Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice.
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.
Mathar
Ilka
I
Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Germany.
Vennekens
Rudi
R
Meissner
Marcel
M
Kees
Frieder
F
Van der Mieren
Gerry
G
Camacho Londoño
Juan E
JE
Uhl
Sebastian
S
Voets
Thomas
T
Hummel
Björn
B
van den Bergh
An
A
Herijgers
Paul
P
Nilius
Bernd
B
Flockerzi
Veit
V
Schweda
Frank
F
Freichel
Marc
M
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*
D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D004837:Epinephrine