Aliskiren increases tissue kallikrein expression and bradykinin levels in the heart

Aliskiren is an orally active highly specific renin inhibitor with IC50 of 0.6 nmol/L for human renin and 4.5 nmol/L for mouse renin. To explore the potential mechanisms of aliskiren's actions, we compared the effects of aliskiren (10 mg/kg per day by subcutaneous osmotic minipump), angiotensin converting enzyme inhibitor perindopril (0.2 mg/kg per day in drinking water), and their combination, on angiotensin (Ang) and bradykinin peptides in non-diabetic and diabetic female heterozygous (mRen-2)27 rats. The (mRen-2)27 rat is a Sprague-Dawley rat transgenic for the mouse Ren-2 gene, and is a high Ang II model of hypertension. Plasma aliskiren levels (∼500 nmol/L) were at the upper part of the therapeutic range in humans. The three treatment regimens produced equivalent reductions in blood pressure, cardiac hypertrophy, and plasma aldosterone levels. Aliskiren reduced Ang I levels in blood and Ang II levels in lung, but did not affect Ang II levels in blood, kidney, or heart. Contrary to what might be expected of a renin inhibitor, aliskiren increased Ang I levels in kidney and Ang II levels in brain, reduced Ang II/Ang I ratio in kidney and lung, and increased bradykinin levels and tissue kallikrein expression in heart. Aliskiren also reduced cardiac fibrosis. We conclude that whereas some of aliskiren's actions were consistent with renin inhibition, others suggested mechanisms additional to renin inhibition. By increasing cardiac tissue kallikrein expression and bradykinin levels, aliskiren offers the potential for a new strategy for prevention and treatment of myocardial dysfunction and heart failure.