The interplay of recently discovered components of the renin–angiotensin–aldosterone system. The protease renin cleaves angiotensinogen to angiotensin I, which is then hydrolyzed by the circulating and local angiotensin-converting enzyme to the active angiotensin II. Angiotensin II may by alternatively formed by chymase, carboxypeptidase, cathepsin G, or tonin. Angiotensin I might also be directly (by neutral endopeptidase) or indirectly (by angiotensin-converting enzyme and angiotensin-converting enzyme 2 with angiotensin 1–9 as intermmediate product) converted to angiotensin 1–7. Angiotensin 1–7 is degraded by angiotensin-converting enzyme to angiotensin 1–5 while angiotensin II is degraded to angiotensin III and IV by aminopeptidase A and M. Receptors of the renin–angiotensin–aldosterone system include the (pro)renin receptor that enhances the activity of renin, activates prorenin, and elicits angiotensin-independent effects as well. The deleterious effects of renin–angiotensin–aldosterone system activation are ascribed to angiotensin type 1 receptors stimulation by angiotensin II and III. The modestly researched angiotensin type 4 receptor (insulin-regulated aminopeptidase), which is stimulated by angiotensin IV, exerts negative effects too. On the other hand, the stimulation of the angiotensin type 2 receptor, which binds angiotensin II, angiotensin 1–9, and angiotensin III, and Mas receptor, which binds angiotensin 1–7, seem to ellicit beneficial effects. AT₁R, angiotensin type 1 receptor; AT₂R, angiotensin type 2 receptor; AT₄R, angiotensin type 4 receeptor; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AMPA, aminopeptidase A; AMPM, aminopeptidase M; NEP, neutral endopeptidase; IRAP, insulin-regulated aminopeptidase; (P)RR, (pro)renin receptor; ROS, reactive oxygen species.

The therapeutic options for aldosterone antagonism. Aldosterone synthase is activated by several factors including angiotensin type 1 receptor stimulation, adrenocorticotropin release and high plasmatic K⁺ concentrations. The synthetized aldosterone activates the mineralocorticoid receptor with its epithelial and non-epithelial effects. The epithelial effects include the activation of epithelial Na⁺ channel with subsequent Na⁺ and water retention; while the non-epithelial effects are participate in tissue remodelling and organ damage. In low aldosterone conditions, the mineralocorticoid receptor might be activated by cortisol as well. The traditional aldosterone antagonist spironolactone antagonises not only the mineralocorticoid receptor receptors but also the androgenic receptors leading to its anti-androgenic side. More recent therapeutic interventions include the inhibition of aldosterone by aldosterone synthase inhibitors; more selective (compared with spironolactone) blockade of mineralocorticoid receptor by eplerenone and finally epithelial Na⁺ channel blockade by amiloride. (A) Recently several dihydropyridine calcium channel blockers were reported to antagonize the mineralocorticoid receptor and to partially block T-type voltage-dependent calcium channels in addition to the blockade of L-type voltage-dependent calcium channel. Therofore, the dihydropyridine structure might be exploited to design non-steroid compounds with dual aldosterone antagonism ± L-type voltage-dependent calcium channel blockade (B). ACTH, adrenocorticotropic hormone; AR, androgen receptor; ANP, atrial natriuretic peptide; ASI, aldosterone synthase inhibitors; AT1R, angiotensin type 1 receptor; ENaC, epithelial sodium channel; MAPK, mitogen-activated protein kinase; MR, mineralcorticoid receptor; ROS, reactive oxygen species; VDCC, voltage-dependent calcium channel.

Recent evolution of dual and triple combinations. Schematic representation demonstrating the most rational (thick lines) combinations of classes of antihypertensive agents according to 2003 guidelines for the management of arterial hypertension.¹⁶⁵ (A) Adaptation of the upper scheme including direct renin inhibitors (and omitting α-blockers) demonstrating dual (red lines) and triple (patterned triangles) combinations recently approved (since 2003) or in advanced (phase II–III) development in addition to the previously established combinations (blue thick lines). ARBs, angiotensin II type 1 receptor blockers; ACE, angiotensin-converting enzyme. In all recent combinations calcium blockers are represented by amplodipine and diuretics by hydrochlorothiazide. Angiotensin-converting enzyme-inhibitors + β-blockers stand for the combination of lisinopril + carvedilol, which is a combined β/α₁-blocker (B).