Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contractility and [Ca2+]I by Activating a Protein Kinase C-Sensitive Ca2+ Entry Pathway
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Endothelin-1 (ET-1) has been implicated in the pathogenesis of coronary vasospasm by enhancing the coronary vasoconstrictor response to vasoactive eicosanoids; however, the cellular mechanisms involved are unclear. We investigated whether physiological concentrations of ET-1 enhance prostaglandin F2α (PGF2α)-induced coronary smooth muscle contraction by increasing [Ca2+]i and the Ca2+ mobilization mechanisms of coronary vasoconstriction. Single smooth muscle cells were freshly isolated from the left anterior descending coronary artery of castrated male pigs and labeled with the Ca2+ indicator fura-2 or with antibodies to specific protein kinase C (PKC) isoforms. In Hank’s solution (1 mM Ca2+), ET-1 (30 pM) caused a small increase in cell contraction (9%) and [Ca2+]i (106±5 nM). PGF2α (10-7 M) increased cell contraction to 11% and [Ca2+]i to 121±7 nM. In cells pretreated with ET-1 (30 pM) for 30 min, PGF2α (10-7 M) significantly increased cell contraction to 32% and [Ca2+]i to 217±8 nM. Membrane depolarization by 24 mM KCl, which stimulates Ca2+ entry from the extracellular space, caused 12% cell contraction and increased [Ca2+]i to 152±6 nM. In cells pretreated with ET-1, KCl significantly increased cell contraction to 34% and [Ca2+]i to 306±8 nM. In Ca2+-free Hank’s, caffeine (10 mM), which stimulates Ca2+ release from intracellular stores, caused cell contraction (9%) and a transient increase in [Ca2+]i (417±14 nM). ET-1 did not significantly affect the caffeine contraction or [Ca2+]i. ET-1 caused significant translocation of α-PKC from the cytosol to the cell membrane, suggesting activation of the isoform. The PKC inhibitor Gö6976 (10-6 M) completely inhibited the ET-1 induced α-PKC translocation and the enhancement of PGF2α− and KCl-induced cell contraction and [Ca2+]i. Thus, ET-1 enhances PGF2α-induced coronary smooth muscle contractility and [Ca2+]i by enhancing Ca2+ entry from the extracellular space, but not Ca2+ release from intracellular stores. The results suggest that the enhancement of PGF2α-induced Ca2+ entry by ET-1 involves activation and translocation of α-PKC isoform.
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- Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contractility and [Ca2+]I by Activating a Protein Kinase C-Sensitive Ca2+ Entry PathwayZohreh N Sirous, John B Fleming and Raouf A KhalilHypertension. 2000;36:720, originally published October 1, 2000https://doi.org/10.1161/01.HYP.36.Suppl_1.720-b
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- Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contractility and [Ca2+]I by Activating a Protein Kinase C-Sensitive Ca2+ Entry PathwayZohreh N Sirous, John B Fleming and Raouf A KhalilHypertension. 2000;36:720, originally published October 1, 2000https://doi.org/10.1161/01.HYP.36.Suppl_1.720-b