title: 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.
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; and.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitrou
authors.affiliation: Department of Physiology and Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
authors.affiliation: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; and wcupples@sfu.ca.
authors.forename: William A
authors.initials: WA
authors.lastname: Cupples
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002229:Carbenoxolone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects*; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D007672:Kidney Cortex / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D012077:Renal Artery / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects*; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C108830:Y 27632; D019695:Glycyrrhizic Acid; D054460:rho-Associated Kinases; D002229:Carbenoxolone
keywords: blood flow; laser speckle contrast imaging; myogenic response; phase synchronization; tubuloglomerular feedback