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

Hypertension, angiotensin synthesis is stimulated by estrogens, angiotensin II, thyroid hormone and glucocorticoids. Increased  levels of angiotensin can cause the body to retain too much fluid or to have elevated blood pressure levels. High angiotensin levels can also lead 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 lower blood pressure by preventing the production of angiotensin II while angiotensin receptor blockers reduce the action of angiotensin  to prevent blood vessel constriction. Angiotensin receptor blockers give a bigger decrease in cardiovascular effects than ACE inhibitors especially in patients with cardiovascular diseases.

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

ACE inhibitors inhibit the synthesis of Angiotensin II by stimulating the dilation of blood vessels. They inhibit the breakdown of bradykinin to an active metabolite which decreases 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?

AT₁ receptors , they  have indirect effects on angiotensin II receptors

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

Kinins produce marked arteriolar direction in several vascular beds, including heart and skeletal muscle. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle.  They maybe mediated by the release of NO, vasodilator prostaglandin such PGE₂ and PGI₂.

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

Beta 1 and Beta 2 receptors.

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

They are vasodilators. ANP is released in atria after tension on heart ventricles.

• 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.

Inhibition of neprilysine blocks angiotensin II type-1-receptor, increasing the levels of peptide degraded by neprilysine. Neprilysine has a biological function of metabolizing ANP and clearing it from circulation. Sacubitril & Valsartan.

• Give examples of endothelium-derived vasodilators and vasoconstrictors. 

Endothelium-derived vasodilators: Nitric Oxide (NO) and Prostacyclin (PG1₂)

Endothelium-derived vasoconstrictors:  Thromboxane(TXA₂₎ and Endothelin-1 (ET-1).