Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice
Ilka Mathar, Rudi Vennekens, Marcel Meissner, Frieder Kees, Gerry Van der Mieren, Juan E. Camacho Londoño, Sebastian Uhl, Thomas Voets, Björn Hummel, An van den Bergh, Paul Herijgers, Bernd Nilius, Veit Flockerzi, Frank Schweda, Marc Freichel
Ilka Mathar, Rudi Vennekens, Marcel Meissner, Frieder Kees, Gerry Van der Mieren, Juan E. Camacho Londoño, Sebastian Uhl, Thomas Voets, Björn Hummel, An van den Bergh, Paul Herijgers, Bernd Nilius, Veit Flockerzi, Frank Schweda, Marc Freichel
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Research Article Cardiology

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

Ilka Mathar, Rudi Vennekens, Marcel Meissner, Frieder Kees, Gerry Van der Mieren, Juan E. Camacho Londoño, Sebastian Uhl, Thomas Voets, Björn Hummel, An van den Bergh, Paul Herijgers, Bernd Nilius, Veit Flockerzi, Frank Schweda, Marc Freichel

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Figure 4

Vascular reactivity in Trpm4–/– mice.

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Vascular reactivity in Trpm4–/– mice. (A) MAP and HR after i.p. inje...
(A) MAP and HR after i.p. injection (at time point 0 minutes) of PE (1.0 mg/kg BW; WT, black, n = 7; Trpm4–/– red, n = 9). (B) Concentration-response curve of PE-induced contraction of isolated aortic rings (WT n = 7, Trpm4–/–n = 8). (C) Time course of vascular resistance of the vasculature of isolated hind limbs calculated from perfusion pressure and perfusate flow (inset); bolus injections (200 μl) of increasing PE concentrations (in μM) are indicated by arrowheads. (D) Dose-response curves of changes in flow and vascular resistance after application of PE in the perfused hind limb vasculature (n = 9 per genotype). (E) Averaged changes in perfusate flow after bolus injections (200 μl) of increasing epinephrine concentrations (in μM; n = 6 per genotype). (F) Changes in vascular resistance of the perfused hind limb after bolus injections (200 μl) of increasing acetylcholine concentrations (n = 7 per genotype). (G and H) Analysis of pressure-induced vascular resistance. Average change in vascular resistance (G) using physiological KH solution (black, red) or Ca2+-free KH (gray, dark red) as perfusate in WT (upper panel, n = 11) or Trpm4–/– mice (lower panel, n = 10); intravascular pressure is indicated. (H) Analysis of the myogenic response in dependence of the intravascular pressure calculated from measurement in G.