Angiotensin effects

Figure 1.5. The renin-angiotensin system, a) Angiotensinogen is cleaved site-specifically by renin to yield angiotensin I. The latter is converted by another specific protease (angiotensin con-vertase or converting enzyme) to angiotensin 11. b) Angiotensin effects vasoconstriction by acting on a G protein-conpled receptor that is fonnd on smooth mnscle cells. This nltimately leads to increased availability of free Ca in the cytosol and contraction of the smooth mnscle cells.

ACE-I. However, because ARBs do not block the metabolism or increase the levels of bradykinin, they are less likely to be associated with nonrenin-angiotensin effects such as cough and angioedema. 

ANPs play an important role in the maintenance of cardiovascular homeostasis by counterbalancing the renin—angiotensin (RAS) system. ANP, the main circulating form of the natriuretic peptides, effectively relaxes vascular smooth muscle, promotes the excretion of sodium and water, and in the CNS inhibits vasopressin release and antagonizes AT-II induced thirst. 

The primary effects of angiotensin II ate (/) produciag vasoconstriction directiy or iadirectiy through activation of the adrenergic nervous system ... 

Indapamide has been shown to possess diuretic and iadependent vasodilatory effects (16). It lowers the elevated blood pressure and reduces total peripheral resistance without an iacrease ia heart rate. ladapamide antagoni2es the vasocoastrictiag effects of the catecholamiaes and angiotensin II (16), a property not shared by other thia2ide-type diuretics. Tripamide is also reported to have direct vasodilatory effects (13). 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

ACE not only activates angiotensin but is also involved in the metabolism of other peptides, e.g., it is a major kinin-degrading enzyme. Therefore, ACE inhibitors also increase kinin concentrations. Furthermore, it has recently been shown that these drugs potentiate kinin effects by modulating a direct interaction between the ACE protein and the kinin B2 receptor, which is independent from the enzymatic activity of ACE. Kinin potentiation may be involved in the beneficial action of ACE inhibition since kinins are known to exert cardio- and renoprotective actions. 

However, it is also the major reason for the adverse side effects of ACE inhibitors, namely cough and angio-oedema. Another observed side effect, first-dose orthostatic hypotension, is probably due to both angiotensin inhibition and kinin potentiation. 

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