CELLULAR MECHANISMS OF ATRIAL MECHANOTRANSDUCTION

Stretch of the cardiac muscle activates several physiological processes leading to changes in the function of the muscle. These changes include increase of the contraction force accompanied by changes in the intracellular calcium concentration. This phenomenon is known as Frank-Starling relation of the heart. In addition to this, stretch also influences the membrane voltage of individual myocytes predisposing the cardiac muscle to arrhythmias. In atrial muscle stretch augments the secretion of theatrial natriuretic peptide(ANP). Although several cellular componentsareknown to be sensiti ve to mechanical stimulus the precise mechanisms participating to these stretch-induced changes are not known in detail. Further it is not known if these changes are causall y related or if they share a common causal factor. This resear ch was aimed to study the stretch-induced changes in the rat atrium. The possible interactive mechanisms were studied by recording intracellular action potentials, changes in the intracellular calcium concentration, contraction force and ANP secretion during stretch. The plausible mechanosensiti ve cellular components were incorporated into a mathematical model that wasused tofurther study themechanisms. Theroleof intracellular acidosis as a possible modulator of the mechanotransduction was of special interest. In isolated rat left atrium moderate stretch produced by increasing the intra-atrial pressure increased the contraction forcein abiphasi cmanner. Theimmediateincreaseof theforcewascaused by altered propertiesof thecontractileelement, but thefollowing slow increasewasaccompanied by an increase of the Ca transient . These changes were followed by lengthening of the late phase of action potentialsand augmented secretion of the ANP. Intensi ve sustained stretch was also found to induce delayed afterdepolarizations (DADs). Gadolinium (Gd), blocker of stretch-activated ion channel s reduced the stretch-dependen t activation of the contraction and inhibited the stretchinduced DADs. The mathematical model simulated the experimental findings at best when stretchactivated channel (SA-channel) activation and increased troponin-C aff inity were used to mimic the stretch. The modelling data suggested that the SA-channel current increases the sarcoplasmic reticulum calcium content in atimedependent manner leading to Ca transient augmentation during systole. Bigger Ca transient s induce a depolarizing current during the late phase of the action potential (AP) repolarization via the Na/Ca exchanger causing the lengthening of the action potentials. A small reduction of the intracellular pH (0.18 units) with 20 mM propionate was found to modulate the stretch-induced changes in the rat atrium. Acidosis leads to an increase in the diastoli c [Ca]i during stretch, inhibits the stretch-induced changes in action potentials and slows down the contraction development during stretch by inhibiting the fast component of the force increase. These changes in E-C-coupling (excitation-contraction-coupling) were accompanied by a simultaneous augmentation of the ANPsecretion. Furthermore, it was shown that contraction force and diastoli c [Ca]i of thestretched tissuearemoresensitiveto acidosisthan in non-stretched tissue. In conclusion, the stretch-induced changes in rat atrial myocytes are mediated by at least two mechanisms; stretch-activatedCainflux andchangeinthepropertiesof thecontractil eelement. The action potential changes can be largely explained by modulation of the membrane voltage by intracellular calcium via Na/Ca-exchanger. The co-occurrence of the changes in the [Ca]i and ANP secretion suggests that the stretch-induced ANP secretion can be mediated by [Ca]i.