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

Hypertension and cardiac hypertrophy

When angiotensinogen levels increase, more angiotensinogen will be converted to ANG I by renin. ACE converts ANG I to ANG II, which then increase blood pressure, ANG II also increase aldosterone release in the adrenal cortex. ANG II also contribute to cardac hypertrophy which can lead to miocardial infarction which leads to heart failure.

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

ACE inhibitors, not only inhibit the conversion of ANG to ANG II, but also prevent bradykinin metabolism. Which leads to level of bradykinin increasing, and can acuse side effects like dry cough.

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

ACE inhibitors works in two ways, 1. Inhibiting the conversion of ANG I to ANG II, and 2. Blocking ANG II type 1 receptors. This causes vasoconstriction, decreasing peripheral resistance and lowering blood pressure. Aldosterone levels decrease, leading to less salt and water retention which decrease CO, cardiac preload and lower blood pressure. ACE inhibitors also prevent bradykinin metabolism which can lead to increased levels of bradykinin and increase arterial vasodilation, lower PR and lowers blood pressure.

• 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 and similar drugs are competitive antagonists at angiotensin AT₁ receptors, but has no effect of angiotensin 2 receptors.

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

Kinins produce arteriolar dilation which is an effect of kinins on arteriolar smooth muscle mediated by nitrite oxide of vasodilation prostaglandins. Kinins causes contraction in veins due to contraction in visceral smooth muscle.

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

Bradykinin 2 receptors.

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

Natriuretic peptides causes vasodilation that leads to decrease in PR and lowers blood pressure in patients with hypertension. These peptides also increase glomerular filtration which leads to more sodium excretion and decreasing sodium reabsorption, thus treating oedema that is associated with congestive heart failure.

• 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 metabolises natriuretic peptides, inhibiting Neprilysin leading vasodilation of ANP and BNP level increase and increase in renin secretion leading to higher levels of ANG II, helping in treatment of heart failure. 

Drug name: Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Vasodilators: Bosentan, macitentan, ambrisentan, sitaxsentan.

Vasoconstrictors: Endothelin 1,2,3