A Randomized, Double-Blind, Placebo-Controlled, Multicentre Trial of the Effects of a Shrimp Protein Hydrolysate on Blood Pressure

Kathy Musa-Veloso, Lina Paulionis, Tetyana Pelipyagina, Mal Evans, Kathy Musa-Veloso, Lina Paulionis, Tetyana Pelipyagina, Mal Evans

Abstract

In this randomized, double-blind, placebo-controlled, multicentre, parallel, 8-week study, the efficacy of a daily dose of 1200 mg of protein hydrolysate from Coldwater Shrimp (Pandalus borealis) on ambulatory and office blood pressure was investigated in 144 free-living adults with mild to moderate hypertension. The primary outcomes of the study were daytime ambulatory systolic blood pressure and office blood pressure. During the 8-week intervention period and in the intention-to-treat analysis (n=144), there were significant reductions in the group consuming the shrimp-derived protein hydrolysate relative to the placebo group in daytime ambulatory systolic blood pressure at 4 weeks (p=0.014) and at 8 weeks (p=0.002), and in office systolic blood pressure at 2 weeks (p=0.031) and 4 weeks (p=0.010), with a trend toward significance at 8 weeks (p=0.087). By 8 weeks, significant and favourable improvements in the group consuming the shrimp-derived protein hydrolysate relative to the placebo group were also observed for several secondary outcomes, including 24-hour ambulatory systolic and diastolic blood pressure, daytime ambulatory diastolic blood pressure, and daytime and 24-hour ambulatory mean arterial pressure. Also by Week 8, there was a statistically significant difference between groups in the distribution of subjects across National Institutes of Health-defined blood pressure categories (i.e., Normotensive, Prehypertensive, Stage 1 hypertension, and Stage 2 hypertension), with a more favourable distribution in the shrimp-derived protein hydrolysate group than in the placebo group (p=0.006). Based on exploratory analyses conducted only in participants in the shrimp-derived protein hydrolysate group, angiotensin II levels were significantly reduced relative to baseline. This study is registered at ClinicalTrials.gov NCT01974570.

Conflict of interest statement

Mal Evans is an employee of and Tetyana Pelipyagina is a former employee of KGK Science Inc., which is the contract research organization that was contracted by Marealis AS to run the clinical study, conduct the statistical analyses, and compile the clinical study report. Kathy Musa-Veloso is an employee of and Lina Paulionis is a former employee of Intertek Scientific & Regulatory Consultancy, which received, from Marealis AS, the sponsor of the study, financial compensation for scientific, and regulatory consulting services, including payment for the review of the clinical study report and preparation of the manuscript.

Figures

Figure 1
Figure 1
Flowchart of study participants.
Figure 2
Figure 2
Proportion of ITT subjects in NIH-defined blood pressure categories at weeks 0, 2, 4, and 8 of the study based on office blood pressure. ITT: intention-to-treat; NIH: National Institutes of Health; RPC: Refined Peptide Concentrate; ∗∗∗: p=0.006, for the difference between groups in the distribution of subjects across NIH-defined blood pressure categories, favouring RPC over placebo.

