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

Increased angiotensin II levels are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased Ang II levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension

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

ACE inhibitors influence bradykins and angiotension II and the Angiotension inhibitors only influence angiotension.

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

ACE inhibitors are considered to have a two-fold mechanism of action in treatment of hypertension, as these inhibitors prevent the conversion of:

Angiotensin I to angiotensin II, thus inhibiting the release of aldosterone. Aldosterone-release inhibition promotes water and salt excretion, decreasing fluid volume and eventually blood pressure. Bradykinin to an active metabolite. Bradykinin is a vasodilator which widens the blood vessels allowing easier flow of blood, eventually decreasing blood pressure. 

4. 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 an angiotensin II receptor blocker and is used to treat hypertension. Losartan competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with more affinity than they bind to the AT₂ receptor, thus having a direct effect on the angiotensin II receptors.

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

They dilate the arteries and veins. Other autocoids like nitric oxide or vasodilator prostaglandins (PGE₂ & PGI₂) can also play a role in this action by acting as mediators.

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

Beta-2-blockers

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

They cause a compensatory increase in renin secretion and plasma angiotensin 2 levels, which will then reduce blood pressure and help in the treatment of hypertension. In heart failure, they cause vasodilation and natriuresis.

8. 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. 

Neprilisien is 'n ensiem wat natriuretiese peptiede afbreek. Sacubitril wat 'n neprilisien inhibeer is word saam met Valsartan gebruik vir behandeling van hartversaking. 

9. Give examples of endothelium-derived vasodilators and vasoconstrictors. 

• NO (Nitric Oxide) is an endothelium-derived vasodilator.
• ET-1 is an endothelium-derived vasoconstrictor.

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