Intrinsic regulation of sinoatrial node function and the zebrafish as a model of stretch effects on pacemaking

Excitation of the heart occurs in a specialised region known as the sinoatrial node (SAN). Tight regulation of SAN function is essential for the maintenance of normal heart rhythm and the response to (patho-)physiological changes. The SAN is regulated by extrinsic (central nervous system) and intrinsic (neurons, peptides, mechanics) factors. The positive chronotropic response to stretch in particular is essential for beat-by-beat adaptation to changes in hemodynamic load. Yet, the mechanism of this stretch response is unknown, due in part to the lack of an appropriate experimental model for targeted investigations. We have been investigating the zebrafish as a model for the study of intrinsic regulation of SAN function. In this paper, we first briefly review current knowledge of the principal components of extrinsic and intrinsic SAN regulation, derived primarily from experiments in mammals, followed by a description of the zebrafish as a novel experimental model for studies of intrinsic SAN regulation. This mini-review is followed by an original investigation of the response of the zebrafish isolated SAN to controlled stretch. Stretch causes an immediate and continuous increase in beating rate in the zebrafish isolated SAN. This increase reaches a maximum part way through a period of sustained stretch, with the total change dependent on the magnitude and direction of stretch. This is comparable to what occurs in isolated SAN from most mammals (including human), suggesting that the zebrafish is a novel experimental model for the study of mechanisms involved in the intrinsic regulation of SAN function by mechanical effects.