title: PC-PLC/sphingomyelin synthase activity plays a central role in the development of myogenic tone in murine resistance arteries.
abstract: Myogenic tone is an intrinsic property of the vasculature that contributes to blood pressure control and tissue perfusion. Earlier investigations assigned a key role in myogenic tone to phospholipase C (PLC) and its products, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Here, we used the PLC inhibitor, U-73122, and two other, specific inhibitors of PLC subtypes (PI-PLC and PC-PLC) to delineate the role of PLC in myogenic tone of pressurized murine mesenteric arteries. U-73122 inhibited depolarization-induced contractions (high external K(+) concentration), thus confirming reports of nonspecific actions of U-73122 and its limited utility for studies of myogenic tone. Edelfosine, a specific inhibitor of PI-PLC, did not affect depolarization-induced contractions but modulated myogenic tone. Because PI-PLC produces IP3, we investigated the effect of blocking IP3 receptor-mediated Ca(2+) release on myogenic tone. Incubation of arteries with xestospongin C did not affect tone, consistent with the virtual absence of Ca(2+) waves in arteries with myogenic tone. D-609, an inhibitor of PC-PLC and sphingomyelin synthase, strongly inhibited myogenic tone and had no effect on depolarization-induced contraction. D-609 appeared to act by lowering cytoplasmic Ca(2+) concentration to levels below those that activate contraction. Importantly, incubation of pressurized arteries with a membrane-permeable analog of DAG induced vasoconstriction. The results therefore mandate a reexamination of the signaling pathways activated by the Bayliss mechanism. Our results suggest that PI-PLC and IP3 are not required in maintaining myogenic tone, but DAG, produced by PC-PLC and/or SM synthase, is likely through multiple mechanisms to increase Ca(2+) entry and promote vasoconstriction.
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland jmauban@umaryland.edu.
authors.forename: Joseph R H
authors.initials: JR
authors.lastname: Mauban
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zacharia
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland.
authors.forename: Seth
authors.initials: S
authors.lastname: Fairfax
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland.
authors.forename: Withrow Gil
authors.initials: WG
authors.lastname: Wier
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D020013:Calcium Signaling / Q000187:drug effects; D004075:Diglycerides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000201:enzymology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D010713:Phosphatidylcholines / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004075:Diglycerides; D004791:Enzyme Inhibitors; D010713:Phosphatidylcholines; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C
keywords: Bayliss; calcium; diacylglycerol; phospholipase C