3+ also block I MIC in a voltage-dependent manner (δ = 0.4-0.5). In addition they inhibit the inward current carried by divalent cations. I MIC is regulated by pH. Decreasing or increasing extracellular pH decreased and increased I MIC , respectively (pH 0.5 = 6.9, n H = 0.98). Qualitatively similar results were obtained on I MIC in rat basophilic leukaemia cells. These effects in cardiac myocytes were absent in the presence of high intracellular buffering by 40 mM Hepes. Our results suggest that I MIC in cardiac cells is due to TRPM channels, most probably to TRPM6 or TRPM7 channels or to their heteromultimeres.

β 3 -adrenergic receptor (β 3 -AR) activation produces a negative inotropic effect in human ventricles. Here we explored the role of β 3 -AR in the human atrium. Unexpectedly, β 3 -AR activation increased human atrial tissue contractility and stimulated the L-type Ca 2+ channel current (I Ca,L ) in isolated human atrial myocytes (HAMs). Right atrial tissue specimens were obtained from 57 patients undergoing heart surgery for congenital defects, coronary artery diseases, valve replacement, or heart transplantation. The I Ca,L and isometric contraction were recorded using a whole-cell patch-clamp technique and a mechanoelectrical force transducer. Two selective β 3 -AR agonists, SR58611 and BRL37344, and a β 3 -AR partial agonist, CGP12177, stimulated I Ca,L in HAMs with nanomolar potency and a 60%-90% efficacy compared with isoprenaline. The β 3 -AR agonists also increased contractility but with a much lower efficacy (~10%) than isoprenaline. The β 3 -AR antagonist L-748,337, β 1 -/β 2 -AR antagonist nadolol, and β 1 -/β 2 -/β 3 -AR antagonist bupranolol were used to confirm the involvement of β 3 -ARs (and not β 1 -/β 2 -ARs) in these effects. The β 3 -AR effects involved the cAMP/PKA pathway, since the PKA inhibitor H89 blocked I Ca,L stimulation and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) strongly increased the positive inotropic effect. Therefore, unlike in ventricular tissue, β 3 -ARs are positively coupled to L-type Ca 2+ channels and contractility in human atrial tissues through a cAMP-dependent pathway.

No abstract

We have identified a new human CSC population able to differentiate into functional CMs. This opens interesting perspectives for cell therapy in patients with ischaemic heart disease.

1 Previously we have described a monovalent cation (MC) current that could be unmasked by the removal of extracellular divalent cations in vascular smooth muscle cells (SMC) and cardiac myocytes, but speci®c and potent inhibitors of MC current have not been found, and the mechanism of its intracellular regulation remains obscure. 2 Here we show that small MC current is present in intact cells and could be dramatically upregulated during cell dialysis. MC current in dialyzed cells strongly resembled monovalent cation current attributed to Ca 2+ release-activated Ca 2+ -selective (CRAC) channels, but its activation did not require depletion of Ca 2+ stores, and was observed when the cells were dialyzed with, or without BAPTA. 3 Intracellular free Mg 2+ inhibits MC current with K d =250 mM. 4 Extracellular (but not intracellular) spermine eectively blocked MC current with K d =3 ± 10 mM, while store-operated cations (SOC) channels and capacitative Ca 2+ in¯ux were not aected. 5 Spermine eectively inhibited MC current-induced SMC depolarization, and prevented Ca 2+ paradox-induced vascular contracture. 6 Both, MC and SOC currents were inhibited by 2-aminoethoxydiphenyl borate (2-APB). 7 It is concluded that MC current could be regulated by intracellular Mg 2+, and low concentrations of extracellular spermine could be used to discriminate it from SOC current, and to assess its role in cellular function.