Abstract

Background: Combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic has proven to be effective in the treatment of hypertension with or without end-organ damage.

Discussion: The mechanism of action of such a combination therapy may involve a opposite effect on the renin-angiotensinaldosterone system (RAAS) with possible "functional" synergistic effects. Indeed, while diuretics can initially reduce intravascular volume leading to an activation of the RAA system with consequent vasoconstriction and salt and water retention, the concomitant presence of an ACE inhibitor may prevent such a counterregulatory response on neurohumoral system. This creates the conditions for the achievement of a maximal antihypertensive effect for both the ACE inhibitor and the diuretic. In recent years, however, experimental evidence has suggested that in addition to the above described mechanism of action, which is common to all the combinations of ACE-inhibitors and diuretics, it can be possible to identify some additional and peculiar mechanisms involving some selected drugs. Such additional mechanisms would be essentially related to some differences in the pharmacokinetic profiles of ACE inhibitors. In particular, the extent of lipophilicity could play an important role in membrane penetration and tissue accumulation and has been correlated with the overall ACE-inibitory activity of various compounds, eg., tissue ACE inhibitory activity could increase with the increase of lipophilicity. For instance, in rats with myocardial infarction, volume depletion induced by concomitant administration of HCTZ can increase the tissue levels of zofenoprilat (the active metabolite of zofenopril, an highly lipophilic ACE inhibitor), but not those of the highly hydrophilic lisinopril. An interesting hypothesis is that associating HCTZ to a highly lipophilic ACE inhibitor translates into peculiar clinical profiles, therefore we suggest further studies on this matter.

Conclusion: Experimental models have shown that hydrochlorothiazide (HCTZ) could act like a "tissue levels enhancer" of lipophilic ACE-inhibitors, eg., can increase tissue concentrations of zofenoprilat (active metabolite of zofenopril, an highly lipophilic compound), and consequently induce an enhancement of its tissue ACE inhibition. On the basis of available experimental data, we suggest a peculiar interaction between zofenopril and HCTZ, i.e., HCTZ could act as a "tissue levels enhancer" of zofenopril. This hypothesis, if confirmed, could imply a relevant therapeutic advantage for the treatment of arterial hypertension.

Keywords: ACE inhibitors, zofenopril, thiazide diuretics, hydrochlorothiazide, lipophilicity, ACE tissue inhibition, hypertension, combination therapy, enhancer