Hawthorn and some of its individual constituents (e.g., oligomeric procyanidins [OPC], flavonoids) have been shown to have effects on nitric oxide (NO) and endothelial function, which are implicated in hypertension and CVD [27
]. Hawthorn has been shown to produce endothelial-dependent arterial vasodilation in mice, rats, pigs, and humans [3
] that is linked to activation of endothelial NO-synthase (NOS) [3
]. Studies of different fractions of HSE have demonstrated that it is the OPC-rich fraction that mediates hawthorn's vasodilatory effects [3
]. Therefore, we sought to investigate the effects of a standardized, OPC-concentrated hawthorn formulation on flow-mediated brachial artery dilation, a measure of NO release. However, we did not detect a dose-response effect on FMD, and no dose appeared to have an effect significantly different than placebo, indicating that HSE may not have a clinically meaningful effect on NO in humans.
Formation of endogenous NO is typically mediated by NOS through the oxidation of the amino acid L-arginine. It is now understood that profound reduction of NO occurs with aging so that a 40 year old adult may only produce half as much NO as a 20 year old [31
]. However, strategies to increase NO production by supplementing with L-arginine have failed to demonstrate any clinically meaningful results in human trials [34
], leading to the conclusion that another pathway may need to be activated to increase NO production.
Exogenous intake of nitrate in humans is converted by commensal bacteria to nitrite, which can then be reduced to NO [35
]. However, the reduction process catalyzed by nitrite reductase is particularly inefficient [36
]. Zand, et al. screened over 100 botanicals and found hawthorn to have the highest nitrate reductase activity. They then tested a combination supplement that was both rich in natural nitrate (beetroot) and nitrite reductase activity (hawthorn) and found that the supplement produced sustained in vitro
NO release with a t1/2
of about 60 minutes and rapid and sustained human plasma NO levels (~1.4 μM) after a single dose in vivo
. Steady state human plasma nitrite concentrations rose from 0.10 μM to 0.28 μM after taking the supplement for 30 days, which was statistically significantly greater than placebo, while plasma nitrite concentrations decreased in the placebo group. Finally, mildly hypertensive participants (systolic BP 135 - 160 mm Hg, n = 9) experienced a mean 7 mm Hg systolic and 2.7 mm Hg diastolic blood pressure reduction, although this was not statistically significant [35
Given what is known about the pathways of NO production, it is possible that hawthorn alone is insufficient to have a meaningful effect on NO and may require addition of nitrate/nitrite to be effective in vivo. We did not measure plasma nitrate concentration in the current study; additionally, the mean age of our participants was 51 years and nearly all participants were older than 40 years, so the ability to produce NO was likely limited in our study population. Therefore, our study results may reflect a poor native ability to produce NO.
Studies of hawthorn to lower BP in humans suggest benefits, although only three small randomized, placebo-controlled trials have been performed [9
]. Asgary, et al. treated mildly hypertensive adults for 16 weeks and observed mean systolic and diastolic BP reductions of 13 mm Hg and 8 mm Hg respectively. Walker, et al. studied both untreated mildly hypertensive patients and treated hypertensive diabetic patients for 10-16 weeks and observed systolic BP reductions of 3.6-10 mm Hg and diastolic BP reductions of 2.6-7 mm Hg. Other studies of the effect of hawthorn on heart failure also suggest that it may have a BP lowering effect, although BP was a secondary outcome in each of those studies [19
]. All hawthorn studies to lower BP have had a minimum 10 week intervention period and the German Commission E recommends a minimum of 6 weeks [37
]. Even if hawthorn has no effect on NO, it is still worthwhile to investigate the effects of hawthorn on blood pressure given the results of these prior trials.
Several limitations of this study should be considered. Although we measured adherence by self-report, poor adherence could have masked any effect of hawthorn, and we did not include a pharmacologic adherence assessment. However, no individual participants exhibited a dose-response effect, and it would be very unlikely that all participants were uniformly poorly adherent. Pharmacokinetic parameters of hawthorn constituents are poorly described for humans. Reports in rodents demonstrate poor oral absorption and bioavailability for some constituents of hawthorn [21
]. Poor absorption of the HSE pills could confound our results, but would not contradict preclinical in vitro
and ex vivo
findings. However, similar doses of HSE have been used for trials in patients with HF that have shown beneficial effects, suggesting there is sufficient oral bioavailability of HSE to demonstrate physiologic effects. It is possible that twice daily dosing of HSE for 4 days is insufficient to have an effect on NO production. However, most mechanisms to increase NO production in response to shear stress, such as that produced during FMD, take minutes to hours to occur (eg. calcium ion flux, eNOS activation, eNOS gene transcription) [23
Little is known about differences among HSE formulations so our results may not be generalizable to other hawthorn formulations. The extract for this trial was a whole leaf and flower formulation with sufficient plant material to provide OPC at high concentrations. Other extraction techniques may favor a different mix of constituents (ie. hydrophilic vs hydrophobic extraction processes), as would doping a low OPC extract with additional OPC-rich fraction to obtain high OPC concentrations.