Stretch-activated channels in the heart: Contributions to length-dependence and to cardiomyopathy

The stretch-induced increase in force production of ventricular muscle is biphasic. An abrupt increase in force coincides with the stretch, which is then followed by a slower response that develops over minutes (the slow force response or SFR). The SFR is accompanied by a slow increase in the magnitude of the intracellular Ca2+ transient, but the stretch-dependent mechanisms that give rise to this remain controversial. We characterized the SFR using right ventricular trabeculae from mouse hearts. Application of three different blockers of stretch-activated non-selective cation channels (SAC(NSC)) reduced the magnitude of the SFR 60s after stretch (400 mu M streptomycin: from 86 +/- 25% to 38 +/- 14%, P < 0.01, n=9; 10 mu M GdCl3: from 65 +/- 21%, to 12 +/- 7%, P < 0.01, n = 7; 10 mu M GsMTx-4 from 122 +/- 40% to 15 +/- 8%, P < 0.05, n = 6). Streptomycin also decreased the increase in Ca2+ transient amplitude 60 s after the stretch from 43.5 +/- 12.7% to 5.7 +/- 3.5% (P < 0.05, n = 4), and reduced the stretch-dependent increase in intracellular Ca2+ in quiescent muscles when stretched. The transient receptor potential, canonical channels TRPC1 and TRPC6 are mechano-sensitive, non-selective cation channels. They are expressed in mouse ventricular muscle, and could therefore be responsible for stretch-dependent influx of Na+ and/or Ca2+ during the SFR. Expression of TRPC1 was investigated in the mdx heart, a mouse model of Duchenne's muscular dystrophy. Resting Ca2+ was raised in isolated myocytes from old mdx animals, which was blocked by application of SAC blockers. Expression of TRPC1 was increased in the older mdx animals, which have developed a dilated cardiomyopathy, and might therefore contribute to the dilated cardiomyopathy. (c) 2008 Elsevier Ltd. All rights reserved.