cell membrane depolarises and calcium channels open to allow an influx of calcium into the cell, which results in different reactions, depending on the type of cells.  In smooth muscle cells, such as are found in the blood vessels walls, and in cardiac muscle of the heart, the response is for the cells to contract.  This causes narrowing of the blood vessels and increases the force and rate of contraction of the heart, which increase blood pressure.   

How calcium channels blockers work

Calcium channels blockers prevent the entry of calcium into smooth muscle cells, which inhibits contraction of these cells allowing them to widen and dilate, a process called vasodilation.  The result of vasodilation is to reduce resistance in peripheral blood vessels, which reduces blood pressure and this in turn reduces the force needed for the heart to pump blood around the body and thereby reduces its oxygen requirement.  The overall effect of calcium channels blockers helps reduce symptoms of cardiovascular disease, such as angina. 

calcium channels blockers for cardiovascular disease and hypertension

Calcium channel blockers are used to treat hypertension and reduce symptoms of cardiovascular disease, such as angina.

The Calcium channel blockers available include nifedipine, amlodipine, diltiazem, felodipine and verapamil

What is cholesterol?

Cholesterol is an insoluble fatty substance that is needed by the body for many functions, such as building cell membranes, producing certain hormones and transporting fat soluble vitamins around the body. It is made in the liver and also obtained from the diet. Cholesterol is transported in the blood along with triglycerides, which is another type of fat. Since cholesterol is not soluble in blood it is carried to and from the liver by lipoproteins. These include low density lipoproteins (LDL) known as “bad” cholesterol because they carry cholesterol from the liver and deposit excess in the arteries. High density lipoproteins (HDL) carry cholesterol back to the liver and are therefore called “good” cholesterol.

High cholesterol and atherosclerosis

If there is more cholesterol in the blood than the body needs, it becomes deposited in the artery walls where it can build up, blocking the arteries and causing hardened areas called plaques, which increases risk of heart disease. This condition is known as atherosclerosis. High cholesterol in the blood and other fats (triglycerides) is known as hypercholesterolaemia and this condition is usually due to lifestyle, including high-fat diet, obesity and lack of exercise, but it can be inherited. The ratio of total cholesterol over HDL (good cholesterol) is also an important consideration.

Cholesterol lowering medications

Cholesterol lowering medications are available to treat hypercholesterolaemia in people who have not responded to a low-fat diet and lifestyle changes alone; also for those with an inherited condition and who cannot lower cholesterol levels by lifestyle changes alone. They include:

• Statins that block the production of cholesterol by the liver, by inhibiting the action of the enzyme HMG-CoA reductase that plays an important role in cholesterol synthesis. Statins only block cholesterol produced in the liver but have no effect on cholesterol that comes from fat in the diet. Several statins are available including, atorvastatin, simvastatin, pravastatin and rosuvastatin.


• Cholesterol absorption inhibitors, like ezetimibe act directly on the small intestine wall to block the action of the sterol transporter in the intestine wall. This action inhibits intestinal absorption of cholesterol from the diet and reduces cholesterol stores in the liver, which helps lower blood cholesterol levels.


• Fibrates like fenofibrate activate the enzyme Peroxisome Proliferator Activated Receptor type alpha (PPARα) that regulates the production of another enzyme involved in the breakdown of lipids in the blood. It also reduces the production of proteins that transport LDL lipids but increases the production of proteins that transport HDL. The overall effect is to lower triglycerides, total cholesterol, and LDL (bad) cholesterol, and increase HDL (good) cholesterol.

What is oedema? 

Oedema is swelling of the tissues due to water retention, as fluid in the spaces between cells (interstitial spaces) does not drain away and accumulates.  Although some interstitial fluid is normal, damaged cells leak fluids causing oedema in various parts of the body, including the feet, ankles and lungs (pulmonary oedema) and this is caused by several conditions, including congestive heart failure.  High blood pressure can also cause blood vessels to become leaky and this forces fluid into the tissues.  

How diuretics work

Diuretics (also known as water tablets) are used to treat oedema and there are different mechanisms of action that the various diuretics work through. 

The diuretics frusemide, amiloride and hydrochlorothiazide act directly on the kidneys to promote the removal of salts and water from the blood, which increase the urine volume and decreases blood volume.  This action draws water out of the tissues and reduces resistance to blood flow in peripheral arteries, which reduces oedema and also helps lower blood pressure. 

Spironolactone has a different mechanism of action and acts as an antagonist of aldosterone, a hormone that promotes the reuptake of salts by the kidneys at the distal end of the kidney tubules.  Spironolactone is known as a potassium sparing diuretic as it promotes fluid loss from the body but also reduces loss of potassium, which can happen with other diuretics. 

Combination diuretic medications

Hydrochlorothiazide is a also available as a combination medication with an ARB, usually losartan or valsartan to provide a more effective reduction in blood pressure than each drug alone and is used to treat hypertension that cannot be controlled by a single medication; also for patients with left ventricular hypertrophy, which is thickening of the left pumping chamber as the heart works harder due to high blood pressure.  The combination of Hydrochlorothiazide with amiloride is used to treat congestive heart failure; also hypertension, in addition to other antihypertensive medications.

What is a vasodilator?

A vasodilator acts on smooth muscle cells in the blood vessel walls and causes them to relax and widen (vasodilation), which reduces resistance to blood flow, thereby increasing blood flow and allowing blood to flow more freely.  

