title: Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice.
abstract: Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4-/- and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4-/- mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Mathar
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Marcel
authors.initials: M
authors.lastname: Meissner
authors.forename: Frieder
authors.initials: F
authors.lastname: Kees
authors.forename: Gerry
authors.initials: G
authors.lastname: Van der Mieren
authors.forename: Juan E
authors.initials: JE
authors.lastname: Camacho Londoño
authors.forename: Sebastian
authors.initials: S
authors.lastname: Uhl
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Björn
authors.initials: B
authors.lastname: Hummel
authors.forename: An
authors.initials: A
authors.lastname: van den Bergh
authors.forename: Paul
authors.initials: P
authors.lastname: Herijgers
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002319:Cardiovascular System / Q000378:metabolism; D019439:Chromaffin Cells / Q000378:metabolism; D004837:Epinephrine / Q000097:blood*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012084:Renin-Angiotensin System / Q000502:physiology; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D004837:Epinephrine