A gap junction inhibitor, carbenoxolone, induces spatiotemporal dispersion of renal cortical perfusion and impairs autoregulation

Abstract

Renal autoregulation dynamics originating from the myogenic response (MR) and tubuloglomerular feedback (TGF) can synchronize over large regions of the kidney surface, likely through gap junction-mediated electrotonic conduction and reflecting distributed operation of autoregulation. We tested the hypotheses that inhibition of gap junctions reduces spatial synchronization of autoregulation dynamics, abrogates spatial and temporal smoothing of renal perfusion, and impairs renal autoregulation. In male Long-Evans rats, we infused the gap junction inhibitor carbenoxolone (CBX) or the related glycyrrhizic acid (GZA) that does not block gap junctions into the renal artery and monitored renal blood flow (RBF) and surface perfusion by laser speckle contrast imaging. Neither CBX nor GZA altered RBF or mean surface perfusion. CBX preferentially increased spatial and temporal variation in the distribution of surface perfusion, increased spatial variation in the operating frequencies of the MR and TGF, and reduced phase coherence of TGF and increased its dispersion. CBX, but not GZA, impaired dynamic and steady-state autoregulation. Separately, infusion of the Rho kinase inhibitor Y-27632 paralyzed smooth muscle, grossly impaired dynamic autoregulation, and monotonically increased spatial variation of surface perfusion. These data suggest CBX inhibited gap junction communication, which in turn reduced the ability of TGF to synchronize among groups of nephrons. The results indicate that impaired autoregulation resulted from degraded synchronization, rather than the reverse. We show that network behavior in the renal vasculature is necessary for effective RBF autoregulation.

A Multicellular Vascular Model of the Renal Myogenic Response

“…, P N AA ). For the time evolution of (22) and (23), we apply standard numerical methods for initial value problems in differential-algebraic form [67,68] implemented in MATLAB (The MathWorks, Natick, MA) using implicit solvers that can efficiently treat the stiffness inherent in (17). Specifically, we opt for the solver ode15s, and supply the Jacobian matrix to improve the solver's efficiency.…”

“…For the myogenic mechanism of each smooth muscle cell we adopt a highly detailed model of subcellular dynamics that has been previously applied on the renal afferent arteriole myocytes [29]. Additionally, to represent accurately conducted responses that have been shown, experimentally and theoretically, to have a significant effect on overall autoregulation [17,24,27,53,54], we incorporate gap junction coupling directly among neighboring smooth muscle cells as well as among smooth muscle cells and a layer of endothelial cells. Lastly, in order to maintain a low computational load, we adopt only a simplified representation of the endothelium similar to existing approaches [7,27,55].…”

“…Among other variables, the smooth muscle cell model predicts muscle membrane potential v i , cytosolic concentrations [k] i for k = K + , Na + , Cl − , Ca 2+ , and the fraction ψ i of phosphorylated myosin light chains. Given our focus on the representation of vascular responses, which are greatly influenced by intercellular communication [17,27,53,55,61,62], we modify the model of [29] which studies cells in isolation and so it ignores signals shared between different smooth muscles. In the present study we consider the addition of gap junctional coupling motivated by the models of [27,30,55].…”

“…At the organ or vascular levels, the myogenic response in the kidney has been well characterized experimentally in vitro as well as in vivo [11][12][13][14][15][16][17][18]. However, theoretically a deeper understanding of the involved processes is lacking which limits our ability to investigate in silico realistic scenarios under health or disease conditions.…”

Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function

“…However, Cbx therapy has been shown to have significant adverse effects such as sodium retention and hypokalaemia [141]. Despite its promising and potent effects on Panx1, Cbx exhibits significant inhibiting effects on Cx channels and may thus be considered non-specific [142]. …”