CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 5, September/October 2010
AFRICA
283
the apparent inhibitory effects of these flavonoids on the
hepatic enzymes controlling glucose homeostasis act directly
or indirectly via upstream regulators of these enzymes, such as
adenosine monophosphate protein kinase (AMPK), the ‘master
energy sensor’, which is known to regulate the activities of the
enzymes.
73-75
That these flavonoids or their derivatives may be
the ultimate anti-diabetic agents in grapefruit is a speculative
possibility, given that AMPK modulators are currently being
investigated as potential anti-diabetic agents.
76
Grapefruit and cardiovascular diseases
That
Citrus
flavonoids are promising compounds against cardio-
vascular diseases is a dream becoming reality. Epidemiological
studies are unanimous that increased dietary intake of flavonoids
has been associated with reduced risk of ischaemic stroke and
cardiovascular diseases.
77,78
The protective effects of flavonoids
include: anti-ischaemic, antioxidant, vasorelaxant and antithrom-
botic properties.
It has been suggested that flavonoids decrease the risk of
coronary heart diseases by improving coronary vasodilatation,
decreasing the ability of the platelets to clot, and preventing
oxidation of low-density lipoproteins (LDL).
79
Recent stud-
ies have shown that naringenin inhibits secretion of apoB and
enhances LDL receptor-mediated apoB uptake.
80
Hesperidin
has similarly been reported to increase high-density lipoprotein
(HDL) and lower LDL, plasma triglycerides and total lipids in
rats.
81
Hesperidin and naringenin have been reported to cause
vasorelaxation of rat intact aortic rings by inhibition of different
phosphodiesterase isoenzymes.
82,83
Another study by Yamamoto
et al
.
84
also reported that glucosyl-hesperidin lowers blood pres-
sure in spontaneously hypertensive rats (SHR) and prevents
endothelial dysfunction and oxidative stress in SHR.
85
A recent
study by Rajadurai
et al
.
86
has demonstrated that naringin
prevents mitochondrial dysfunction during isoproterenol (ISO)-
induced myocardial infarction in rats, suggesting that naringin
has a cardioprotective role against myocardial infarction, perhaps
due to its reported antioxidant effects.
87
However, grapefruit has been implicated in the prolongation
of QTc in healthy volunteers,
88
as well as in patients with post-
ischaemic dilated cardiomyopathy or hypertensive cardiomyopa-
thy.
89
Naringenin has been identified as the culprit.
90
This obser-
vation suggests that naringenin in grapefruit has pro-arrythmic
actions which may block the therapeutic effects of anti-arrythmic
drugs.
These observations, therefore, strongly suggest that hespe-
ridine and naringin, acting alone or synergistically with other
chemical compounds in grapefruit, affect the cardiovascular
system in many ways. However, it is not clear at this stage how
these flavonoids could be mediating such effects. It is tempt-
ing to speculate that the actions of hesperidine and naringin (or
naringenin) could be mediated by AMPK, which is known to
increase glucose uptake, fatty acid uptake and utilisation, and
glycolysis in the heart and other peripheral tissues.
It is therefore not surprising that the cardioprotective effects
of metformin have now been recognised, and AMPK-mediated
pathways are currently considered potential therapeutic targets
in cardio-metabolic diseases. It has recently been reported that
a single dose of metformin results in acute increase in AMPK
activity, and induces a significant reduction in infarct size 24
hours after metformin administration.
91
Metformin-like effects
of grapefruit juice in the regulation of blood glucose have been
reported.
61
Could grapefruit have similar effects on the cardio-
vascular system?
Conclusions
In the last 10 years, grapefruit has been a pharmacologoist’s
nightmare, given its popularity and potential for interaction with
many therapeutic drugs. To date, no clear guidelines have been
put forward to protect vulnerable patients against the hazardous
consequences of grapefruit–drug interactions. However, it is now
emerging that apart from drug interactions, which have largely
been attributed to furanocoumarins, flavonoids such as naringin
and hesperidin could be playing more important roles in the
prevention of diabetes and cardiovascular diseases. Attention has
now shifted to investigating the molecular mechanisms by which
these flavonoids exert their protective cardiovascular effects. In
the coming years, basic and clinical research in cardiovascular
pharmacology should be focused on grapefruit and its flavonoids
and/or their chemical derivatives.
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