Hormetic response of resveratrol against cardioprotection

Abstract

Resveratrol, a grape- and red wine-derived polyphenolic phytoalexin, shows diverse health benefits including cardioprotection. Recent studies implicate that resveratrol displays hormetic action, protecting the cells at a lower dose while killing them at relatively higher doses. Because such hormetic behaviour may have a significant impact on epidemiological and clinical studies, the present study sought to determine dose-response curves for resveratrol action. In parallel, another resveratrol formulation was tested, namely, Longevinex (Resveratrol Partners LLC, USA). A group of rats were force-fed three different doses of resveratrol or Longevinex (2.5 mg/kg, 25 mg/kg and 100 mg/kg) for up to 30 days, while the control group was only given placebo. The results showed hormesis for pure resveratrol, which was cardioprotective at lower doses and detrimental for higher doses, but surprisingly Longevinex did not display any hormetic action. In the concentration range studied, Longevinex remained cardioprotective even at 100 mg/100 g body weight - a dose that killed 100% of the hearts when tested with pure resveratrol. To further test whether Longevinex doses are beneficial for other animal species, Longevinex was gavaged to a group of rabbits for six months, and showed exactly the same degree of cardioprotection. Cardioprotection was examined in isolated working hearts subjected to 30 min of ischemia followed by 2 h of reperfusion; left ventricular performance and infarct size was also examined. It appears that Longevinex does not show any hormetic action, while resveratrol clearly does.

Keywords: Dose response; Hormesis; Longevinex; Resveratrol.

Figure 1)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on aortic flow. Isolated perfused rat hearts were subjected to 30 min ischemia followed by 2 h of reperfusion. Aortic flow was measured at baseline and during reperfusion. Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control; ^†P<0.05 versus 25 mg/kg

Figure 2)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on coronary flow. Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. Coronary flow was measured at baseline and during reperfusion. Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control

Figure 3)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on left ventricular developed pressure (LVDP). Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. LVDP was measured at baseline and during reperfusion. Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control; ^†P<0.05 versus 25 mg/kg

Figure 4)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on the maximum first derivative of left ventricular developed pressure (LV[dP/dt]_max). Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. LV(dP/dt)_max was calculated from left ventricular developed pressure at baseline and during reperfusion. Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control; ^†P<0.05 versus 2.5 mg/kg

Figure 5)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on myocardial infarct size. Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. At the end of each experiment, infarct size was calculated by the triphenyl tetrazolium chloride staining method. Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control; ^†P<0.05 versus 2.5 mg/kg

Figure 6)

The effects of resveratrol and Longevinex (Resveratrol Partners LLC, USA) on cardiomyocyte apoptosis. Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. At the end of each experiment, cardiomyocyte apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling method (as described in the Methods section). Results are expressed as mean ± SEM (six rats per group). *P<0.05 versus control; ^†P<0.05 versus 2.5 mg/kg

Figure 7)

Hormetic action of resveratrol. Resveratrol dose (x axis) is plotted against the values of cardiac function, infarct size and apoptosis. Resveratrol at a dose of 2.5 mg/kg provided maximum protection (peak), which progressively and steadily declined. LVDP Left ventricular developed pressure; LV(dp/dt)_max Maximum first derivative of left ventricular developed pressure

Figure 8)

The effects of resveratrol and longevinex (100 mg/kg) on myocardial infarct size in isolated rabbit hearts. Isolated perfused rabbit hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. At the end of each experiment, infarct size was calculated by the triphenyl tetrazolium chloride staining method. Results are expressed as mean ± SEM (six rabbits per group)