Functional Expression of the TRPM4 Cationic Current in Ventricular Cardiomyocytes From Spontaneously Hypertensive Rats

Abstract

Cardiac hypertrophy is associated with electrophysiological modifications, including modification of action potential shape that can give rise to arrhythmias. We report here a higher detection of a calcium-activated nonselective cation current in cardiomyocytes of spontaneously hypertensive rats (SHRs), a model of hypertension and heart hypertrophy when compared with Wistar-Kyoto (WKY) rat, its normotensive equivalent. Freshly isolated cells from the left ventricles of 3- to 6-month-old WKY rats or SHRs were used for patch-clamp recordings. In inside-out patches, the channel presented a linear conductance of 25+/-0.5 pS, did not discriminate Na(+) over K(+), and was not permeable to Ca(2+). Open probability was increased by depolarization and a rise in [Ca(2+)](i) (dissociation constant=10+/-5.4 micromol/L) but reduced by 0.5 mmol/L [ATP](i), 10 micromol/L glibenclamide, or flufenamic acid (IC(50)=5.5+/-1.7 micromol/L). Thus, it owns the fingerprint of the TRPM4 current. Although rarely detected in WKY cardiomyocytes, the current was present in >50% of patches from SHR cardiomyocytes. Moreover, by performing RT-PCR from ventricular samples, we observed that TRPM4 mRNA detection was higher in SHRs than in WKY rats. We propose that a TRPM4 current is expressed in ventricular cardiomyocytes from SHRs. According to its properties, this channel may contribute to the transient inward current implicated in delayed-after-depolarizations observed during [Ca(2+)] overload of cardiomyocytes.

Diacylglycerol Kinase ζ Inhibits Ventricular Tachyarrhythmias in a Mouse Model of Heart Failure

“…13 DAG and/or PKC stimulate a calcium-activated nonselective cation channel, such as TRPM4 channel, particularly in the setting of hypertrophy. 8, 26 However, TRPM4 might not participate in the induction of PVC and VT in this model because SK&F96365 inhibits TRPC channels but not TRPM4 channels. 27, 28 In fact, the TRPM4 channel was reported to be expressed more in atrial than in ventricle cardiomyocytes.…”

On Potential Interactions between Non-selective Cation Channel TRPM4 and Sulfonylurea Receptor SUR1

“…TRPM4-mediated currents are up-regulated in cardiomyocytes from spontaneous hypertensive rats (40), and gain-of-function mutations in TRPM4 have been associated with familial heart disease (41,42). TRPM4 channel kinetics are finely tuned by diverse cellular factors, including Ca 2ϩ -calmodulin, adenine nucleotides, and phosphoinositide 4,5-bisphosphate (15).…”

Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice

“…In addition to mast cells, Trpm4 mRNA was also detected in several murine cell types or organs of the cardiovascular system, including heart, endothelial cells, and kidney (20,25), and in rat cerebral artery and smooth muscle cells (26). In the heart, Trpm4 mRNA was amplified from cells of the sinoatrial node (27) and Purkinje fibers (28), and cardiac TRPM4 expression was reported to be upregulated in spontaneously hypertensive rats (29).…”