The mechanoelectrical feedback (MEF) mechanism in the heart that plays a significant role in the occurrence of arrhythmias, involves cation flux through cation nonselective stretch-activated channels (SACs). It is well known that nitric oxide (NO) can act as a regulator of MEF. Here we addressed the possibility of SAC's regulation along NO-dependent and NO-independent pathways, as well as the possibility of S-nitrosylation of SACs. In freshly isolated rat ventricular cardiomyocytes, using the patch-clamp method in whole-cell configuration, inward nonselective stretch-activated cation current I_SAC was recorded through SACs, which occurs during dosed cell stretching. NO donor SNAP, α1-subunit of sGC activator BAY41-2272, sGC blocker ODQ, PKG blocker KT5823, PKG activator 8Br-cGMP, and S-nitrosylation blocker ascorbic acid, were employed. We concluded that the physiological concentration of NO in the cell is a necessary condition for the functioning of SACs. An increase in NO due to SNAP in an unstretched cell causes the appearance of a Gd³⁺ -sensitive nonselective cation current, an analog of I_SAC , while in a stretched cell it eliminates I_SAC . The NO-independent pathway of sGC activation of α subunit, triggered by BAY41-2272, is also important for the regulation of SACs. Since S-nitrosylation inhibitor completely abolishes I_SAC , this mechanism occurs. The application of BAY41-2272 cannot induce I_SAC in a nonstretched cell; however, the addition of SNAP on its background activates SACs, rather due to S-nitrosylation. ODQ eliminates I_SAC , but SNAP added on the background of stretch increases I_SAC in addition to ODQ. This may be a result of the lack of NO as a result of inhibition of NOS by metabolically modified ODQ. KT5823 reduces PKG activity and reduces SACs phosphorylation, leading to an increase in I_SAC . 8Br-cGMP reduces I_SAC by activating PKG and its phosphorylation. These results demonstrate a significant contribution of S-nitrosylation to the regulation of SACs.

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