Uses for vasodilators

Vasodilators are used to treat several conditions in which vasodilation helps improve the condition.  These include:

Hypertension

Blood pressure is the force needed to pump blood around the body.  Blood pressure measurements are divided into systolic pressure, which is when the heart contracts forcing blood out into the arteries, and diastolic when the heart rests and fills with blood.  Blood pressure measurement is expressed as systolic pressure over diastolic pressure.  Hypertension is high blood pressure at rest and causes reduced blood flow, increases the force needed to pump blood around the body, increases workload on the heart and increases oxygen demand.  This can cause damage to blood vessels as well as end organ tissue damage to the kidneys, eyes and nerves.  Hypertension also increases risk of cardiovascular disease, including stroke and heart attack. 

Angina

Angina is a symptom of coronary artery disease when the heart does not get enough oxygen and compensates by pumping harder and faster.  Symptoms include discomfort or pain in the chest and breathlessness on exertion.  Angina is not the same as heart attack as it is not caused by a blockage only a narrowing of the arteries and there is no permanent damage to the heart muscle. 

Peripheral arterial disease

Peripheral arterial disease is narrowing of the arteries due to a blockage and may be caused by atherosclerosis, thrombosis or an embolism.  Peripheral arterial disease occurs mainly in arteries supplying blood to the legs, causing pain, weakness, numbness and muscle cramps.  

Classes of vasodilators

Several classes of vasodilator are available that work by different mechanism of action.

• Oxpentifylline is used to treat conditions caused by poor circulation including peripheral artery disease.  It works by several mechanisms, including acting directly on blood vessel wall to cause vasodilation, preventing the formation of chemicals that cause vasocontriction, decreasing the viscosity of blood, reducing the formation of blood clots.
• Minoxidil is used to treat severe hypertension in addition to other medications and acts directly on smooth muscle cells in blood vessel walls causing them to relax.
• Glyceryl trinitrate is used to treat angina and is absorbed through the skin under the tongue to be converted to nitric oxide in the blood vessel walls causing rapid vasodilation and relief from symptoms. 

Blood pressure

Blood pressure is the force needed to pump blood around the body.  Blood pressure measurements are divided into systolic pressure, which is when the heart contracts forcing blood out into the arteries, and diastolic when the heart rests and fills with blood.  Blood pressure measurement is expressed as systolic pressure over diastolic pressure. 

Hypertension:

is high blood pressure at rest and causes reduced blood flow, increases the force needed to pump blood around the body, increases workload on the heart and increases oxygen demand.  This can cause damage to blood vessels as well as end organ tissue damage to the kidneys, eyes and nerves.  Hypertension also increases risk of cardiovascular disease, including stroke and heart attack. 

Hypotension:

is low blood pressure resulting in insufficient blood flow to the brain and vital organs which causes symptoms including dizziness, fainting, nausea, headache, blurred vision, numbness and tingling.  Low blood pressure can be due to several conditions including dehydration, loss of blood or as a result of a neurological condition, or secondary to a condition like diabetes.  Orthostatic or postural hypotension is a sudden drop in blood pressure when changing position from lying or sitting to standing, caused by pooling of blood in the extremities, thereby reducing the volume of blood available to be pumped by the heart to the brain and vital organs. 

Adrenergic receptors and blood pressure

Adrenergic receptors bind to specific chemicals that cause contraction of blood vessel walls or vasoconstriction, like the neurotransmitters adrenaline and noradrenaline.  Vasoconstriction increases resistance to blood flow, which increases blood pressure.  Vasodilation or relaxation of blood vessels reduces resistance to blood flow, which lowers blood pressure.  

Adrenergic receptors exist as alpha and beta forms and alpha receptors have the subtypes alpha1 and alpha 2.  Both alpha subtypes are found in smooth muscle such as in blood vessels and promote vasoconstriction in response to binding of adrenaline and noradrenaline to the receptor.  Alpha 2 receptors are also found in the central nervous system, where they inhibit the release of adrenaline and noradrenaline when activated.  

Drugs that target adrenergic receptors to reduce blood pressure

Several drugs are used to treat high blood pressure by interacting with alpha adrenergic receptors:

• Doxazosin is an alpha-1 adrenergic antagonist that blocks the direct action of vasoconstrictors like adrenaline and noradrenaline on smooth muscle of the blood vessels
• Clonidine is an alpha-2 adrenergic agonist that acts on the central nervous system and stimulates receptors in the brain that inhibits the release of adrenaline and noradrenaline, which reduces vasoconstriction.  It also acts to slow heart rate due to stimulation by the vagus nerve . 

Drugs that target adrenergic receptors to increase blood pressure

Midodrine is a produg for desglymidodrine, a potent alpha adrenergic agonist that binds to alpha 1 adrenergic receptor in smooth muscle of blood vessels and mimics the action of neurotransmitters like noradrenaline that cause vasoconstriction.  This action increases blood pressure. 

Drugs that target cardiac muscle

Cardiac muscle is a type of muscle only found in the heart and contraction of cardiac muscle propels blood through the chambers of the heart and around the body.  Heart failure is a condition in which the heart muscle no longer pumps efficiently and results in symptoms including shortness of breath and oedema (water retention in the tissues) causing swelling.  Arrhythmias like atrial fibrillation result in irregular heart beat and are caused by abnormal electrical activity in the heart. 

Drugs known as cardiac glycosides, like digoxin act directly on the heart muscle to slow down the rate but increase the force of contraction to improve pumping efficiency, which helps reduce symptoms of heart failure.

Digoxin also corrects abnormal electrical activity in the heart by acting on the ion pump (Na+/K+ pump) in the membrane of heart cells.  This action helps restore normal heart beat in the treatment of arrhythmias.