1. In which diseases are angiotensinogen levels increased? What are the implications of this?

Hyperthyroidism, hypertension and heart failure causes an increase in angiotensinogen levels. Increased levels of angiotensinogen can lead to increased Angiotensin 1 and 2 .This is because angiotensinogen is the molecule required for ANG 1 and 2 formation. This leads to hypertension due to due to vasoconstrictive effects of increased ANG 2 binding to AT-2 receptors and disorders of fluid and electrolyte balance in the body due to increased aldosterone release.

2. Why do drugs which inhibit the angiotensinogen system by acting on angiotensin receptors have fewer side effects than those that inhibit ACE?

ACE inhibitors may cause a dry cough and angioedema due to the increased levels of bradykinin. Due to the fact that angiotensinogen receptor blockers do not have an effect on bradykinin there is little to no dry cough as a side effect.

3. In which way do ACE inhibitors have a two-fold mechanism of action in the treatment of hypertension?

ACE inhibitors block the conversion of ANG I to ANG II and also inhibit the degradation of other substances such as bradykinin, substance P and enkephalins. Therefore, the action of ACE inhibitors to inhibit bradykinin and other substances contributes to the treatment of hypertension.

4. At which type of angiotensin receptor do losartan and similar drugs act?  Do they have any effect, direct or indirect, at other angiotensin II receptors?

The drugs act at AT1 receptors and when Angiotensin II is increased, they act on the AT2 receptors. They have no direct activity at the AT-2 receptor. They can have an indirect effect on the AT-2 receptor.

5. What are the physiological effects of kinins on arteries and veins?  Do other autacoids play a role in this action?  Explain.

Kinins cause vasodilation on arteries due to the direct inhibitory effect of kinins on arteriolar smooth muscle or it is mediated by the release of nitric oxide or vasodilator prostaglandins such as PGE2 and PGI2. The kinins are potent vasodilators of the arteries and veins. Their physiological role is mediated by G-proteins and their second messengers. Autacoids such as bradykinin play a role as bradykinin is a potent vasodilator.

6. Which receptor is probably the most involved in the important clinical effects of kinins?

B-2 receptor

7. In which way are natriuretic peptides possibly effective in the treatment of hypertension, as well as congestive heart failure?

Drugs that combine neprilysin inhibition with ACE inhibition (vasopeptidase inhibitors) include omapatrilat, sampatrilat and fasidotrilat lower the blood pressure in hypertensive patients and improve cardiac function in patients with heart failure. The natriuretic peptides such as carperitide, nesiritide, ularitide, urodilatin cause vasodilation and natriuresis for the treatment of congestive heart failure. They also reduce sodium reabsorption which aids in the bodies fluid balance and thus reduces oedema that is caused by congestive heart failure.

8. What is neprilysin and what is the rationale for inhibiting its action in the treatment of heart failure? Can you name the drug being used as such? Refer to Study unit 1 where you have also come across this drug.

Neprylisine is a neutral endopeptidase that is responsible for the degradation of natriuretic peptides in the kidneys, liver and lungs. By inhibiting its action, we can increase circulating levels of ANP and BNP which can lead to diuresis and natriuresis which reduces oedema caused by heart failure and thus reduces the pre and after load on the heart which can all aid in treating heart failure. The drug is Sacubitril.

9. Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasodilators- PGI2 and NO

Vasoconstrictors- Endothelins (ET-1, ET-2 and ET-3)