title: Mechanism of inhibition of tubuloglomerular feedback by CO and cGMP.
abstract: Tubuloglomerular feedback (TGF) is a mechanism that senses NaCl in the macula densa (MD) and causes constriction of the afferent arteriole. CO, either endogenous or exogenous, inhibits TGF at least in part via cGMP. We hypothesize that CO in the MD, acting via both cGMP-dependent and -independent mechanisms, attenuates TGF by acting downstream from depolarization and calcium entry into the MD cells. In vitro, microdissected rabbit afferent arterioles and their MD were simultaneously perfused and TGF was measured as the decrease in afferent arteriole diameter. MD depolarization was induced with ionophores, while adding the CO-releasing molecule-3 to the MD perfusate at nontoxic concentrations. CO-releasing molecule-3 blunted depolarization-induced TGF at 50 μmol/L, from 3.6±0.4 to 2.5±0.4 µm (P<0.01), and abolished it at 100 μmol/L, to 0.1±0.1 μm (P<0.001; n=6). When cGMP generation was blocked by guanylyl cyclase inhibitor LY83583 added to the MD, CO-releasing molecule-3 no longer affected depolarization-induced TGF at 50 μmol/L (2.9±0.4 versus 3.0±0.4 µm) but partially inhibited TGF at 100 μmol/L (to 1.3±0.2 μm; P<0.05; n=9). Experiments using eicosatetraynoic acid and indomethacin suggest arachidonic acid metabolites do not mediate the cGMP-independent effect of CO. We then added the calcium ionophore A23187 to the MD, which caused TGF (4.1±0.6 μmol/L); A23187-induced TGF was inhibited by CO-releasing molecule-3 at 50 μmol/L (1.9±0.6 μmol/L; P<0.01) and 100 μmol/L (0.2±0.5 μmol/L; P<0.001; n=6). We conclude that CO inhibits TGF acting downstream from depolarization and calcium entry, acting via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations.
authors: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA.
authors: Yilin
authors: Y
authors: Ren
authors: Martin A
authors: MA
authors: D'Ambrosio
authors: Jeffrey L
authors: JL
authors: Garvin
authors: Hong
authors: H
authors: Wang
authors: Oscar A
authors: OA
authors: Carretero
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000494:pharmacology*; D025461:Feedback, Physiological; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits
chemical_list: D000963:Antimetabolites; D002248:Carbon Monoxide; D006152:Cyclic GMP
keywords: afferent arteriole; cGMP; carbon monoxide; macula densa; tubuloglomerular feedback
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