RAS peptide profiles in arterial hypertension

The classical endocrine renin-angiotensin aldosterone system (RAS) plays an important role in blood pressure and fluid balance regulation. Important effectors of the RAS are small bioactive peptides like angiotensin II (Ang 1-8) or Ang 1-7. The possibility to reliably quantify the low abundance RAS peptides in serum using a mass spectrometry based method opened up new opportunities to investigate their role as possible biomarkers in patients treated with cardiovascular drugs that modulate the RAS cascade. In a pilot study in healthy individuals, RAS peptide concentrations were quantified under normal conditions and after administration of approved drugs that inhibit key enzymes of the RAS (renin, angiotensin-converting enzyme) or block the effect of Ang 1-8 (angiotensin receptor antagonists). Changes reflecting the mechanism of action of the different drugs were evident within a few hours after single dose administration. Based on these promising pilot data, the goal of the subsequent three clinical studies performed in the framework of this dissertation was to systematically characterize the RAS peptide profiles in normotensive healthy subjects as well as in patients with arterial hypertension. The work should contribute to a better understanding of the RAS peptides and investigate their possible role as biomarkers for patients under treatment with RAS modulating drugs.
In the first study, we assessed RAS peptide concentrations after single and repeated oral administration of the renin inhibitor aliskiren, the ACE inhibitor enalapril, and the angiotensin receptor antagonist losartan in healthy normotensive subjects. RAS peptide profiles showed drug-specific changes which directly reflected the mechanism of action of the different RAS inhibitors after single and multiple dose treatment for one week. While inhibition of renin decreased downstream RAS peptide concentrations, the ACE inhibitor caused a decrease of the ACE products Ang 1-8 and Ang 1-5. The angiotensin receptor antagonist on the other hand caused an increase of upstream Ang 1-10 and Ang 1-8 mainly by enhanced renin-feedback. Overall, the data suggested that RAS peptide profiles could be of value for the assessment of patients under RAS inhibitor therapy.
In the second study, the potential of drug-specific profiles found in healthy normotensive subjects as possible biomarkers were assessed in patients before and after start of monotherapy for arterial hypertension. Patients were randomized to four groups and RAS peptide concentrations were assessed after 4 weeks of consecutive oral treatment with intermediate or high doses of the ACE inhibitor
perindopril, the angiotensin receptor antagonist olmesartan, the calcium channel antagonist amlodipine or the thiazide diuretic hydrochlorothiazide. These four drugs are used as first line treatments in clinical practice. After treatment with the ACE inhibitor and the angiotensin receptor antagonist, RAS peptide profiles again showed the drug-specific changes observed in healthy normotensive subjects. The changes observed with the calcium channel antagonist and the thiazide diuretic were similar but less pronounced as for the ones observed after an angiotensin receptor antagonist treatment. The study showed that the drug-specific changes are preserved for at least 8 weeks of treatment.
Next it was of interest whether drug-specific changes could also be detected in patients under combination drug treatment. In the third study we therefore investigated RAS peptide profiles in patients with uncontrolled arterial hypertension, as such patients per definition are treated with at least three different antihypertensive drugs. With insufficient therapeutic response despite receiving combination drug treatment, patients with treatment resistant arterial hypertension belong to the most complex patient group. However, these patients are at great risk of stroke, myocardial infarction, heart failure, and/or chronic kidney disease and the benefits of successful treatment are substantial. Even in this heterogeneous patient group, the drug-specific RAS peptide profile changes observed in healthy normotensive subjects and patients under antihypertensive monotherapy were maintained. Data generated by this study suggest that RAS peptide profiles might also be useful in other patient populations treated with cardiovascular drug combinations.
In conclusion, data generated by our studies showed a correlation between RAS peptide concentrations and treatment with an ACE inhibitor or angiotensin receptor antagonist in normotensive healthy subjects as well as in patients with arterial hypertension under monotherapy or in patients with uncontrolled hypertension with a combination drug treatment. Taken together, RAS peptide profiles as biomarkers for the assessment of drug adherence and (in combination with drug concentrations in plasma) true drug resistance as well as their potential usefulness in the guidance of antihypertensive treatment in patients with insufficient treatment response merits further investigation.