Casein-derived tripeptide Ile-Pro-Pro improves angiotensin-(1-7)- and bradykinin-induced rat mesenteric artery relaxation.

Aims: Milk casein-derived bioactive tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) lower blood pressure in animal models of hypertension and humans. In some studies, their angiotensin-converting enzyme (ACE)-inhibitory effect has been demonstrated. Besides classical ACE-angiotensin II-AT(1)-receptor pathway (ACE-Ang II- AT(1)), the significance of ACE2-angiotensin-(1-7)-Mas-receptor (ACE2-Ang-(1-7)-Mas) axis in the blood pressure regulation has now been acknowledged. The present study was aimed to further evaluate the renin-angiotensin system (RAS)-related vascular effects of Ile-Pro-Pro in vitro using rat mesenteric arteries.

Main Methods: Superior mesenteric arteries of spontaneously hypertensive rat (SHR) were isolated, cut into rings and mounted in standard organ bath chambers. Endothelium-intact arterial rings were incubated in Krebs solution either with Ile-Pro-Pro, proline-proline (Pro-Pro), isoleucine (Ile), proline (Pro) or captopril for 6h at +37°C and vascular reactivity was measured.

Key Findings: In the presence of AT(1)-antagonist valsartan, Ang II induced vasodilatation, which was more pronounced in the arteries incubated with Ile-Pro-Pro (P<0.05) compared to the other compounds. Ang-(1-7)-induced vasodilatation was augmented by Ile-Pro-Pro or Pro (P<0.001 vs. control). Mas-receptor antagonist A-779 did not alter the responses. Ile-Pro-Pro and Pro augmented also bradykinin-induced relaxations (P<0.001 vs. control). Control arteries and arteries incubated with captopril showed only slight relaxations at higher bradykinin concentrations.

Significance: Casein-derived tripeptide Ile-Pro-Pro and amino acid Pro enhance the vasodilatory effect of Ang-(1-7) and bradykinin. The role of ACE2-Ang-(1-7)-Mas axis in the modulation of vascular tone by these compounds seems probable.