1.In what disease states were angiotensinogen levels increased? What are the implications of this?
Hypertension and heart failure, because there is an over activity of renin-angiotensin-aldosterone system (RAAS). This leads to more angiotensin II in the body and thus it will increase the production of angiotensinogen. The implication of this is more angiotensinogen is present for the formation of angiotensin II which worsens the disease state because it causes vasoconstriction effects for example.

2.What is the reason why drugs that inhibit the angiotensin system by acting on angiotensin receptors have fewer side effects than those that inhibit AOE?
The angiotensin antagonists act directly on the receptors and will immediately elicit the therapeutic effect without exerting an effect on another system and thus there are fewer side effects present, where with the ACE inhibitors it will have an effect on the bradikini system. AOE converts bradykinin to its inactive peptide, when the enzyme is inhibited it means there will be increased levels of bradikinin. These high levels give rise to side effects, namely a dry cough and bronchoconstriction, which can have a bad effect on asthma leaders, for example.

3.In what way do ACE inhibitors have a dual mechanism of action in the treatment of hypertension?
AOE acts on two systems namely where angiotensin II is formed and bradykinin is converted to inactive form.
 When AOE is inhibited it gives rise to the inhibition of angiotensin II formation because it means angiotensin II is not present to elicit vasoconstrictive and increase in blood volume effects so blood pressure will decrease.
Bradykinin has hypotensive activity because it is a vasodilator and if the AOE is not present to convert bradikinin to inactive peptide, it means that there is an increased concentration of bradikinin present and therefore a greater effect on the decrease in blood pressure.

4.What type of angiotensin receptors does losartan and similar drugs work on? Do they have any effects, directly or indirectly, on other angiotensin II receptors?
Lorsartan is a competing antagonist and acts on the AT1 receptors. They have an indirect effect on AT2 receptors. This is because the long use of these antagonists can lead to an increase in renin release and therefore there is an increase in angiotensin II that can bind to these AT2 receptors and elicit a vasodilatory effect that can be beneficial for treatment.

5.What are the physiological effects of quinines on arteries and veins? Do other autacoids play a role in this action? Explain.
The physiological effect is arterial dilatation and venous contraction, other autacoids namely prostaglandins also play a role in the blood vessels because they are released in response to quinines.

6.Which receptor is probably most involved in the clinically important effects of quinines?
Bradycin receptors. (B1 & B2)

7.In what ways are natriuretic peptides potentially effective in treating hypertension as well as congestive heart failure?
Atrial natriuretic peptide (ANP) and Brain natriuretic peptide (BNP) are both effective in both conditions because they are vasodilatory and decrease blood volume by inducing natriuresis and diuresis. This can lead to a decrease in blood pressure as well as preload and afterload on the heart.

8.What is neprylisine and what is the rationale for inhibiting its activity in the treatment of heart failure. Can you name the remedy that is used as such. Also refer to study unit 1 where you also dealt with the specific remedy.
Niprylisine is the enzyme that breaks down ANP and BNP. A niprylisine inhibitor such as Sucubitril is effective in treating heart failure because it prevents the breakdown of ANP and BNP which means they increase their concentration. This therefore leads to a better effect of natriuresis and diuresis which decreases the blood volume and it relieves tension on the heart. This drug can be combined with valsartan, valsartan is an angiotensin II antagonist and will therefore counteract the effects of RAAS. The name of the combined remedy is Entresto.

9.Give examples of endothelial-derived vasodilators and vasoconstrictors.
Vasodilators: Bosentan. (endothelial antagonist)
Vasoconstrictors: Endothelin 1, 2 and 3.