Evaluation of Dual Inhibitory Effect of Anagliptin, Ramipril, and Lisinopril on Angiotensin-Converting Enzyme and DPP-4 Activities.

We previously tested two angiotensin-converting enzyme (ACE) inhibitors and two dipeptidyl peptidase-4 (DPP-4) inhibitors for dual enzyme inhibitory effect. Only two DPP-4 inhibitors, linagliptin and sitagliptin, were able to inhibit ACE. In the present study, we investigated if other inhibitors of ACE or DPP-4 could simultaneously inhibit the activities of both DPP-4 and ACE. Forty Sprague Dawley rats were used. The control group received saline only. The other three groups were treated with anagliptin, ramipril, or lisinopril. Two different doses were tested, separated with a 6-day drug-free interval. Angiotensin II (ang II) levels, the activities of ACE, and DPP-4 were measured from blood samples at baseline and days 1, 10, and 14. After the oral glucose challenge, levels of the active form of glucagon-like peptide-1 (GLP-1) were measured. Regardless of the dose, anagliptin did not show any inhibitory effect on the activity of ACE or ang II levels. For ramipril and lisinopril, only a high dose of lisinopril was able to produce a modest reduction of the DPP-4 activity, but it was not enough to inhibit the inactivation of GLP-1. It seems that while most ACE inhibitors cannot affect DPP-4 activity, inhibitors of DPP-4 vary in their effect on ACE activity. The selection of DPP-4 inhibitors under different clinical situations should take into account the action of these drugs on ACE.