Ubiquitous inactivation of TRPM4 leads to elevated blood pressure in mice

Abstract

Recently we showed that transient receptor potential TRPM4 proteins act as Ca2+‐activated nonselective cation channels in mast cells that critically limit the driving force for Ca2+ influx, release of inflammatory mediators and anaphylactic responses. In addition to mast cells we detected TRPM4 proteins in heart, aortic endothelial cells, kidney and adrenal gland from mice. Earley et al suggested that TRPM4 is expressed in vascular smooth muscle cells and it is supposed to act as a mechanosensor regulating vascular myogenic tone.Telemetric blood pressure measurements reveal that mean arterial blood pressure (MAP) is elevated in TRPM4‐/‐ mice by 11mmHg under basal conditions. Blood pressure elevation is observed during the complete circadian period and most notable under resting conditions. Plasma aldosterone levels, renin mRNA expression in the kidney and renin plasma concentrations are not different in TRPM4‐/‐ mice and there are no differences in MAP in response to application of phenylephrine (PE), norepinephrine and L‐NAME. PE induced contraction and acetylcholine induced relaxation of aortic rings is not altered. Currently we analyse the contractility of resistance vessels with respect to smooth muscle‐dependent contraction and endothelium‐dependent relaxation. Inhibition of ganglionic transmission with hexamethonium abolishes the difference in MAP between both genotypes similarly like application of prazosin. Analysis of plasma catecholamine level revealed a significant elevation of epinephrine in TRPM4‐/‐ mice. These results suggest that an increased neurogenic tone contributes to the development of the hypertension.