RAAS Physiology as a Pharmacotherapy Target
The primary function of the RAAS is the regulation of resistance vessel tone, circulating blood volume, and electrolyte balance. The biochemical cascade of reactions proceeds as follows:
- Renin secretion. This process is triggered in the juxtaglomerular cells of the kidneys during inadequate blood supply or $\beta_1$-adrenergic receptor stimulation. Released renin acts as an enzyme: in the systemic circulation, it encounters the inactive precursor angiotensinogen and converts it into angiotensin I.
- Angiotensin II formation. Angiotensin I encounters angiotensin-converting enzyme (ACE), also known as kininase II or peptidyl-dipeptidase A. ACE cleaves two amino acid residues from the precursor, generating the active octapeptide angiotensin II in the systemic circulation.
- Vascular effects. The active octapeptide stimulates $AT_1$ receptors on the smooth muscle of resistance vessels. This leads to an increase in total peripheral resistance (TPR) and elevated blood pressure.
- Aldosterone pathway. Additionally, angiotensin II stimulates $AT_1$ receptors in the adrenal cortex, prompting the release of the mineralocorticoid aldosterone. Aldosterone acts on receptors in the epithelium of the distal convoluted tubules and collecting ducts of the kidneys, increasing the number of active sodium channels. Sodium ions ($Na^+$) are actively reabsorbed, dragging water along with them. As a result, extracellular fluid volume and circulating blood volume increase, further raising blood pressure.
Classification of Drugs by Mechanism of Action
Depending on the stage at which the described cascade is interrupted, drugs are divided into three main groups:
- Renin secretion inhibitors. These include $\beta$-blockers, which deprive the juxtaglomerular apparatus of its stimulatory signal.
- Agents disrupting angiotensin II formation. This group includes ACE inhibitors and vasopeptidase inhibitors. They disable the enzyme responsible for assembling the active octapeptide.
- Agents blocking angiotensin II action. These are $AT_1$ receptor blockers (ARBs, or sartans). They do not interfere with substance synthesis, but block the target receptors.
ACE Inhibitors: Characteristics and Clinical Use
Angiotensin-converting enzyme (ACE) inhibitors exert their antihypertensive effect by influencing two systems simultaneously: the RAAS and the kinin system. In clinical practice, they are used for hypertension (especially when RAAS activity is elevated) and chronic congestive heart failure.
Based on their duration of action, this 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 Adverse Effect: Why Does Cough Develop?
Adverse effects of ACE inhibitors are divided into hemodynamic effects and specific effects directly stemming from their mechanism of action. The most well-known specific effect is a dry cough.
Because ACE (kininase II) normally degrades not only angiotensin I but also several other mediators, its blockade leads to the accumulation of bradykinin.
Clinical features of this cough:
- It does not stop while therapy is continued.
- It cannot be relieved by standard antitussive medications.
- The development of this symptom is a direct indication for drug discontinuation.