Polyphenol Pharmacokinetics and Cardiovascular, Cognitive and Exercise Pharmacodynamics following Montmorency Tart Cherry Intake in Humans

Cardiovascular disease is the primary cause of global mortality (Naghavi, 2015). Given the global health issues associated with poor cardiovascular function, interventions that help reduce the severity and prevalence of these diseases would not only have economic implications, but would also improve health, wellbeing and quality of life. Epidemiological studies have suggested that polyphenol-rich foods can exert positive cardiovascular health benefits and as a result could reduce the severity of the primary pathology and increase the capacity to stay physically and mentally active (Joshipura et al., 1999; Bazzano et al., 2002; Hung et al., 2004). One of most studied polyphenol-rich, functional foods in recent years, in both the clinical and exercise domains, has been tart cherries. Tart cherries and their derivatives are high in numerous polyphenols (Wang et al., 1999; Seeram et al., 2001; Seymour et al., 2014; Bell et al., 2014) that include the flavonoids isorhamnetin, kaempferol, quercetin, catechin, epicatechin, procyanidins, and anthocyanins (Kim et al., 2005; Kirakosyan et al., 2009). Indeed, there has been an enormous research effort over the past decade to delineate the physiological and biochemical effects that tart cherries (and its constituents) might afford, and how these effects could be exploited to improve health outcomes. There is now strong evidence that tart cherries attenuate inflammation (Wang et al., 1999), oxidative stress (Howatson et al., 2010; Bell et al., 2014) and accelerate exercise recovery (Howatson et al., 2010; Bowtell et al., 2011; Bell et al., 2014; 2016). Furthermore, cherry extracts have been shown, in cell and animal models, to exert a range of cardioprotective effects that include increasing nitric oxide production and antioxidant (AOX) status, reducing lipid oxidation and inhibiting inflammatory pathways (Wang et al., 1999; Seeram et al., 2001). However, data from human trials are not always consistent. Furthermore, it is yet to be explored whether MC concentrate can be used for performance enhancement. Thus, the overarching aim of this thesis was to elucidate the effects of Montmorency, a specific cultivar of tart cherry, (MC) supplementation on vascular function and exercise performance in humans. The series of investigations that set out to address this aim have led to many novel and interesting findings. To begin, study 1 was the first to show that protocatechuic and vanillic acid were identified in the plasma post MC consumption. Furthermore, a combination of PCA and VA increased cell migration, but had no effect on the proliferation of vascular smooth muscle cells. Secondly, and perhaps the most novel finding of this thesis was that MC supplementation showed promise as an effective adjuvant in the management of hypertension. This was a consistent finding throughout the thesis; in all instances MC supplementation was able to significantly reduce systolic blood pressure. Another important finding was that MC supplementation resulted in an acute modulation of cerebral blood flow parameters in the front cortex during task performance with no changes in cognition or mood. Finally, the final study of this thesis demonstrated that MC supplementation can improve aspects of exercise performance with no changes in V̇O2 kinetics, NO2- concentrations or muscle oxygenation. All of these findings suggest that circulating phenolic metabolites derived from MC juice are at least partly responsible for these effects. Collectively, findings of this thesis provide novel information to literature surrounding the application of MC in health maintenance and exercise performance. In addition to identifying and quantifying some of the primary downstream metabolites of the principal anthocyanins contained in the concentrate, this research is the first to provide efficacy for the use of MC supplementation to acutely modulate various aspects of vascular function including systolic blood pressure, total and oxy-Hb during a cognitively challenging task. The underlying mechanisms that govern these effects remain elusive, although data from study 1, 2 and 4 would suggest that it is not likely to be attributed to NO, at least systemically. A more likely idea by which MC supplementation improves factors associated with CVD is based on the uptake of polyphenols that possess cardio-protective properties. To conclude, this thesis highlights the ability of MC to improve aspects of cardiovascular function and exercise performance. Circulating phenolic metabolites derived from MC are at least partly responsible for these acute improvements. Further work is required to; fully elucidate the mechanisms by which MC exerts its protective effects, determine whether the effects reported would be amplified using chronic supplementation and demonstrate effects of MC supplementation within habitual dietary practices