title: Mechanism of impaired afferent arteriole myogenic response in Dahl salt-sensitive rats: role of 20-HETE.
abstract: The afferent arteriole (Af-Art) controls glomerular capillary pressure, an important determinant of glomerular injury. Af-Art myogenic response is mediated by ATP, and ATP signaling is in turn mediated by 20-HETE. Dahl salt-sensitive rats (Dahl SS) have decreased renal 20-HETE production. We hypothesized that Dahl SS have an impaired myogenic response and constrictor response to ATP, due to decreased 20-HETE. Af-Arts from Dahl SS or Dahl salt-resistant rats (Dahl SR) were microdissected and perfused. When myogenic response was induced by increasing Af-Art perfusion pressure from 60 to 140 mmHg, luminal Af-Art diameter decreased in Dahl SR but not in Dahl SS (-3.1 ± 0.8 vs. 0.5 ± 0.8 μm, P < 0.01). The 20-HETE antagonist 20-HEDE (10(-6) M) blocked the myogenic response in Dahl SR but had no effect in Dahl SS. Addition of a subconstrictor concentration of 20-HETE (but not a subconstrictor concentration of norepinephrine) restored the myogenic response in Dahl SS. We then perfused Af-Arts at 60 mmHg and tested the effects of the ATP analog α,β-methylene-ATP (10(-6) M). Maximum ATP-induced constriction was attenuated in Dahl SS compared with Dahl SR (1.5 ± 0.5 vs. 7.4 ± 0.8 μm, P < 0.001). 20-HEDE attenuated ATP-induced Af-Art constriction in Dahl SR but not in Dahl SS, and consequently, ATP-induced constriction was no longer different between strains. In conclusion, Dahl SS have an impaired myogenic response and ATP-induced Af-Art constriction due to a decrease in Af-Art 20-HETE. The impaired myogenic responses may contribute to the nephrosclerosis that develops in Dahl SS.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: YiLin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Martin A
authors.initials: MA
authors.lastname: D'Ambrosio
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; ocarret1@hfhs.org.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000344:Afferent Pathways / Q000503:physiopathology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply / Q000503:physiopathology*; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D024510:Muscle Development / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C494667:20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000255:Adenosine Triphosphate; D009638:Norepinephrine
keywords: 20-HETE; ATP; afferent arteriole; myogenic response; salt-sensitive hypertension