Key result
KMUP-1 (30μM) abolished UTP-inhibited delayed rectifying K+ currents in rat pulmonary artery smooth muscle cells, predominantly via RhoA/ROCK inhibition.
KMUP-1 reverses UTP-induced inhibition of delayed rectifying K+ currents in pulmonary artery smooth muscle cells via RhoA/ROCK signaling, highlighting a potential mechanism to prevent abnormal pulmonary vasoconstriction.
May target ROCK to mitigate pulmonary vasoconstriction; leaves open translation from this animal model to human disease.
We have demonstrated that KMUP‐1 (7‐[2‐[4‐(2‐chlorobenzene)piperazinyl]ethyl]‐1,3‐dimethylxanthine) blunts monocrotaline‐induced pulmonary arterial hypertension by altering Ca 2+ sensitivity, K + ‐channel function, endothelial nitric oxide synthase activity, and RhoA/Rho kinase (ROCK) expression. This study further investigated whether KMUP‐1 impedes uridine 5′‐triphosphate (UTP)‐inhibited delayed rectifying K + (K DR ) current in rat pulmonary arteries involved the RhoA/ROCK signaling. Pulmonary artery smooth muscle cells (PASMCs) were enzymatically dissociated from rat pulmonary arteries. KMUP‐1 (30μM) attenuated UTP (30μM)‐mediated membrane depolarization and abolished UTP‐enhanced cytosolic Ca 2+ concentration. Whole‐cell patch‐clamp electrophysiology was used to monitor K DR currents. A voltage‐dependent K DR current was isolated and shown to consist of a 4‐aminopyridine (5mM)‐sensitive component and an insensitive component. The 4‐aminopyridine sensitive K DR current was suppressed by UTP (30μM). The ROCK inhibitor Y27632 (30μM) abolished the ability of UTP to inhibit the K DR current. Like Y27632, KMUP‐1 (30μM) similarly abolished UTP‐inhibited K DR currents. Superfused protein kinase A and protein kinase G inhibitors (KT5720, 300nM and KT5823, 300nM) did not affect UTP‐inhibited K DR currents, but the currents were restored by adding KMUP‐1 (30μM) to the superfusate. KMUP‐1 reversal of K DR current inhibition by UTP predominantly involves the ROCK inhibition. The results indicate that the RhoA/ROCK signaling pathway plays a key role in eliciting PASMCs depolarization caused by UTP, which would result in pulmonary artery constriction. KMUP‐1 blocks UTP‐mediated PASMCs depolarization, suggesting that it would prevent abnormal pulmonary vasoconstriction.
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Dai et al. (2016) studied Pulmonary arterial hypertension. KMUP-1 vs. UTP alone was evaluated on UTP-inhibited delayed rectifying K+ (KDR) current. KMUP-1 (30μM) abolished UTP-inhibited delayed rectifying K+ currents in rat pulmonary artery smooth muscle cells, predominantly via RhoA/ROCK inhibition.
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