Interstitial volume modulates the conduction velocity-gap junction relationship

Cardiac conduction through gap junctions is an important determinant of arrhythmia susceptibility. Yet, the relationship between degrees of G(j) uncoupling and conduction velocity (θ) remains controversial. Conflicting results in similar experiments are normally attributed to experimental differences. We hypothesized that interstitial volume modulates conduction velocity and its dependence on G(j). Interstitial volume (V(IS)) was quantified histologically from guinea pig right ventricle. Optical mapping was used to quantify conduction velocity and anisotropy (AR(θ)). Albumin (4 g/l) decreased histologically assessed V(IS), increased transverse θ by 71 ± 10%, and lowered AR(θ). Furthermore, albumin did not change isolated cell size. Conversely, mannitol increased V(IS), decreased transverse θ by 24 ± 4%, and increased AR(θ). Mannitol also decreased cell width by 12%. Furthermore, mannitol was associated with spontaneous ventricular tachycardias in three of eight animals relative to zero of 15 during control. The θ-G(j) relationship was assessed using the G(j) uncoupler carbenoxolone (CBX). Whereas 13 μM CBX did not significantly affect θ during control, it slowed transverse θ by 38 ± 9% during mannitol (edema). These data suggest changes in V(IS) modulate θ, AR(θ), and the θ-G(j) relationship and thereby alter arrhythmia susceptibility. Therefore, V(IS) may underlie arrhythmia susceptibility, particularly in diseases associated with gap junction remodeling.