References

    1. World Health Organization. Global Status Report on Noncommunicable Diseases 2010. 2011. Reviewed in World Health Organization, 2013.
    1. World Health Organization. Raised Blood Pressure. Global Health Observatory (GHO) data, 2018,
    1. Kithas P. A., Supiano M. A. Practical recommendations for treatment of hypertension in older patients. Vascular Health and Risk Management. 2010;6:561–569.
    1. Hasnain M. M., Vieweg W. V. Possible role of vascular risk factors in alzheimer's disease and vascular dementia. Current Pharmaceutical Design. 2014;20(38):6007–6013. doi: 10.2174/1381612820666140314153440.
    1. World Health Organization. Global Brief on Hypertension. 2013, .
    1. Hideaki K., Masayoshi K., Shigeru S., et al. Oral administration of peptides derived from bonito bowels decreases blood pressure in spontaneously hypertensive rats by inhibiting angiotensin converting enzyme. Comparative Biochemistry and Physiology Part C: Comparative Pharmacology. 1993;104(2):351–353. doi: 10.1016/0742-8413(93)90047-O.
    1. Fujii M., Matsumura N., Mito K., et al. Antihypertensive effects of peptides in autolysate of bonito bowels on spontaneously hypertensive rats. Bioscience, Biotechnology, and Biochemistry. 1993;57(12):2186–2188. doi: 10.1271/bbb.57.2186.
    1. Fujita H., Yokoyama K., Yasumoto R., Yoshikawa M. Antihypertensive effect of thermolysin digest of dried bonito in spontaneously hypertensive rat. Clinical and Experimental Pharmacology and Physiology. 1995;22(1):S304–S305. doi: 10.1111/j.1440-1681.1995.tb02929.x.
    1. Fujita H., Yoshikawa M. LKPNM: A prodrug-type ACE-inhibitory peptide derived from fish protein. International Journal of Immunopharmacology. 1999;44(1-2):123–127. doi: 10.1016/S0162-3109(99)00118-6.
    1. Qian Z., Je J., Kim S. Antihypertensive effect of angiotensin I converting enzyme-inhibitory peptide from hydrolysates of bigeye tuna dark muscle, Thunnus obesus. Journal of Agricultural and Food Chemistry. 2007;55(21):8398–8403. doi: 10.1021/jf0710635.
    1. Otani L., Ninomiya T., Murakami M., Osajima K., Kato H., Murakami T. Sardine peptide with angiotensin i-converting enzyme inhibitory activity improves glucose tolerance in stroke-prone spontaneously hypertensive rats. Bioscience, Biotechnology, and Biochemistry. 2009;73(10):2203–2209. doi: 10.1271/bbb.90311.
    1. Li Y., Zhou J., Huang K., Sun Y., Zeng X. Purification of a novel angiotensin I-converting enzyme (ACE) inhibitory peptide with an antihypertensive effect from loach (Misgurnus anguillicaudatus) Journal of Agricultural and Food Chemistry. 2012;60(5):1320–1325. doi: 10.1021/jf204118n.
    1. Yang P., Jiang Y., Hong P., Cao W. Angiotensin I converting enzyme inhibitory activity and antihypertensive effect in spontaneously hypertensive rats of cobia ( Rachycentron canadum ) head papain hydrolysate. Food Science and Technology International. 2013;19(3):209–215. doi: 10.1177/1082013212442196.
    1. Zou P., Wang J., He G., Wu J. Purification, identification, and in vivo activity of angiotensin I-converting enzyme inhibitory peptide, from ribbonfish (Trichiurus haumela) backbone. Journal of Food Science. 2014;79(1):C1–C7. doi: 10.1111/1750-3841.12269.
    1. Ngo D., Kang K., Ryu B., et al. Angiotensin-I converting enzyme inhibitory peptides from antihypertensive skate (Okamejei kenojei) skin gelatin hydrolysate in spontaneously hypertensive rats. Food Chemistry. 2015;174:37–43. doi: 10.1016/j.foodchem.2014.11.013.
    1. Jensen I., Eysturskarð J., Madetoja M., Eilertsen K. The potential of cod hydrolyzate to inhibit blood pressure in spontaneously hypertensive rats. Nutrition Research. 2014;34(2):168–173. doi: 10.1016/j.nutres.2013.11.003.
    1. Vignesh R., Srinivasan M., Jayaprabha N., Badhul Haq M. A. The functional role of fish protein hydrolysate derived bioactive compounds in cardioprotection and antioxdative functions. International Journal of Pharmacy and Biological Sciences. 2012;3(1):B560–B566.
    1. Bordenave S., Fruitier I., Ballandier I., et al. HPLC preparation of fish waste hydrolysate fractions. Effect on guinea pig ileum and ace activity. Preparative Biochemistry and Biotechnology. 2002;32(1):65–77. doi: 10.1081/PB-120013162.
    1. He H. L., Chen X. L., Wu H., Sun C. Y., Zhang Y. Z., Zhou B. C. High throughput and rapid screening of marine protein hydrolysates enriched in peptides with angiotensin-I-converting enzyme inhibitory activity by capillary electrophoresis. Bioresource Technology. 2007;98(18):3499–3505. doi: 10.1016/j.biortech.2006.11.036.
    1. Nii Y., Fukuta K., Yoshimoto R., et al. Anti-hypertensive effects of izumi-shrimp extracts in stroke-prone spontaneously hypertensive rats(SHRSP) Journal of the Japanese Society for Food Science and Technology. 1998;45(11):671–675. doi: 10.3136/nskkk.45.671.
