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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 ?mol/L, from 3.6±0.4 to 2.5±0.4 µm (P<0.01), and abolished it at 100 ?mol/L, to 0.1±0.1 ?m (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 ?mol/L (2.9±0.4 versus 3.0±0.4 µm) but partially inhibited TGF at 100 ?mol/L (to 1.3±0.2 ?m; 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 ?mol/L); A23187-induced TGF was inhibited by CO-releasing molecule-3 at 50 ?mol/L (1.9±0.6 ?mol/L; P<0.01) and 100 ?mol/L (0.2±0.5 ?mol/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.

SUBMITTER: Ren Y 

PROVIDER: S-EPMC3821182 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Mechanism of inhibition of tubuloglomerular feedback by CO and cGMP.

Ren Yilin Y   D'Ambrosio Martin A MA   Garvin Jeffrey L JL   Wang Hong H   Carretero Oscar A OA  

Hypertension (Dallas, Tex. : 1979) 20130506 1


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  ...[more]

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