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 microM streptomycin: from 86+/-25% to 38+/-14%, P<0.01, n=9; 10 microM GdCl3: from 65+/-21%, to 12+/-7%, P<0.01, n=7; 10 microM GsMTx-4 from 122+/-40% to 15+/-8%, P<0.05, n=6). Streptomycin also decreased the increase in Ca2+ transient amplitude 60s 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.

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Acute dilation of the right atrium (e.g., via increased venous return) raises spontaneous beating rate (BR) of the heart in many species. Neural mechanisms contribute to this behavior in vivo, but a positive chronotropic response to stretch can also be observed in isolated right atrial tissue preparations and even at the level of single sino-atrial node (SAN) cells. The underlying mechanism has previously been reported to be compatible with stretch-activation of cation nonselective ion channels (SAC). This review reports species peculiarities in the chronotropic response of isolated SAN tissue strips to stretch: in contrast to guinea pig, murine SAN preparations respond to distension with a reduction in spontaneous BR. This differential response need not necessarily involve disparate (sub-)cellular mechanisms, as SAC activation would occur against the background of very different SAN electrophysiology in the two species. On the basis of single SAN cell action potential recordings, this review illustrates how this may give rise to potentially opposing effects on spontaneous BR. Interestingly, streptomycin (a useful SAC blocker in isolated cells) has no effect on stretch-induced chronotropy in situ, and this is interpreted as an indication of protection of SAC, in native tissue, from interaction with the drug.

Isolated, spontaneously beating rabbit sinoatrial node cells were subjected to longitudinal stretch, using carbon fibers attached to both ends of the cell. Their electrical behavior was studied simultaneously in current-clamp or voltage-clamp mode using the perforated patch configuration. Moderate stretch ( approximately 7%) caused an increase in spontaneous beating rate (by approximately 5%) and a reduction in maximum diastolic and systolic potentials (by approximately 2.5%), as seen in multicellular preparations. Mathematical modeling of the stretch intervention showed the experimental results to be compatible with stretch activation of cation nonselective ion channels, similar to those found in other cardiac cell populations. Voltage-clamp experiments validated the presence of a stretch-induced current component with a reversal potential near -11 mV. These data confirm, for the first time, that the positive chronotropic response of the heart to stretch is, at least in part, encoded on the level of individual sinoatrial node pacemaker cells; all reported data are in agreement with a major contribution of stretch-activated cation nonselective channels to this response.

Effects of mechanical stimulation on cardiac electrical activity, gene expression, protein synthesis, and tissue remodelling have received increasing attention in recent years, as reviewed in this issue of PBMB. Little is known, though, about how changes in ventricular filling affect the cell configuration of cardiomyocytes in the ventricular wall. Here, we present first electron-microscopic insight into changes in cardiomyocyte cell structure in situ during acute ventricular volume manipulation. Apart from confirming the anticipated ventricular volume-related changes in cardiomyocyte sarcomere length, there is evidence of (i) unfolding of 'slack' membrane, primarily from sarcolemmal invaginations near the Z-lines, and (ii) stretch-induced incorporation of sub-membrane caveolae into the surface membrane. The functional relevance of these changes in cardiomyocyte membrane configuration-other than to cater for the length-dependent modulation of the cell surface to cell volume ratio-remains to be elucidated.