This randomized, placebo-controlled, double blind crossover study demonstrated that combined alpha-lipoic acid/acetyl-L-carnitine treatment was associated with an increase in baseline brachial artery diameter. Furthermore, we observed a non significant trend for a blood pressure lowering effect of alpha lipoic acid/acetyl-L-carnitine in all subjects and a significant reduction in systolic blood pressure in subjects with systolic blood pressures above the median and in subjects with the metabolic syndrome. These findings suggest the possibility that these mitochondria-directed antioxidants reduce basal arterial tone, particularly in two clinically relevant subgroups. In contrast, we observed no effect of treatment on the dilator responses to increased flow, nitroglycerin, or ischemia (reactive hyperemia).
A prior study demonstrated a decrease in systolic blood pressure and a direct vasodilator effect in nailfold capillaries after treatment with oral L-carnitine (3g/d for 20days) in patients with digital vasospastic disease.29
An open-label study of patients with diabetic nephropathy, reported that long-term alpha lipoic acid treatment (600 mg/d for 18 months) prevented the increases in blood pressure and urine albumin concentration observed in control patients.30
Experimental studies have consistently demonstrated an anti-hypertensive effect of alpha-lipoic acid or L-carnitine in various rat models of hypertension, including spontaneously hypertensive rats,8,9
uninephrectomized deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats10
and salt-loaded Dahl and Wistar-Kyoto rats.11,12
Our study differs from several previous human studies that examined the effects of lipoic acid or carnitine on endothelial function. For example, Heitzer and colleagues observed an acute improvement in endothelium-dependent dilation of forearm microvessels following an intra-arterial infusion of lipoic acid (final concentration 0.2 mmoles/L) in patients with diabetes mellitus.26
Sola and colleagues recently reported improved brachial artery flow-mediated dilation following treatment with lipoic acid 300 mg/d for four weeks in young patients with the metabolic syndrome (mean age 46 years).27
Intravenous administration of L-carnitine (3 gram bolus) enhanced reactive hyperemia in patients with peripheral arterial disease.31
The apparent discrepancies between the results of those prior studies and the present study likely relate to the marked differences in dose, route of administration, vascular bed studied and/or patient population.
The mechanisms accounting for the increased brachial artery diameter and suggestive anti-hypertensive effects of alpha-lipoic acid and acetyl-L-carnitine in our study remain undefined. We observed no effect of treatment on serum lipids, glucose, and insulin, which might have influenced endothelial function or arterial diameter. Experimental studies indicate that alpha-lipoic acid and acetyl-L-carnitine play important and potentially synergistic roles in normal mitochondrial function, and that reduced levels of these compounds are associated with increased mitochondrial oxidant production.6,25,32
In addition, lipoic acid supplementation has favorable effects on cellular redox state and has been shown to decrease lipid peroxidation and cellular production of reactive oxygen species.6,7,32,33
The effects of alpha-lipoic acid and acetyl-L-carnitine on oxidative stress which contributes to the pathogenesis and cardiovascular complications of hypertension suggests that these compounds may be useful adjuncts in treatment.34
In the present study, we investigated the possibility that these compounds reduced oxidative stress and inflammation, but observed no effect of treatment on urinary F2
isoprostanes or serum C-reactive protein. It is important to point out, however, that these systemic markers may not accurately reflect events in the vascular wall.
Despite the effects on blood pressure and basal diameter, it is notable that we only observed a trend for increased total serum carnitine following treatment. It is known that acetyl-L-carnitine and alpha-lipoic acid are rapidly metabolized in human subjects with plasma half lives of 4.2 hours35
and 30 minutes,36
respectively. Thus, it is likely that acetyl-L-carnitine and lipoic acid metabolites and/or tissue levels may be more relevant for the observed effects. Similarly, the lack of effect of treatment on urine F2 isoprostanes does not rule out an effect of active treatment on oxidative stress at the tissue level.
We observed a particular benefit of alpha-lipoic acid/acetyl-L-carnitine in patients with the metabolic syndrome. This syndrome of insulin resistance is associated with hypertension; improvement of insulin sensitivity could have an anti-hypertensive effect. Consistent with our findings, several experimental studies suggest a blood pressure-lowering effect in models of diabetes mellitus or insulin resistance.13-16
Those results and our findings are consistent with the growing evidence linking insulin resistance to mitochondrial dysfunction.37,38
Our study has a number of limitations. First, we observed a significant effect on baseline arterial diameter in all subjects, but the observed effects on blood pressure were significant only in subgroup analyses. These findings are difficult to reconcile, but could reflect a preferential effect on basal conduit artery tone. Further studies will be required to confirm these findings and elucidate the responsible mechanisms. Secondly, arterial tissue was not available for mechanistic analysis in this human study, so it remains speculative whether our findings actually reflect improved mitochondrial function and reduced oxidative stress. Third, we studied the combination of alpha-lipoic acid because these compounds may act synergistically,32
but it remains unknown whether either compound given alone would have had a similar effect. Finally, our observations about blood pressure were based on subgroup analyses, and as such, could reflect chance findings. Balancing these limitations is the double blind, prospective, crossover design of our study. Our results are consistent with prior experimental work, and the reduction in initial blood pressure, blood pressure after nitroglycerin, and the observed increase in brachial artery diameter all support an effect of active treatment on arterial tone and blood pressure.
The findings of the present study could have clinical implications. Hypertension remains the most prevalent form of cardiovascular disease, and there is a growing need for new and well-tolerated therapeutic approaches.39
The observed reduction in systolic blood pressure during alpha-lipoic acid/acetyl-L-carnitine treatment (9 mmHg in subjects with higher blood pressure) could potentially have a major effect on cardiovascular risk.39
Clearly, additional prospective studies are needed to confirm these findings and define the mechanism of benefit. However, our results appear to be consistent with the possibility that mitochondrial dysfunction contributes to the pathogenesis of hypertension, particularly in the setting of insulin resistance, and that therapy designed to restore mitochondrial function might prove useful for patient management.