Mechanism of inhibition of delayed rectifier K+ current by diphenyl phosphine oxide‐1 in porcine coronary smooth muscle (1079.10)

Abstract

Mechanisms involved in DPO‐1‐induced block of KDR were studied in myocytes isolated from the porcine coronary artery. DPO‐1 inhibited the slowly inactivating KDR in a dose‐dependent manner (IC50 = 212 ± 28 nM). Neither the time constant of activation (+20 mV) nor the time constant of deactivation (‐40 mV) was affected by DPO‐1 (1 μM). However, the fast and slow time constants of inactivation at +20 mV were notably shortened by DPO‐1 (fast = 0.52 ± 0.07 vs. 0.14 ± 0.01 s; slow = 5.8 ± 1.1 vs. 0.6 ± 0.2 s). These results suggest that DPO‐1 preferentially binds to the channel in the open state, producing an open channel block of KDR. As such, if KDR channels were open under resting conditions in vascular smooth muscle, then DPO‐1 should depolarize the membrane potential and cause vasoconstriction. To test this hypothesis and show functional relevance, we determined the effect of DPO‐1 on the membrane potential and coronary blood flow. DPO‐1 depolarized membrane potential from –29 ± 1 to ‐14 ± 3 mV. Further, DPO‐1 reduced coronary artery blood flow at 100 mmHg perfusion pressure from 21 to 14 ml/min. Together, these data indicate that DPO‐1 blocks KDR channels in the open state and that KDR channels in vascular smooth muscle are open under resting conditions. Thus, therapeutic tools that target KDR activity could be used to regulate vascular tone and mechanisms controlling KDR merit further study.Grant Funding Source: Supported by T32HL090610, T32HL079995, AHA 13POST1681001813, HL092245