## 4 Discussion  
Alcalase-generated amaranth peptides can lower the SBP in SHR through ACE-1 inhibition [4]. This enzyme inhibition hampers the formation of the potent vasoconstrticr angiotensin II and reduces the hydrolysis of the endothelium-dependent vasodilator bradykinin [21; 22]. ACE-1 inhibitor drugs are widely used for controlling blood pressure mainly because they are low-cost, effective drugs and their potential side effects cause discomfort but are not life-threatening, with the exception of angioedema [23]. The alcalase-generated amaranth protein hydrolysate evaluated in the present study inhibits ACE-1 and can be used as a food-derived antihypertensive ingredient for developing functional foods [5; 6]. These ACE-1-inhibiting foods could be used not only to help control hypertension but also other cardiovascular diseases, since ACE-1 inhibitors are useful for treating systolic and diastolic left ventricle dysfunction and acute coronary syndrome, among other conditions [24]. Ideally, antihypertensive functional foods should not trigger side effects neither in the target nor the healthy population. The rationale for the latter relies on the fact that in normotensive organisms that lack ACE-1 or have reduced serum levels of it, blood pressure could be unnecessarily lowered [25], and also that hypotension, a physiological side effect, could occur as a first-dose phenomenon after ACE-1 inhibitor administration [23; 26]. The present study shows that at first dose, the oral administration of the alcalase-generated amaranth protein hydrolysate has an effect similar to captopril in normotensive rats and SHR [4; 27; 28; 29]. This implies a lack of any effect on SBP in normotensive rats, but a significant antihypertensive effect in SHR. Other researchers have reported similar findings using milk-derived peptides [30; 31]. For some [32], the use of ACE-1 inhibitor drugs should be replaced with angiotensin receptor blockers to treat hypertension. This observation is based on data supporting that the rate of cough (9.9% vs 3.2%) and the incidence of angioedema (0.3% vs 0.13%) are significantly greater in patients treated with ACE-1-1 inhibitor drugs than in those treated with angiotensin receptor blockers. Overall, our findings should be taken as the first proof of concept about the safety of alcalase-generated amaranth protein hydrolysate, which supports the development of functional foods for controlling SBP or for use as an adjunct in lifestyle interventions in essential hypertension cases and potentially in other cardiovascular diseases. The antihypertensive effect of alcalase-generated amaranth protein hydrolysate can occur as fast as three hours after its administration by gavage, as shown in the present and other studies [4]. Additionally, the present study shows that this antihypertensive effect can be sustained for weeks or months as long as the hydrolysate is consumed in specific doses once a day. In long-term use of ACE-1 inhibitors, the inhibition of this enzyme in tissues other than blood becomes more relevant since angiotensin II can be produced through alternative pathways [24; 33], e.g., ACE-independent angiotensin II production by the serine protease chymase [33; 34]. In SHR, there is a trend to produce high levels of angiotensin II due to angiotensinogen being overexpressed at the intrarenal level [34; 35; 36]. Current evidence supports that alcalase-generated amaranth peptides that enter into the blood stream after protein hydrolysate consumption can inhibit ACE-1 in plasma [4], but it does not directly support that food-derived peptides can inhibit ACE-1 in the kidneys, lungs, or tissues other than blood. The fact that amaranth peptides can develop a sustained antihypertensive effect suggests that these food-derived peptides can act in tissues other than blood. Certainly, the mechanism underlying ACE-1 inhibition among different compounds, including peptides, is not expected to largely differ but rather the main targeted organ and pharmacokinetics will determine the clinical effect [24].