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

Elevated levels of Angiotensinogen is associated with the following diseases:

- High Blood pressure, Ischemic heart disease, Ischemic cerebrovascular disease.

The implications of these diseased conditions include the occurrence of cardiac as well as vascular hypertrophy. This will ultimately lead to decreased cardiac output, vasoconstriction, increased blood volume due to increased renal Na+ and H2O retention.It can develop into a stroke and cell death.

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

ACE inhibitor administration leads to an increase in Bradykinin activity for it decreases the extent of Bradykinin's metabolism. Bradykinin then interacts  with a number of systems due tot non-specificity and leads to the  serious cough which is unwanted. It also has a serious vasodilating effect. The inhibitors of  the angiotensinogen system only works in on this system by decreasing the renin produced, renin enzymatic actions, the conversion of ANG1 to ANG2, and extreme selective blockage of the AT1 receptors (which cause vasoconstriction).

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

The ACE inhibitors:

Prevents the metabolism of Bradykinin allowing this molecule to exert its vasodilating effects on the vasculature, this leads to a decrease in vascular resistance and so a decrease in hypertension.

They also decrease the peripheral vascular resistance, hence vasodilation occurs and a decrease in blood pressure is seen.

• 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 2 receptor antagonist.

These drugs block (direct effect) the AT1 receptor, which is under normal conditions responsible for vasoconstriction. Thus these drugs will lead to an indirect effect which includes the subsequent domination of the AT receptor's biological effect (Vasodilation). 

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

Kinins are vasodilator peptides. Thus the diameter of the lumen of the veins and especially arteries will increase. Other autacoids such as histamine, serotonin also play a role in this action for NO & PGI is released after the activation of the kinin (ex, bradykinin).

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

Bradykinin 2 receptor (B2)

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

Natriuretic peptides lead to  the following physiological occurrences:

- Increased renin production, increased ANG2, vasodilation and natriuresis.

Thus these effects will cause a decrease in the peripheral vascular resistance, counteracting the high vascular resistance required to establish hypertension. It is also used in congestive heart failure seeing that the cardiac load is decreased by the use of this drug due to vasodilation, volume decrease and so an overall decrease in the cardiac output. Making it better and safer for the failing heart.

• 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 is the catalytic enzyme that break down the Natriuretic peptides to their metabolites and so inactivate them. The rationale of inhibiting this (ANRi usage) is to ensure an increase in the systemic concentration of the Natriuretic peptides and so ensure that their physiological effects (as mentioned above) will predominate the cardiovascular system. Ultimately decrease cardiac work.

ANRi drug name: Sacubitril & Entresto.

• Give examples of endothelium-derived vasodilators and vasoconstrictors

Vasodilators: Bosentan, NO, PGI2, vasoactive intestinal  peptide, Substance P, Neurokinin A/B.

Vasoconstrictors: ET1,2,3 & ETA receptor stimulants, Neuropeptide Y