Post on 30-Mar-2015
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