Altered electrical reactivity of endothelial tubes with aging: Role of mitochondria and Ca2+‐activated K+channels

Abstract

Hyperpolarization of endothelial cells (ECs) is integral to coordinating smooth muscle cell relaxation throughout resistance networks and endothelial function is compromised with aging. Aberrations in mitochondrial function may contribute to endothelial dysfunction however little is known of such effects with aging in the microcirculation. We tested (P<0.05) whether disrupting the proton gradient across the inner mitochondrial membrane (IMM) altered plasma membrane potential (Vm) in endothelial tubes (width, 60 μm; length, 1–3 mm) freshly isolated (bath pH, 7.4; 32°C) from superior epigastric arteries of Young (4–6 mo) and Old (24–26 mo) male C57BL/6 mice. The IMM proton ionophore FCCP (10 nM‐10 μM) depolarized Young ECs progressively (from resting Vm of −33±2 mV to −17±2 mV; n=5). In contrast, FCCP (10 nM‐10 μM) hyperpolarized Old ECs progressively (from −42±4 to −67±3 mV; n=5) which was abolished by SKCa/IKCa channel blockade with apamin (Ap, 300 nM) + charybdotoxin (ChTx, 100 nM). In Old, 300 nM FCCP hyperpolarized ECs by −12±1 mV and this reversed to 9±1 mV depolarization with Ap+ChTx (n=4). Despite no effect on Vm of Young, BKCa channel activation (NS1619, 30 μM) hyperpolarized Old ECs by −13±1 mV (n=6). We hypothesize that changes in endothelial function with aging reflects mitochondrial dysregulation of SKCa/IKCa channels with acquired BKCa channel activity. (R01HL086483, R37HL041026, F32HL110701).