110 Counterintuitively, GsMTx-4 sensitizes the bacterial channels, MscS and MscL, to tension, 111 while it has no effect on TREK-1 channels, 72 so that overall the mode of action of GsMTx-4 still requires further elucidation. TREK-1 is poorly responsive to classic potassium channel blockers, 112 but PA-824 clinical trial its functions are modified by a variety of pharmacologic agents such as volatile anaesthetics, 112 riluzole, 113 fluoxetine 114 and spadin. 115,116 Recently, new modulators of TREK-1 were identified by Bagriantsev et al. 117 They characterized inhibitors and, importantly, activators (which are very rare for SAC channels). Known

openers for SAC are amphipathic substances which insert selectively into one membrane leaflet only, locally inducing either concave or convex curvature, which may induce SAC-activating tension. 118 Other useful substances include probenicid, which is a TRP agonist that is fairly specific to TRPV2, 119 and 9-phenanthrol, which blocks TRPM4. 120 It is important to note, though,

that not all SAC blockers that work at the level of isolated or cultured cells are equally efficient in native tissue. Streptomycin, for example, may not be able to easily access SAC in whole cardiac tissue, 121 even though it is an efficient SACNS blocker in single cardiomyocytes (an important consideration for cell-culture based work, which often employs media containing streptomycin by default). This will be one of the reasons for which antibiotics, such as streptomycin, can be prescribed to patients without instantaneous side effects on stretch-sensing. Another compound, Gd3+, is used clinically in a chelated formulation, which explains the lack of pronounced immediate SAC-effects in radio-contrast studies. As an aside, Gd3+ precipitates in physiologically buffered solutions. 122 Clearly caution is called

for when assessing (potentially false-) negative results on Gd3+ effects in physiological solutions, or on streptomycin effects in vivo. Discussion The heart is a superbly mechanosensitive organ. SAC are thought to provide one of the mechanisms underlying cardiac MEF, 20,123,124 the process Carfilzomib by which changes in the mechanical environment of the heart lead to altered cardiac electrical activity. Identification of molecular substrates for cardiac SAC will not only provide novel insight into processes that underlie MEF, but also support the long-term aim of developing SAC-specific drugs for the treatment of mechanically induced cardiac pathologies. 106 In terms of physiological beat-by-beat effects, activation of SAC has been shown to underlie the stretch-induced increase in spontaneous sino-atrial node (SAN) cell pacemaking rate.