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

Hypertension

The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II.

It can increase blood pressure by constricting the blood vessels. It can also trigger thirst or the desire for salt. Angiotensin is responsible for the release of the pituitary gland's anti-diuretic hormone.

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

Angiotensin blockers do not affect the metabolism of bradykinin which is responsible for the side effect of a dry cough, it decreases the renin produced. ACE inhibitors affect the metabolism of bradykinin therefore the side effect of dry cough is experienced. It also has a serious vasodilating effect.

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

ACE inhibitors block the conversion ANG I and ANG II it also blocks the metabolism of bradykinin to an inactive metabolite. ANG II causes an increase in Blood pressure thus by blocking the conversion of ANG I to ANG II ACE inhibitors decrease blood pressure significantly.

• 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?

Losartan, is a selective non-peptide antagonist blocking the AT1 receptors. They influence AT2 receptors when Angiotensin 2 is increased.

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

Kinins are proteins in the blood that cause inflammation and affect blood pressure (especially low blood pressure). They also: Increase blood flow throughout the body. Make it easier for fluids to pass through small blood vessels. Through bradykinin ability to elevate vascular permeability and to cause vasodilatation in some arteries and veins. Kinins are potent vasodilators and increase the blood flow in the body.Autocoids such as Histamine and Serotonin also play a role in this action Histamine - H1 and H2 receptors dilatate blood vessels and capillaries.

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

Kinins are a family of peptides implicated in several pathophysiological events. Most of their effects are likely mediated by the activation of two G-protein-coupled receptors: B₁ and B₂.

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

Agonists binding to ANP receptors cause vasodilation with increased glomerular filtration rate and enhanced Na⁺ and water excretion, while BNP receptor stimulation inhibits renin production. These peptides reduce blood pressure through vasodilation of both the arterial and venous systems 

• What is neprylisine 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.

Neprilysin enzyme is also called neutral endopeptidase that plays a role in the degradation of natriuretic peptides and other vasoactive peptides including bradykinin. Natriuretic peptides remove sodium from the blood and excrete it in the urine.

Neprilysin inhibitors are a new class of drugs used to treat high blood pressure and heart failure. They work by blocking the action of neprilysin thus preventing the breakdown of natriuretic peptides. The drug used is sacubitril  

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasodilators – Nitric Oxide

Vasoconstrictors - ET1