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A story from the heart: the lactotripeptide IPP--from past to present: from the discovery that led to the first pharmaceutical drug for hypertension, we trace the unusual scientific journey of blood pressure-lowering solutions ... right up to today's developments in food ingredients.

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Hypertension, or high blood pressure, is a significant health problem worldwide: 25% of the global adult population now suffers from the condition. This problem touches everyone, be it through personal experience, a friend or family member or, worse still, an undiscovered health issue that may lead to other complications later in life. Research has shown that even small blood pressure reductions can lower the risk of cardiovascular disease and other conditions, including heart disease, kidney failure and stroke. Healthy eating and exercise are an indispensable part of blood pressure management. However, if lifestyle changes are not adequate, several pharmaceutical drugs are currently available that reduce blood pressure, among which angiotensin converting enzyme (ACE) inhibitors are well known.

An amazing sequence of scientific discoveries has paved the road to the development of both ACE inhibiting drugs as well as the effective antihypertensive food ingredients that are available today. Interestingly, the discovery of a peptide in snake venom was the key starting point for the development of the first synthetic ACE inhibiting drug. Many years of extensive research ensued to look for natural sources of ACE inhibitors. Now, in 2009, specific tripeptides derived from milk are the basis for new food ingredients used in the battle against hypertension. This paper highlights the scientific significance and chronology of the various discoveries (Figure 1).

Tension Control

Scientists only discovered the rennin--angiotensin system--the body's main mechanism for controlling blood pressure--in the 1950s. This system is activated when blood pressure becomes too low. When this happens, the kidneys release renin, which activates angiotensin I. ACE then converts angiotensin I into angiotensin II, which effectively increases blood pressure to a normal level by tightening the blood vessels. People with high blood pressure often produce too much angiotensin II, which means that their blood pressure is constantly increased. Finding a source and developing a product that inhibits ACE was a challenge. Such an ACE inhibitor would prevent the activation of angiotensin II and thereby relax the blood vessels, leading to a lower blood pressure.

The Eureka Moment

So, how did scientists succeed in developing these ACE inhibitors? The work of the scientist Ferreira was the start of decades of groundbreaking research into ACE inhibiting compounds from different sources. (1) In 1965, he isolated a compound from snake venom that was the first effective inhibitor of ACE. At almost the same time, Ondetti and colleagues isolated and determined the sequences of several other ACE inhibiting peptides from the same source. (2) The most potent of these peptides was a nonapeptide, SQ 20.881. Knowing the specific sequence of this potent nonapeptide, Cushman and Ondetti, from the Squibb laboratory, had the revolutionary idea of constructing a compound that would be very similar in structure. Using a hypothetical model of the active site of the enzyme, they developed a synthetic compound that fitted ACE exactly, resulting in its inhibition (Figure 2). This was the basis of the development of the first-ever ACE inhibiting drug, Captopril, in 1975. (3,4)

This totally new concept of structure-based drug design is now widely used for drug development. When Captopril gained FDA approval in 1982, it was prescribed to alleviate high blood pressure and improve the well-being of millions of people worldwide. Following this groundbreaking development, research continued. After the launch of Captopril, however, the study of this revolutionary nonapeptide took an interesting new turn.

Milking It!

In 1985, Chi and colleagues came up with a surprising discovery about the structure of the nonapeptide. They found that when they removed amino acids from the peptide, it was still capable of inhibiting ACE. Around 90% of the original activity was still present when the nonapeptide was reduced to a tripeptide containing the last three amino acids: Ile-Pro-Pro (Figure 3). So, it was concluded that it is just the Ile-Pro-Pro (IPP) tripeptide that is vital to effect ACE inhibition, which then leads to the crucial reduction in blood pressure. (5) Knowing what the exact structure of the active peptide should be, the time was ripe to look for natural sources. Scientists set about finding protein-rich sources that might offer the same benefit--preferably in a food grade format.

Extensive analyses of all the possible protein sources that potentially held the key to successful blood pressure reduction led to the next significant breakthrough. It was discovered that one of the richest sources of IPP proteins was, in fact, milk. In 1991, Japanese scientists created the first ever milk-based ACE inhibitor in the form of a fermented milk drink, using specific cultures to liberate the IPP from the dairy protein. Interestingly, Val-Pro-Pro (VPP) is also liberated in this process--another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. Shortly after this, in 1996, the first human study confirmed the blood pressure lowering effect of IPP in fermented milk. (6) Although twice the amount of VPP is needed to achieve the same ACE inhibiting activity as the originally discovered IPP, it is assumed that VPP also adds to the total blood pressure lowering effect. (7,8)

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An Enzymatic Solution to Take the Pressure Off

The fermented milk innovation was an important step forward in finding a natural source of IPP; but there were still several obstacles to overcome. The fermentation process created slightly off notes, the taste of which could not be masked in many food applications. The end product would never appeal to a broad range of consumers. Suitable only for consumption as a fermented milk drink, its market limitations were evident: it failed to provide optimal concentration, application potential and cost-effectiveness. Continued research was needed to make further progress. The next step took place in 2003. A special enzyme technology was developed to effectively liberate the desired IPP from milk protein. Using this technology, a higher concentration of IPP could be achieved in the end product, which was also completely taste neutral. The IPP ingredient could now be used in non-dairy-specific applications too and offered clear benefits; it had no noticeable off taste and was suitable for applications such as tablets and capsules. A safe and effective food grade solution that could be used in numerous applications across the food and beverage sector had finally been found. Since the first lactotripeptide discovery, more than 20 human clinical trials have been conducted in many different countries. These published studies have proven the effectiveness of lactotripeptides in blood pressure control. (9) Today, the first IPP-containing ingredients are commercially available.

