B-PO04-012 ACUTE TESTOSTERONE ADMINISTRATION DOES NOT SHORTEN ACTION POTENTIAL DURATION IN LANGENDORFF PERFUSED RABBIT VENTRICLES

Abstract

A previous study showed that testosterone (T) rapidly shortens the action potential duration (APD) with EC50=2.1 to 8.7 nmol/L in guinea pig ventricular myocytes due to non-transcriptional enhancement of IKs and suppression of ICa,L. These findings have not been reproduced in intact rabbit ventricles. To test the hypothesis that T and dihydroxytestosterone (D) acutely shorten epicardial APD in rabbit ventricles. We performed optical mapping studies in 6 female and 7 male Langendorff-perfused rabbit hearts. Blebbistatin (10-20 μM) was used to suppress motion. Right atrium was paced during mapping. After baseline recording, mapping was done with T (N=10) or D (N=3). In T group, either high (3 μM) or low (1 to 100 nM) doses were applied to 5 and 4 hearts respectively, and 1 received both low and high doses. In D group, 1 received only low (3 to 100 nM), and 2 received low and then high dose (1 μM). In one heart we determined the QT interval recorded with widely spaced bipolar electrodes by using Tyrode’s solution only, without optical dye (RH237) or blebbistatin. At pacing cycle length (PCL) 350 ms, 300 ms, and 250 ms, there were no significant differences of APD (ms) at baseline vs high dose T (182 ± 15 vs 186 ± 5, p=0.73; 160 ± 24 vs 159 ± 20, p=0.95, 152 ± 23 vs 149 ± 15 ms, p=0.71, respectively). High-dose D tends to lengthen APD (ms) in 2 hearts at PCL 350 ms (161 vs 179 and 143 vs 153), 300 ms (152 vs 167 and 139 vs 148), and 250 ms (139 vs 158 and 129 vs 137). APDs (ms) at baseline vs low-dose T were (144 ± 9 vs 147 ± 8 at 1nM, p=0.23 and 150 ± 8 at 10 nM, p=0.05). APDs at baseline vs low dose D were 146 ± 9 vs 153 ± 10 at 3 nM (p=0.34), 162 ± 15 at 10 nM (p=0.34), and 160 ± 11 at 100 nM (p=0.19) at PCL 300 ms. APD significantly lengthened after 100 nM of T (154 ± 12 ms at 100 nM, p=0.01). In one rabbit heart without RH237 or blebbistatin, QT interval (ms) at PCL 280 ms did not shorten after T (170 at baseline, 172 at 10 nM, and 176 at 100 nM). When separately analyzed, neither male nor female hearts showed APD shortening with T or D. T and D do not shorten and may lengthen ventricular repolarization in normal male or female rabbit hearts. These findings do not support non-transcriptional regulation of cardiac ion currents by T or D to shorten APD.