Antihypertensive peptides

Casein-derived phosphorylated peptides are believed to enhance the bioavailability of calcium from milk and dairy products (Pihlanto and Korhonen, 2003), and a phosphopeptide derived from (3-casein has been shown to increase iron bioavailability (Bouhallab et ah, 2002 Peres, 1999). Other casein-derived peptides have been found to contain antihypertensive activity in rats (Leclerc et ah, 2002 Miguel et ah, 2009). A number of casein fragments demonstrate antibacterial activity (Kilara and Panyam, 2003). 

Several peptides possessing antihypertensive effect proved to play a promising role in regnlating vascnlar fnnctions as described in the past researches. The present chapter is aimed to offer an overview of a new functionality of small peptides in preventing hypertension and vessel dysfunctions including atherosclerosis. 

A physiological function of a given food that maintains our homeostasis and contributes to our health quality is currently known as a tertiary function of food. In Japan, the Ministry of Health, Labor and Welfare accepts the prophylaxis of lifestyle-related diseases by functional foods. Presently, many functional foods are available in the market as food for specific health use (FOSHU) products. To date, more than 940 items to prevent lifestyle-related diseases such as hypertension, diabetes and hyperlipidemia are accepted as a FOSHU product. Amongst the products, antihypertensive foods are unique rather than others, since their candidates (in most cases, peptides) can improve elevated blood pressure (BP) after intact absorption into our body. 

Table 1 summarizes the antihypertensive effects of ACE inhibitory small peptides. Information of dosage is also listed. It is clear that small peptides can exert an antihypertensive action following oral administration to mild hypertensive subjects, similar to therapeutic ACE inhibitory drugs, despite their poor potency on ACE inhibitory activity. It seems likely that ca. 20-fold higher doses of small peptides than drugs are required to... 

It has been clarified that absorbed VY was accumulated in the kidney and aorta in orally administrated SHR, along with the suppression of local ACE activities in both organs (Eig. 2). This finding suggested that both organs must be a targeted tissue for antihypertensive VY. The report that therapeutic ACE inhibitor captopril controlled vessel fimctions also allowed us to consider the potential role of ACE inhibitory small peptides in contracted vessels. 

Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Osajima Y. (2000) Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. 

Lee SH, Qian ZJ, Kim SK. (2010) A novel angiotensin 1 converting enzyme inhibitory peptide from tuna frame protein hydrolysate and its antihypertensive effect in spontaneously hypertensive rats. Food Chem 118 96-102. 

Apart from pharmaceuticals, peptides are also used for diagnostics and vaccines. More than 40 peptides are in commercial use today. A dozen of them is shown in Table 3.1. As shown in column 3 of the table, the number of amino acids that make up a specihc peptide varies widely. At the low end there are dipeptides, like the blockbuster antihypertensive drug enalapril and the artihcial sweetener Aspartame (not shown in the table). In terms of volumes produced, there are by far the most important product group. At the high end there is the anticoagulant Hirudin, which is composed of 65 amino acids. Sales of synthetic peptides are estimated at 4 billion as formulated drugs (resp. 300- 400 million as APIs). 

T. Hedner, X. Sun, I. L. Junggren, A. Pettersson, L. Edvinsson (1992). Peptides as targets for antihypertensive drug development. J. Hypertem. 10 S121. 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

Bioactive peptides as products of hydrolysis of diverse marine invertebrate (shellfish, crustacean, rotifer, etc.) proteins are the focus of current research. After much research on these muscles and byproducts, some biologically active peptides were identified and applied to useful compounds for human utilization. This chapter reviews bioactive peptides from marine invertebrates in regarding to their bioactivities. Additionally, specific characteristics of antihypertensive, anti-Alzheimer, antioxidant, antimicrobial peptide enzymatic production, methods to evaluate bioactivity capacity, bioavailability, and safety concerns of peptides are reviewed. 

Gly-Asn-Leu-Tyr-Pro-Gly (Table 4.1). The purified peptide was evaluated for antihypertensive effects in SHRs following oral administration. 

FIGURE 4.3 Antihypertensive activities of ACE-inhibitory peptides after single oral administration in SHRs. SHRs were administered captopril (O), the ACE-inhibitory peptide from rotifer ( ) at a dose of 50mg/kg. Changes in systolic blood pressure were expressed as mean SE [n—5). Statistical analyses were done by Student t-test (P<0.05) (Skeggs et at., 1957). 

Katano, S., Oki, T., Matsuo, Y., Yoshihira, K., Nara, Y., Miki, T., Matsui, T., and Matsumoto, K. (2003). Antihypertensive effect of alkaline protease hydrolysate of the pearl oyster Pinctada fucata martencii separation and identification of angiotensin-I converting enzyme inhibitory peptides. Nippon Suisan Gakk. 69, 975-980. 

Maria, M. C., Rosalia, C., Maria, J. M., Mercedes, R., and Isidra, R. (2009). Novel casein-derived peptides with antihypertensive activity. Int. Dairy J. 19, 566-573. 

Wang, J., Hu, J., Cui, Z., Bai, X., and Du, Y. (2008b). Purification and identification of a ACE inhibitory peptide from oyster proteins hydrolysate and the antihypertensive effect of hydrolysate in spontaneously hypertensive rats. Food Chem. Ill, 302-308. 

According to Lee et al. (2010), the peptide Gly-Asp-Leu-Gly-Lys-Thr-Thr-Thr-Val-Ser-Asn-Trp-Ser-Pro-Pro-Lys-Try-Lys-Asp-Thr-Pro, derived from big-eye tuna frame protein hydrolysate, showed a strong suppressive effect on the systolic blood pressure of SHRs, while its antihypertensive activity was similar to that of captopril, a commercially available antihypertensive drug. Further, they reported no side effects after the administration of this antihypertensive peptide to rats. In addition, these marine antihypertensive peptides exhibit stronger antihypertensive activity in vivo than in vitro. The exact mechanisms underlying this phenomenon have yet to be identified however, it was suggested that bioactive peptides have a higher tissue affinity and are eliminated more slowly than captopril (Fujita and Yoshikawa, 1999). 

Jung, W. K., Mendis, E., Je, J. Y., Park, P. J., Son, B. W., Kim, H. C, Choi, Y. K., and Kim, S. K. (2006b). Angiotensin-I-converting enzyme inhibitory peptide from yellowfin sole (Limanda aspera) frame protein and its antihypertensive effect in spontaneously hypertensive rats. Food Chem. 94, 26-32. 

Pan, D. D., Luo, Y. K., and Tanokura, M. (2005). Antihypertensive peptides from skimmed milk hydrolysate digested by cell-free extract of Lactobacillus helveticus. Food Chem. 91, 123-129. 

Suetsuna, K. (2002). Identification of antihypertensive peptides from peptic digest of the short-necked clam tapes philippinarum and the pearl oyster pinctada fucata martensii. 

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