Vasorelaxing and antihypertensive activities of synthesized peptides derived from computer-aided simulation of pepsin hydrolysis of yam dioscorin (original) (raw)
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Bioactive Peptides - Are There More Antihypertensive Mechanisms Beyond ACE Inhibition?
Current Pharmaceutical Design, 2012
Diet has a high relevance in health. Hypertension is a major risk factor for cardiovascular diseases and has an important impact on public health, and consequently on countries economy. Scientific research gathered strong evidence about the role of several dietary factors either in etiology or in treatment/prevention of these diseases. Peptides from different food matrices have been studied, and indicated as compounds with particular interest in the context of hypertension. The classical approach involves the identification of peptides with an in vitro ACE inhibitory activity and the assumption that the observed in vivo effects are due to this enzyme blockade. However, in some cases the potency of ACE blockade does not correlate with the antihypertensive activity in vivo. This paper reviews the current literature that identifies mechanisms of action, other than ACE inhibition, that might explain antihypertensive effects of biologically active peptides from different food sources.
… Nutrition & Food …, 2011
The aim of this study was to investigate the antihypertensive effect of a peptide fraction (PepC) obtained from a whey protein concentrate following hydrolysis by Cynara cardunculus, as well as of its fraction with MW below 3 kDa (PepCF). Both these concentrates encompassed peptides that exhibited potent in vitro inhibition of angiotensin-converting enzyme (ACE): two were released from a-lactalbumin-KGYGGVSLPEW and DKVGINYW, and one from b-lactoglobulin-DAQSAPLRVY. Methods and results: Upon oral administration, by gastric intubation, of 400 mg/kg body weight (bw) of those peptide concentrates, or 5 mg/kg bw of the corresponding synthetic peptides, to 12 wk-old spontaneously hypertensive rats (SHR), the systolic and diastolic blood pressures were monitored by the tail-cuff method-before, and 2, 4, 6, 8 and 24 h afterwards. Water and zofenopril (5 mg/kg bw)-a known ACE-inhibitor, were used as negative and positive controls, respectively. Acute administration of PepC, PepCF, KGYGGVSLPEW, DKVGINYW and DAQSAPLRVY caused antihypertensive effects in SHR; the maximum effect occurred by 4 h and 6 h after administration of the peptide concentrates and the synthetic peptides, respectively. PepC and KGYGGVSLPEW also showed ACE-inhibitory activity in vivo: the pressor effect of angiotensin I was significantly lower, and the response to bradykinin increased when the rats were pre-treated with either product. Conclusion: Our results strongly suggest that PepC will be effective as nutraceutical ingredient for the formulation of functional foods aimed at hypertension control.
Journal of Agricultural and Food Chemistry, 2007
In this study, we have identified novel antihypertensive peptides derived from egg-white proteins. The sequences YRGGLEPINF and ESIINF produced an acute blood-pressure-lowering effect in spontaneously hypertensive rats upon a single oral administration. Our results suggest that the antihypertensive action could be attributed to a vascular-relaxing mechanism that would occur in vivo independently of angiotensin I-converting enzyme (ACE) inhibition, because neither these peptides nor their main digestion fragments, except for the dipeptide YR, acted as ACE inhibitors in vitro. The vasodilator and antihypertensive activity of the sequences ESI and NF would explain the bloodpressure-lowering effect of ESIINF. With regard to YRGGLEPINF, in addition to NF, YR appeared as the main fragment responsible for its activity. The dipeptide YR, named kyotorphin and previously identified as an endogenous analgesic neuropeptide in the central nervous system, showed strong vasodilator and antihypertensive properties. The structure-activity features of the vasodilator peptides are discussed. DGSRQPV (ovotransferrin 230-236). The fragments resulting from the simulation of the gastrointestinal digestion of YRGGLEPINF and ESIINF (YRGGLEPI, YR, GGLEPI, ESI, and NF) were also synthesized. All of these peptides were obtained by conventional Fmoc solid-phase synthesis with a 431A peptide synthesizer (Applied Biosystem, Inc., Ü berlingen, Germany) according to the method described by Atherton and Sheppard (29). They were synthesized and provided by the Unitat de Pèptids of Barcelona University, and their purity (>90%) was verified in our laboratory by reversed-phase high-performance liquid chromatography-tandem mass spectrometry (RP-HPLC-MS/MS) (30). The drugs and the peptides were dissolved in distilled water for the reactivity experiments and administration to the rats.
