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

Angiotensinogen is increased in hypertension and heart failure. Increased levels of angiotensinogen increases the amount of angiotensin I that can be converted into angiotensin II, thus decreasing the amount of bradykinin in the body, which causes an increase in vasoconstriction. This leads to hypertension, retention of fluid into the urinary tract and ventricular hypertophy.

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 more complete blockage of the angiotensin system than ACE inhibitors, thus there is no increase in bradykinin, which leads to fewer side effects. The angiotensin blockers are also more selective than the non-selective ACE inhibitors, thus it will have less effects since the non-selective ACE inhibitors.

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

ACE inhibitors first inhibits the conversion of angiotensin I to angiotensin II, which increases bradykinin, which causes vasodilation and thus a decrease in blood pressure. It also decreases peripheral ventricular 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?

Losartan acts on the agiotensin II receptors by blocking it, it also has action on the 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 capilliary permeability. Prostaglandins also play a role here.

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

Bradykinin receptors (1&2)

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

• VASODILATOR
• increase glomerular filtration
• deacrese renin secretion & Aldosterone mechanism (↓Na reabsorption) & inhibit angiotensin II.
• ↓ effect of Angiotensin and 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.

it is a neutral endopeptidase which is responisble the breakdown of natiuretic peptides in the kidney liver and lungs.

inhibition of this increases circulating levels of ANP and BNP and thus causes natriuresis and diureses. (Sacubitril)

Give examples of endothelium-derived vasodilators and vasoconstrictors.

vasodilators: PGI₂ & NO

vasoconstrictors: Endothelin - ET₁, ET₂, ET₃