RAAS Physiology as a Pharmacotherapy Target
The main task of the RAAS is the regulation of resistance vessel tone, circulating blood volume (CBV), and electrolyte composition. The biochemical cascade of reactions is as follows:
- Renin secretion. The process is triggered in the juxtaglomerular cells of the kidneys in case of insufficient blood supply or stimulation of $\beta_1$-adrenergic receptors. The released renin acts as an enzyme: in the systemic circulation, it finds the inactive precursor angiotensinogen and converts it into angiotensin I.
- Formation of angiotensin II. Angiotensin I meets angiotensin-converting enzyme (ACE). This enzyme has synonyms: kininase II and peptidyl-dipeptidase A. ACE cleaves two amino acid residues from the precursor, resulting in the formation of the active octapeptide — angiotensin II — in the systemic circulation.
- Realization of vascular effects. The active octapeptide stimulates $AT_1$ receptors of the smooth muscle of resistance vessels. This leads to an increase in total peripheral vascular resistance (TPVR) and an elevation in blood pressure (BP).
- Aldosterone pathway. Additionally, angiotensin II stimulates $AT_1$ receptors of the adrenal cortex, prompting them to secrete the mineralocorticoid aldosterone. It acts on the epithelial receptors of the distal convoluted tubules and collecting ducts of the kidneys, increasing the number of sodium channels there. Sodium ions (Na^+) are actively reabsorbed, drawing water along with them. Result: extracellular fluid volume and CBV increase, which further elevates blood pressure.
Classification of Drugs by Mechanism of Action
Depending on which stage the cascade described above is interrupted at, three main groups of drugs are distinguished:
- Inhibiting renin secretion. These include $\beta$-blockers, which deprive the juxtaglomerular apparatus of the stimulating signal.
- Disrupting the formation of angiotensin II. This group includes ACE inhibitors (ACEIs) and vasopeptidase inhibitors. They turn off the enzyme that assembles the active octapeptide.
- Preventing the action of angiotensin II. These are $AT_1$ receptor blockers (sartans). They do not interfere with the synthesis of substances, but block the target receptors.
ACE Inhibitors: Characteristics and Application
Angiotensin-converting enzyme inhibitors (ACEIs) exert their antihypertensive effect by affecting two systems simultaneously: the RAAS and the kinin system. In clinical practice, they are used for arterial hypertension (especially when RAAS activity is elevated) and chronic congestive heart failure.
According to the duration of action, the group is strictly divided into two categories:
- Short-acting (4–8 hours): captopril.
- Long-acting (24 hours or more): enalapril, lisinopril, fosinopril, perindopril, ramipril, trandolapril.
Specific Side Effect: Why Does Cough Occur?
Side effects of ACEIs are divided into hemodynamic and specific ones, i.e., directly stemming from their mechanism of action. The most well-known specific effect is dry cough.
Since ACE (aka kininase II) normally degrades not only angiotensin I but also a number of other mediators, its blockade leads to the accumulation of bradykinin.
Clinical features of such a cough:
- It does not stop when therapy is continued.
- It cannot be alleviated by standard antitussive medications.
- The development of this symptom is a direct indication for drug discontinuation.
Briefly: answers to topical questions
Where are the juxtaglomerular cells that secrete renin located?
Juxtaglomerular cells are located in the kidneys and serve as the source of renin secretion. Renin in the bloodstream converts inactive angiotensinogen into angiotensin I.
Stimuli for renin release are:
- insufficient blood supply to the kidneys;
- stimulation of $\beta_1$-adrenergic receptors of the juxtaglomerular apparatus.
You can remember the points of drug action by the stages of the cascade: $\beta$-blockers prevent the system from starting (no renin), ACEIs break the assembly "factory" (no angiotensin II), and AT₁ receptor blockers close the "doors" of target cells.
Class and exam questions
How does aldosterone raise blood pressure?
It increases the number of sodium channels in the epithelium of the distal convoluted tubules and collecting ducts of the kidneys. This enhances sodium reabsorption, followed by water retention, which increases circulating blood volume (CBV).
Can cough from ACE inhibitors be cured with syrups?
No, antitussive medications are ineffective in this case. The cough is associated with the accumulation of bradykinin due to enzyme blockade, so the only way out is drug discontinuation.
Where does the conversion of angiotensin I to angiotensin II take place?
This biochemical process occurs in the systemic circulation upon contact of the precursor with angiotensin-converting enzyme (ACE).
What else to study on this topic
- Hemodynamic side effects of ACE inhibitors
- Mechanism of action of vasopeptidase inhibitors
- Features of ACEI use in chronic congestive heart failure
- The role of $\beta_1$-adrenergic receptors of the juxtaglomerular apparatus in renin secretion
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