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(Hypertension. 2008;51:239.)
© 2008 American Heart Association, Inc.

Original Articles

Low Concentrations of Sphingosylphosphorylcholine Enhance Pulmonary Artery Vasoreactivity

The Role of Protein Kinase C and Ca²⁺ Entry

Vladimir A. Snetkov; Gavin D. Thomas; Bonnie Teague; Richard M. Leach; Yasin Shaifta; Greg A. Knock; Philip I. Aaronson; Jeremy P.T. Ward

From the King’s College London School of Medicine, Division of Asthma, Allergy and Lung Biology, London, United Kingdom.

Correspondence to Jeremy P.T. Ward, Department of Physiology, Henriette Raphael House, King’s College London, Guy’s Hospital Campus, London SE1 1UL, United Kingdom. E-mail Jeremy.ward{at}kcl.ac.uk

Sphingosylphosphorylcholine (SPC) is a powerful vasoconstrictor, but in vitro its EC₅₀ is 100-fold more than plasma concentrations. We examined whether subcontractile concentrations of SPC (1 µmol/L) modulated vasoreactivity of rat intrapulmonary arteries using myography and measurement of intracellular [Ca²⁺]. SPC (1 µmol/L) had no effect on force or intracellular [Ca²⁺] on its own, but dramatically potentiated constrictions induced by 25 mmol/L [K⁺], such that at 40 minutes, force and intracellular [Ca²⁺] (Fura PE3 340/380 ratio) were increased by 429±96% and 134±26%, respectively. The potentiation was stereospecific, apparent at concentrations >100 nmol/L of SPC, and independent of the endothelium, 2-aminoethoxydiphenylborane–sensitive Ca²⁺ entry, and Rho kinase. It was abolished by the phospholipase C inhibitor U73122, the broad spectrum protein kinase C (PKC) inhibitor Ro31-8220, and the PKC inhibitor rottlerin, but not by Gö6976, which is ineffective against PKC. The potentiation could be attributed to enhancement of Ca²⁺ entry. SPC also potentiated the responses to prostaglandin F₂ and U436619, which activate a 2-aminoethoxydiphenylborane sensitive nonselective cation channel in intrapulmonary arteries. In this case, potentiation was partially inhibited by diltiazem but abolished by 2-aminoethoxydiphenylborane, Ro31-8220, and rottlerin. SPC (1 µmol/L) caused translocation of PKC to the perinuclear region and cytoskeleton of cultured intrapulmonary artery smooth muscle cells. We present the novel finding that low, subcontractile concentrations of SPC potentiate Ca²⁺ entry in intrapulmonary arteries through both voltage-dependent and independent pathways via a receptor-dependent mechanism involving PKC. This has implications for the physiological role of SPC, especially in cardiovascular disease, where SPC is reported to be elevated.

Key Words: pulmonary artery • lysosphingolipids • sphingosylphosphorylcholine • L-type Ca²⁺ channels • protein kinase C