The effect of dietary nitrate on blood pressure in type 2 diabetes

Dr Mark GilchristPeninsula Medical School

12th September 2011

Background

Health and vegetable rich diet

• Effects attributed to multiple factors:

Carter et al BMJ 2010

Chlorophyll

β-carotenePolyphenols

Ascorbic acid

Mg2+

Inorganic nitrate and vegetables

• Green leafy vegetables (and beetroot) particularly rich in inorganic nitrate

• In mammals previously thought to be inert waste product

Organic vs inorganic nitrate

Isosorbide mononitrate Nitrate ion

• Nitric oxide key regulator of vascular tone Palmer

et al Nature 1987

• Diminished production of NO in hypertension, hyperlipidemia, chronic kidney disease, type 2 diabetes

Forte et al Lancet 1997

Scherrer et al Eur J Endocrinol 2000

Nitrate, nitrite, and nitric oxide

• Nitrate involved in complex cycle with nitrite and nitric oxide

NO3- ⇌ NO2

- ⇌ NO

Nitrate NitriteNitric oxide

Nitrate, nitrite, and nitric oxide

Nitrate, nitrite, and nitric oxide

• Generate 1mmol nitrate/day from oxidation nitric oxide from L-arginine NOS pathway

• 1-2mmol nitrate per day typical Western diet

• Nitrate and nitrite may act as a storage pool of NO, delivering nitric oxide where it is required

Lundberg et al Nat Rev Micro 2004

Simplified representation of the entero-salivary circulation of dietary nitrate

Gilchrist et al Cardiovasc Res 2011

Duncan et al Nature Med 1995

Nitrate, nitrite, and blood pressure

Reichart Am J Med Sci 1880

Stieglitz JAMA 1930

Larsen et al NEJM 2006

Nitrate, nitrite, and blood pressure

Effect of oral nitrate on plasma nitrite and BP

Webb et al Hypertension 2008

Systolic Blood Pressure Plasma Nitrite

Time (hours)Time (hours)

Beneficial effects of dietary nitrate and nitrite

• Protection against IR injury

(Webb et al Hypertension 2008)

• Improvement in exercise efficiency

(Bailey et al JAP 2009)

• Reverse features of metabolic syndrome in eNOS KO mice

(Carlstrom et al PNAS 2010)

2 weeks2 weeks

Placebo

Active

Study design

• Randomised, double blind, placebo controlled crossover design

Active

Placebo

4 weeks

24 hr ABPM 24 hr ABPM

Placebo

• Beetroot juice treated with anion exchange resin Purolite A520e

• Selectively removes nitrate

• Active juice (250mls) nitrate dose 7.5mmol

• Placebo juice nitrate (250mls) dose 0.002mmol

Results

• 23 subjects, 15male, 8 female

Mean SDAge (yrs) 67.2 5.0

Duration of diabetes (yrs) 13.8 8.6Systolic BP (mmHg) 143.4 12.3Diastolic BP (mmHg) 82.3 9.0

BMI 30.8 3.3HbA1c (%) 7.6 1.2

Number antihypertensives 2.2 1.1

Plasma nitrate

Plasma nitrite

Systolic Diastolic MAP50.0

60.0

70.0

80.0

90.0

100.0

110.0

120.0

130.0

140.0

150.0

PlaceboActive

mm

Hg

Dietary nitrate and BP133.5 134.7

77.6 75.6

95.6 94.7

(p=0.43)(95% CI: -1.87 to 4.23).

Conclusion and discussion

• Dietary nitrate supplementation did not have a detectable effect on blood pressure in individuals with type 2 diabetes

Future work

• Is nitrate, nitrite and NO handling disordered in type 2 diabetes?

• Is this partly responsible for excess cardiovascular risk in type 2 diabetes?

Acknowledgements

• Supervisors– Prof Nigel Benjamin– Prof Angela Shore– Prof Paul Winyard

CRF Nurses◦ Christine Anning◦ Claire Ball◦ Linda Haynes◦ Andrew Pitt

Supported by: Peninsula NIHR Clinical Research Facility

WHO JEFCA 2003

“Overall, the epidemiological studies showed no consistently increased risk for cancer with increasing consumption of nitrate. These data, combined with the results of the epidemiological studies considered by the Committee at its forty-fourth meeting, do not provide evidence that nitrate is carcinogenic to humans.”

Ionic composition of juices

  Source Placebo Typical Daily Intake

Sodium 4.43mmol 4.1mmol 150mmol

Potassium 19.15mmol 18.25mmol 71mmol

Calcium 0.12mmol 0.095mmol 20mmol

Magnesium 1.85mmol 1.93mmol 7mmol

Chloride 6.83mmol 15.13mmol 150mmol