Extracellular Zinc Enhances Cardiomyocyte Relaxation Function in Diabetic Rats

Diabetes mellitus (DM) leads to a cardiomyopathy in humans and rodent models. Interestingly, the chronic infusion of zinc in DM mice prevents the development of the cardiomyopathy. To elucidate the possible mechanism underlying this observation, we examined the effects of extracellular zinc ion (Zn2+) on cardiomyocyte function in DM rats (n=5) compared to non-DM controls (Ctrl, n=5). Both the DM and Ctrl rats were hypothyroid, which assured similar upregulation of β-myosin heavy chain (β-MHC) in both populations. Isolated cardiomyocytes were electrically stimulated at 2, 4, 6 and 6.5 Hz, maintained at 35°C and exposed to 1.2 mM extracellular Ca2+. Sarcomere shortening and relengthening dynamics were monitored using a video-based Fourier-transform technique. Without extracellular Zn2+ peak shortening as a fraction of diastolic sarcomere length was statistically greater (P<0.05) in the DM (6.56 ± 0.99 %; n = 16) compared to Ctrl (5.27 ± 1.91 %; n = 20) at 2 Hz, but not at higher frequencies. Time to 50% return to diastolic sarcomere length was not statistically different between the groups at every pacing frequency. Exposure to 12 μM extracellular Zn2+ significantly reduced (P<0.001) peak shortening in both the DM and Ctrl at all frequencies. There was a strong trend (P = 0.070) toward Zn2+ exposure significantly shortening the time to 50% return in the DM but not in the Ctrl, as revealed by repeated-measures ANOVA. Similar trends were found for time to peak shortening (P=0.087) and time to 10% return (P=0.048). These results suggest that extracellular Zn2+ inhibits cardiomyocyte contractile function independent of DM, perhaps by competing with intracellular Ca2+, and enhances cardiomyocyte diastolic function in the DM. The enhanced sensitivity of the DM to the relaxing effects of Zn2+ may underlie the protective effects of Zn2+ against diabetic cardiomyopathy.