KATP Although classically considered to be ligand-gated, Van Wagoner et al. 99 obtained single-channel inside-out patch clamp recordings from neonatal rat atrial myocytes which revealed that patch pipette Rapamycin price negative pressure increased KATP channel ATP-sensitivity. 99 Synergistically, ATP-reduction potentiated stretch sensitivity. 99

Ischaemia, simulated in adult guinea pig ventricular myocytes by application of a metabolic uncoupler, also uncovered KATP mechanosensitivity that was absent in control conditions, 27 an observation that was more recently confirmed in rat cardiomyocytes. 100 The synergism for KATP channel activation by metabolic and mechanical stress might explain differences in quantitative aspects of ATP reduction needed to activate KATP in isolated cells, compared to the organ level (where KATP open at less depleted ATP levels). A reason for this difference

could be the fact that isolated cells are not normally subjected to mechanical co-activation, while at the organ level ischaemia is usually associated with decreased shortening, or even stretch, of the tissue affected by reduced availability of ATP. In keeping with this notion, ‘stretch-preconditioning’ has been reported to reduce ischaemia- reperfusion injury, an effect that disappears when KATP channels are blocked. 68 Moreover, cardiac fibroblasts progressively express functional KATP channels in scar and border zone tissue following infarction, suggesting that we must consider the effect of cells other than cardiomyocytes in pre-/post- conditioning of the heart, and the role of SAC in these processes. 101–103 Although there is little evidence to suggest that KATP are responsible for mechanosensitivity of the heart in normal beat-by-beat physiology (in healthy cells and tissue, diastolic mechanical stimulation depolarizes cardiomyocytes), the potential role of these ion channels in ischaemic or other disease conditions

warrants further research. SAC modulators Several pharmacological compounds have been identified to modulate SAC activity (Figure 3), 104,105 and their potential role as pharmacological tools for heart rhythm management has been previously reviewed by White. 106 Most of Cilengitide the known SAC-modulators are non-specific inhibitors, such as gadolinium ions, amiloride and cationic antibiotics (streptomycin, penicillin, kanamycin). Among the very few specific SAC inhibitors 107 reported so far is the peptide GsMTx-4. It inhibits TRPC5 when activated by hypo-osmotic and receptor stimulation, 108,109 as well as TRPC6, 56 and Piezo1 channels when applied to the external face of the membrane. 72,73 GsMTx-4 is active both in its D and L enantiomers, showing the mechanism of action is not stereospecfic or chiral.