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

Disease like hypertension and heart failure has increased angiotensinogen levels because of the over activity of the RAAS.

An increase in angiotensinogen leads to an increase in the amount of angiotensin I that is converted by renin. There are higher levels of angiotensin I that can be converted into angiotensin II. This causes hypertension, cardiac and vascular hypertrophy and systemic vasoconstriction.

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

Drugs that inhibit the angiotensinogen system have a complete blockage of the angiotensin receptors compared to drugs that inhibits the ACE. Bradykinin does not increase which leads to fewer side effects. ACE inhibitors are non-selective while the angiotensin blockers are selective. This leads to the angiotensin blockers having less effects.

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

ACE inhibitors inhibits the conversion of angiotensin I to angiotensin II and the conversion of Bradykinin to Inactive peptide. Bradykinin will increase which causes an increase in PG synthesis, vasodilation, a decrease in peripheral vascular resistance which leads to a decrease in 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?

It acts on angiotensin II receptors by blocking it (antagonist). It also has action on angiotensin I receptors.

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

Kinins are potent vasodilators. It increases cAMP, IP3, Dag, NO, PG and capillary permeability. Prostaglandins also have a role here.

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

Bradykinin receptors

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

Vasodilators increase glomerular filtration and decrease renin secretion and aldosterone mechanism which leads to a decrease in Na reabsorption, it also inhibits angiotensin II. There is a decrease in the effect of angiotensin, aldosterone and Na secretion.

• 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.

Neprylisine is ‘n neutral endopeptidase that metabolize natriuretic peptides. Inhibition of this leads to a increase in the circulating levels of natriuretic peptides and an increase in natriuresis and diuresis.

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Vasoconstrictors: Endothelin

Vasodilators: PGI₂, NO, Vasoactive intestinal peptide