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

Hypertension.

An increase in angiotensinogen cause an increase in conversion to angiotensin I through renin. ACE (angiotensin converting enzyme) converts angiotensin I to angiotensin II which activates angiotensin II type 1 receptors. This cause vasoconstriction ( and an increase in peripheral resistance and BP), an increase in aldosterone secretion (increased Na and H2O reabsorption and increased bood volume) and cardiac hypertrophy and remodelling which will aggravate hypertension further. This can 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?

Drugs which blocks ACE will also lead to the inhibition of bradykinin breakdown. Increased bradykinin concentrations cause bradykinin 2 receptor mediated bronchoconstriction (a vagal cough reflex) which cause the negative side-effect of a dry, irritating cough.

Drugs which act specifically on angiotensin receptors will not inhibit bradykinin breakdown and thus will not have this adverse effect because; [bradykinin] will not be increased.

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

ACE inhibitors firstly block the conversion of angiotensin I to angiotensin II. Angiotensin II type I receptors are also blocked. This leads to vasodilation instead of vasoconstriction which leads to a decrease in peripheral resistance and BP. Aldosterone secretion decreases which leads to less salt and water retention and more excretion which lowers cardiac preload, decrease cardiac output and decrease BP. Left ventricular hypertrophy is also reversed.

ACE inhibitors also inhibit bradykinin breakdown. Increased bradykinin concentrations, increase prostaglandin synthesis which increase arterial vasodilation, lowers peripheral resistance and lowers BP. This is all therapeutically useful in hypertension.

• 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?

They act on angiotensin II type 1 receptors. They have no affect on angiotensin II type 2 receptors.

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

Kinins cause vasodilation of arteries and vasoconstriction of veins. Yes, there are many other autacoids that also cause vasodilation; Natriuretic peptides, vasoactive intestinal peptides, substance P, neurokinin A, neurokinin B, Calcitonin gene-related peptide.

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

Bradykinin 2 receptors

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

Natriuretic peptides cause vasodilation which decrease peripheral resistance and decrease BP that can be effective in treating hypertension.

Natriuretic peptides increase glomerular filtration and sodium excretion, decrease renin secretion, decrease sodium reabsorption and decrease the effect of angiotensin and aldosterone. This will relieve the oedema associated with congestive heart failure.

• 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 metabolizes the natriuretic peptides ANP and BNP which lead to a decrease in their concentrations. In reducing ANP and BNP, their positive therapeutic effects in congestive heart failure is also reduced (less vasodilation and rather vasoconstriction,  decreased glomerular filtration and sodium excretion, increased renin secretion, increased sodium reabsorption and increased effect of angiotensin and aldosterone). Thus neprilysin should be blocked so that the therapeutic positive effects of ANP and BNP can dominate.

Neprilysin inhibitor drug: Sacubitril

• Give examples of endothelium-derived vasodilators and vasoconstrictors.

Endothelium derived vasodilators: PGI2, NO (nitric oxide)

Endothelium derived vasoconstrictors: ET1, ET2, ET3, ETA, ETB

Endothelium antagonists that cause vasodilation: Bosentan, macitentan, ambrisentan, sitaxsentan.