    1. Enari H., Takahashi Y., Kawarasaki M., Tada M., Tatsuta K. Identification of angiotensin I-converting enzyme inhibitory peptides derived from salmon muscle and their antihypertensive effect. Fisheries Science. 2008;74(4):911–920. doi: 10.1111/j.1444-2906.2008.01606.x.
    1. Gildberg A., Arnesen J. A., Sæther B., Rauø J., Stenberg E. Angiotensin I-converting enzyme inhibitory activity in a hydrolysate of proteins from Northern shrimp (Pandalus borealis) and identification of two novel inhibitory tri-peptides. Process Biochemistry. 2011;46(11):2205–2209. doi: 10.1016/j.procbio.2011.08.003.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human Use. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) ICH Harmonised Tripartite Guideline - Current Step 4 version, 2016, .
    1. KGK Science Inc. Effect and Safety of Marealis RPC (Refined Peptide Concentrate) in Mild or Moderate Hypertensive Subjects. KGK Science Inc. in collaboration with Marealis AS, Identifier: NCT01974570 Other Study ID Numbers: 13TBHM, 2013, .
    1. Dieterle T. Blood pressure measurement--an overview. Swiss Medical Weekly. 2012;42:p. 9.w13517
    1. Pickering T. G., Hall J. E., Appel L. J., et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the american heart association council on high blood pressure research. Circulation. 2005;111(5):697–716. doi: 10.1161/01.CIR.0000154900.76284.F6.
    1. O'Brien E., Waeber B., Parati G., Staessen J., Myers M. G. Blood pressure measuring devices: recommendations of the european society of hypertension. British Medical Journal. 2001;322(7285):531–536. doi: 10.1136/bmj.322.7285.531.
    1. Van Hoof R., Hespel P., Fagard R., Lijnen P., Staessen J., Amery A. Effect of endurance training on blood pressure at rest, during exercise and during 24 hours in sedentary men. American Journal of Cardiology. 1989;63(13):945–949. doi: 10.1016/0002-9149(89)90145-8.
    1. Myburgh D. P., Verho M., Botes J. H., Erasmus T. P., Luus H. G. 24-hour blood pressure control with ramipril: comparison of once-daily morning and evening administration. Current Therapeutic Research. 1995;56(12):1298–1306. doi: 10.1016/0011-393X(95)85074-0.
    1. Soergel M., Kirschstein M., Busch C., et al. Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: A multicenter trial including 1141 subjects. Journal of Pediatrics. 1997;130(2):178–184. doi: 10.1016/S0022-3476(97)70340-8.
    1. Staessen J., Bulpitt C. J., Fagard R., et al. Reference values for the ambulatory blood pressure and the blood pressure measured at home: A population study. Journal of Human Hypertension. 1991;5(5):355–361.
    1. Chishti A. S. Ambulatory blood pressure monitoring. A pediatric review. Saudi Medical Journal. 2003;24(12):1292–1295.
    1. Hansen T. W., Kikuya M., Thijs L., et al. Diagnostic thresholds for ambulatory blood pressure moving lower: a review based on a meta-analysis—clinical implications. The Journal of Clinical Hypertension. 2008;10(5):377–381. doi: 10.1111/j.1751-7176.2008.07681.x.
    1. Jones H. E., Sinha M. D. The definition of daytime and nighttime influences the interpretation of ABPM in children. Pediatric Nephrology. 2011;26(5):775–781. doi: 10.1007/s00467-011-1791-3.
    1. Mortensen R. N., Gerds T. A., Jeppesen J. L., Torp-Pedersen C. Office blood pressure or ambulatory blood pressure for the prediction of cardiovascular events. European Heart Journal. 2017;38(44):3296–3304. doi: 10.1093/eurheartj/ehx464.
    1. R Core Team. R Statistical Software Package Version 3.5.1. R Project for Statistical Computing, 2018,
    1. Kannel W. B., Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studies. Journal of Hypertension. 1990;8(5):S3–S8.
    1. Alper A. B., Calhoun D. A., Oparil S. Encyclopedia of Life Sciences. New York, NY, USA: Wiley Online Library, John Wiley & Sons; 2001. Hypertension.
    1. Li G.-H., Le G.-W., Shi Y.-H., Shrestha S. Angiotensin I-converting enzyme inhibitory peptides derived from food proteins and their physiological and pharmacological effects. Nutrition Research. 2004;24(7):469–486. doi: 10.1016/j.nutres.2003.10.014. doi: 10.1016/S0271-5317(04)00058-2.
    1. Cheung H. S., Wang F. L., Ondetti M. A., Sabo E. F., Cushman D. W. Binding of peptide substrates and inhibitors of angiotensin-converting enzyme. Importance of the COOH-terminal dipeptide sequence. The Journal of Biological Chemistry. 1980;255(2):401–407.
    1. Asmar R. Evaluation of the placebo effect and reproducibility of blood pressure measurement in hypertension. American Journal of Hypertension. 2001;14(6):546–552. doi: 10.1016/S0895-7061(00)01286-3.

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