title: Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback.
abstract: Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the macula densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached macula densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching macula densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5 × 10(-5) mol/L) to the macula densa blunted TGF from 3.3 ± 0.3 to 2.0 ± 0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10(-6) mol/L) enhanced TGF (5.8 ± 0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5 ± 0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2 × 10(-6) mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0 ± 0.7 μm; KT-5823+CORM-3, 5.9 ± 0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10(-6) mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07 ± 0.31 μm; BAY-60-7550+CORM-3, 1.84 ± 0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10(-3) mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6 ± 0.5 μm; dibutyryl-cAMP+CORM-3, 5.0 ± 0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Ren
authors.forename: Martin A
authors.initials: MA
authors.lastname: D'Ambrosio
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000378:metabolism / Q000502:physiology*; D007686:Kidney Tubules, Distal / Q000098:blood supply / Q000378:metabolism / Q000502:physiology*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D014227:Triazines / Q000494:pharmacology
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D000634:Aminoquinolines; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009942:Organometallic Compounds; D014227:Triazines; C476530:tricarbonylchloro(glycinato)ruthenium(II); C073601:KT 5823; D003994:Bucladesine; D002248:Carbon Monoxide; C041715:6-anilino-5,8-quinolinedione; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006162:Guanylate Cyclase; D006152:Cyclic GMP