Journal of Agricultural and Food Chemistry, 2006
Food-derived bioactive peptides with ACE-inhibitory properties are receiving special attention due to their beneficial effects in the treatment of hypertension. In this work we evaluate the impact of a simulated gastrointestinal digestion on the stability and activity of two bioactive peptides that derive from ovalbumin by enzymatic hydrolysis, YAEERYPIL and RADHPFL. These peptides possess in vitro ACE-inhibitory activity and antihypertensive activity in spontaneously hypertensive rats (SHR). The results showed that YAEERYPIL and RADHPFL were susceptible to proteolytic degradation after incubation with pepsin and a pancreatic extract. In addition, their ACE-inhibitory activity in vitro decreased after the simulated digestion. The antihypertensive activity on SHR of the end products of the gastrointestinal hydrolysis, YAEER, YPI, and RADHP, was evaluated. The fragments YPI and RADHP significantly decreased blood pressure, 2 h after administration, at doses of 2 mg/kg, but they probably did not exert their antihypertensive effect through an ACE-inhibitory mechanism. It is likely that RADHP is also the active end product of the gastrointestinal digestion of the antihypertensive peptides FRADHPFL (ovokinin) and RADHPF (ovokinin 2-7).
Proline rich-oligopeptides: Diverse mechanisms for antihypertensive action
Peptides, 2013
Keywords: Proline-rich oligopeptides Argininosuccinate synthetase Muscarinic acetylcholine receptor Nitric oxide Mean arterial pressure Heart rate a b s t r a c t Bradykinin-potentiating peptides from Bothrops jararaca (Bj) discovered in the early 1960s, were the first natural inhibitors of the angiotensin-converting enzyme (ACE). These peptides belong to a large family of snake venom proline-rich oligopeptides (PROs). One of these peptides, Bj-PRO-9a, was essential for defining ACE as effective drug target and development of captopril, an active site-directed inhibitor of ACE used worldwide for the treatment of human arterial hypertension. Recent experimental evidences demonstrated that cardiovascular effects exerted by different Bj-PROs are due to distinct mechanisms besides of ACE inhibition. In the present work, we have investigated the cardiovascular actions of four Bj-PROs, namely Bj-PRO-9a, -11e, -12b and -13a. Bj-PRO-9a acts upon ACE and BK activities to promote blood pressure reduction. Although the others Bj-PROs are also able to inhibit the ACE activity and to potentiate the BK effects, our results indicate that antihypertensive effect evoked by them involve new mechanisms. Bj-PRO-11e and Bj-PRO-12b involves induction of [Ca 2+ ] i transients by so far unknown receptor proteins. Moreover, we have suggested argininosuccinate synthetase and M3 muscarinic receptor as targets for cardiovascular effects elicited by Bj-PRO-13a. In summary, the herein reported results provide evidence that Bj-PRO-mediated effects are not restricted to ACE inhibition or potentiation of BK-induced effects and suggest different actions for each peptide for promoting arterial pressure reduction. The present study reveals the complexity of the effects exerted by Bj-PROs for cardiovascular control, opening avenues for the better understanding of blood pressure regulation and for the development of novel therapeutic approaches.
Journal of medicinal food, 2015
Ala-His-Leu-Leu (AHLL) was isolated and purified from the loach (Misgurnus anguillicaudatus) hydrolysate in our previous study. The aim of this study was to investigate the antihypertensive effects of angiotensin-I-converting enzyme (ACE) inhibitory peptide AHLL in spontaneously hypertensive rats (SHRs). AHLL showed good antihypertensive effects in SHRs during the long-term oral administration and no allergic reactions or coughing were observed. After 2 months of oral administration of AHLL, the body weight growth was normal. The decrements in systolic blood pressure of the high dose (5 mg/kg bw) and the low dose of AHLL (1 mg/kg bw) treatment groups were 22.1 and 5.0 mmHg at week 8, respectively. Compared to the control group, the concentrations of triglyceride and sodium in serum were reduced significantly in the high-dose group after 2 months. The ACE activity of kidney and lung decreased significantly, which indicated that AHLL exerted an antihypertensive effect on kidney and lu...
