The hypertension patient population has doubled since 1990, affecting 1.3 billion globally and >
75% live in low-and middle-income countries. Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) are the most prescribed drugs (>
160 million times in the US), but mortality increased >
30% since 1990s globally. Clinical relevance of Myxomatous Mitral Valve Disease (MMVD) is directly linked to WHO group 2 pulmonary hypertension, with no disease specific therapies. Therefore, MMVD pet dogs with elevated systolic blood pressure treated with ACEI/ARB, were supplemented with oral ACE2 enzyme and Angiotensin1-7 (Ang1-7) bioencapsulated in plant cells. The oral ACE2/Ang1-7 was well tolerated by healthy and MMVD dogs with no adverse events and increased sACE2 activity by 670-755% with ARB (Telmisartan) than with ACEI (Enalapril) background therapy. In vitro rhACE2 activity was inhibited >
90% by ACEIs enalapril/benazeprilat at higher doses but lisinopril inhibited at much lower doses. Membrane ACE2 activity evaluated in exosomes was 43-fold higher than the sACE2 and this was also inhibited 211% by ACEI, when compared to ARB. Background ACEI treatment reduced the Ang-II pool by 11-20-fold and proportionately decreased the abundance of Ang1-7 + Ang1-5 peptides. In contrast, ARB treatment increased Ang-II pool 11-20-fold and Ang1-7 + Ang1-5 by 160-260%. Systolic blood pressure was regulated by ARB better than ACEI, despite very high Ang-II levels. This first report on evaluation of metabolic pools in the RAS pathway identifies surprising interactions between ACEI/ARB/ACE2 and significant changes in key molecular dynamics. Affordable biologics developed in plant cells may offer potential new treatment options for hypertension.