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Conclusion

From the interesting discovery that led to the first ever blood pressure lowering medication, the protein structure that made this all possible is now coming into its own. After many years of dedicated scientific research, we have reached the point of discovering the wide range of practical applications for food grade IPP products. With a scientifically proven beneficial effect, they present the food and beverage sector with a safe, blood pressure lowering tool that is both flexible and suitable as a food ingredient. Blood pressure lowering foods offer a convenient method of maintaining a healthy diet to control blood pressure. Suitable for widespread food and beverage applications, the market potential for IPP-containing products is huge. From their clearly successful beginnings, these groundbreaking food ingredients look set to take the lead in this exciting history of scientific discovery.

Award Winning Solution

tensVida is one of the first ever ingredients to be developed as a result of the successful isolation of natural lactotripeptides. It presents the food and beverage sector with a safe and clinically proven blood pressure lowering tool. Providing an effective way to help control blood pressure through dietary intervention, tensVida is an appealing proposition in the context of the growing global market for the treatment of hypertension. tensVida is produced using a patented process and has been designed for use in many different food applications. This offers exciting opportunities for food and dietary supplement companies. tensVida has a unique clean taste, dissolves as a clear solution in water, necessitates only low dosages and is stable under most food processing conditions.

This new ingredient is developed for use by people who want to follow a balanced diet and maintain a healthy lifestyle to control their blood pressure. tensVida is particularly beneficial for those people who have high normal or mildly hypertensive blood pressure, and who do not require blood pressure medication. It is not intended for use as a replacement for drugs to lower blood pressure. tensVida has received global acclaim, winning this year's NutrAward in the US and CFIA award in France, after also securing Gold at the 2008 Hi Awards for ingredient innovation.

References

(1.) S.H. Ferreira, "A Bradykinin-Potentiating Factor (BPF) Present in the Venom of Bothrops jararaca," Br. J. Pharmacol. 24, 163-169 (1965).

(2.) D.W. Cushman, "Development of Specific Inhibitors of Angiotensin I Converting Enzyme," Federation Proc. 38, 2778-2782 (1979).

(3.) D.W. Cushman and M.A. Ondetti, "History of the Design of Captopril and Related Inhibitors of Angiotensin Converting Enzyme," Hypertension 17(4), 589-592 (1991).

(4.) C.G. Smith and J.R. Vane, "The Discovery of Captopril," FASEB J. 17, 788-789 (2003).

(5.) C.W. Chi, "Structure-Function Studies on the Bradykinin Potentiating Peptide from Chinese Snake Venom (Agkistrodon halys Pallas)," Peptides 6 (Suppl. 3), 339-342 (1985).

(6.) Y. Hata, et al., "A Placebo-Controlled Study of the Effect of Sour Milk on Blood Pressure in Hypertensive Subjects," Am. J. Clin. Nutr. 64, 767-771 (1996).

(7.) Y. Nakamura, "Purification and Characterization of Angiotensin I-Converting Enzyme Inhibitors from Sour Milk," J. Dairy Sci. 78, 777-783 (1995).

(8.) Y. Nakamura, et al., "Antihypertensive Effect of Sour Milk and Peptides Isolated from it that are Inhibitors to Angiotensin I-Converting Enzyme," J. Dairy Sci. 78, 1253-1257 (1995).

(9.) E. Boelsma and J. Kloek, "Lactotripeptides and Antihypertensive Effects: A Critical Review," Br. J. Nutr. 101(6), 776-786 (2009).

Glossary

IPP or Ile-Pro-Pro: the tripeptide with the amino acid sequence Isoleucine-Proline-Proline.

Lactotripeptides: Ile-Pro-Pro and/or Val-Pro-Pro, specific milk-derived tripeptides with clinically proven blood pressure control properties.

ACE: Angiotensin Converting Enzyme--normally part of a reaction in the body that causes the blood vessels to narrow (constrict).

ACE Inhibitor: helps to block the angiotensin-converting enzyme. By blocking this enzyme, ACE inhibitors cause blood vessels to relax, which can lower blood pressure.

For more information

Luc van der Heyden

Business Manager, Heart Health

DSM Food Specialties

Tel. +31 15 279 3263

info.functionalfood-ingredients@dsm.com

www.dsm-foodspecialties.com/www.tensvida.com
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Title Annotation:cardiovascular health
Author:van der Heyden, Luc
Publication:Nutraceutical Business & Technology
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2009
Words:1749
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