Journal of Food Science, 2000
Angiotensin I-converting enzyme (ACE)-inhibitory peptides from the thermolysin digest of chicken muscle and the peptic digest of ovalbumin were isolated. However, some of them failed to show antihypertensive activity in spontaneously hypertensive rats (SHR). To clarify this discrepancy, ACE-inhibitory peptides from various sources were preincubated with ACE before measurement of ACE-inhibitory activity and classified into 3 groups: (1) inhibitor type, IC 50 values of peptides that are not affected after preincubation with ACE;( 2) substrate type, peptides that are hydrolyzed by ACE to give peptides with weaker activity; and (3) prodrug-type inhibitor, these peptides are converted to true inhibitors by ACE or gastrointestinal proteases. Peptides belonging to the 1st and the 3rd groups exert antihypertensive activities even after oral administration in SHR.
Background: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. Method: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. Results: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. Conclusion: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed.
Journal of Pharmacology and Experimental Therapeutics, 2007
Angiotensin-converting enzyme (ACE) inhibitors were developed based on proline-rich oligopeptides found in the venom of Bothrops jararaca (Bj) previously known as bradykinin-potentiating peptides (BPPs). However, the exact mechanism of action of BPPs remains unclear. The role of the ACE in the cardiovascular effects of two of naturally proline-rich oligopeptides (Bj-BPP-7a and Bj-BPP-10c) was evaluated in vitro and in vivo. Bj-BPP-7a does not potentiate the cardiovascular response to bradykinin and is a weak inhibitor of ACE C and N sites (K i ϭ 40,000 and 70,000 nM, respectively), whereas Bj-BPP-10c is a strong bradykinin potentiator and inhibitor of the ACE C site (K i ϭ 0.5 versus 200 nM for N site). Strikingly, both peptides, in doses ranging from 0.47 to 71 nmol/kg, produced long-lasting reduction (Ͼ6 h) in the mean arterial pressure of conscious spontaneously hypertensive rats (maximal change, 45 Ϯ 6 and 53 Ϯ 6 mm Hg for Bj-BPP-7a and Bj-BPP-10c, respectively). The fall in blood pressure was accompanied by variable degrees of bradycardia. In keeping with the absence of relationship between ACE-inhibitory and antihypertensive activities, no changes in the pressor effect of angiotensin I or in the hypotensive effect of bradykinin were observed at the peak of the cardiovascular effects of both peptides. Our results indicate that the antihypertensive effect of two Bj-BPPs containing the motif Ile-Pro-Pro is unrelated to their ability for inhibiting ACE or potentiating bradykinin (BK), indicating as a major component ACE and BK-independent mechanisms. These results are in line with previous observations suggesting ACE inhibition-independent mechanisms for angiotensin I-converting enzyme inhibitor.
Role of Bioactive Peptides in Reducing the Severity of Hypertension with the Inhibition of ACE
International Journal of Peptide Research and Therapeutics, 2019
Bovine milk protein, fermented with LC (Lactobacillus casei) was used to evaluate its ACE inhibitory activity in-vitro. After evaluating the health status of animals by running hemto-chemical tests, four young dairy animals (22, 26, 30 and 34 months old) were selected on the basis of serum protein level for milk collection. Twenty-two months old animal was considered as control. After co-culturing of skim milk with LC for 24 h, peptide samples were purified via ultrafiltration by using Molecular weight cutoff ; 10000 Da (PM-10) membrane. Protein hydrolysis was confirmed by applying ninhydrin reaction and SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Milk of 34-months old animal (D-34) showed greater ACE inhibitory activity in-vitro via ACE inhibitory assay. Moreover, D-34 was further analyzed for its peptides profile by using Q exactive Hybrid Quadrapole-Orbitrap Mass Spectrometry as shown in Graphical abstract. Peptides with higher concentration of Proline, Lysine and aromatic amino acid was identified and higher concentration of hydrophobic aliphatic amino acids in PIN-94 and PIN-332 indicated the usefulness of D-34 as ACE-inhibitor. On the basis of those hydrophobic amino acids it was concluded that Serum protein and milk protein level are interconnected and milk of middle-aged Animals with higher serum protein level is useful to inhibit ACE because with the growth of animal, serum protein contents also increases and those protein contents indicate the health status of the animal. Fermented milk peptides of middle-aged animals can be used as functional food and nutraceutical to reduce hypertension.