title: Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats.
abstract: Inflammation contributes to ANG II-associated impairment of renal autoregulation and microvascular P2X1 receptor signaling, but its role in renal autoregulation in mineralocorticoid-induced hypertension is unknown. Autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. Hypertension was induced in uninephrectomized control rats (UNx) by subcutaneous implantation of a DOCA pellet plus administration of 1% NaCl in the drinking water (DOCA-salt) for 3 wk. DOCA-salt rats developed hypertension that was unaltered by anti-inflammatory treatment with pentosan polysulfate (DOCA-salt+PPS) but was suppressed with "triple therapy" (hydrochlorothiazide, hydralazine, and reserpine; DOCA-salt+TTx). Baseline arteriolar diameters were similar across all groups. UNx rats exhibited pressure-dependent vasoconstriction with diameters declining to 69 ± 2% of control at 170 mmHg, indicating intact autoregulation. DOCA-salt treatment significantly blunted this pressure-mediated vasoconstriction. Diameters remained between 91 ± 4 and 98 ± 3% of control over 65-170 mmHg, indicating impaired autoregulation. In contrast, pressure-mediated vasoconstriction was preserved in DOCA-salt+PPS and DOCA-salt+TTx rats, reaching 77 ± 7 and 75 ± 3% of control at 170 mmHg, respectively. ATP is required for autoregulation via P2X1 receptor activation. ATP- and β,γ-methylene ATP (P2X1 receptor agonist)-mediated vasoconstriction were markedly attenuated in DOCA-salt rats compared with UNx (P < 0.05), but significantly improved by PPS or TTx (P < 0.05 vs. DOCA-salt) treatment. Arteriolar responses to adenosine and UTP (P2Y2 receptor agonist) were unaffected by DOCA-salt treatment. PPS and TTx significantly reduced MCP-1 and protein excretion in DOCA-salt rats. These results support the hypothesis that hypertension triggers inflammatory cascades but anti-inflammatory treatment preserves renal autoregulation in DOCA-salt rats, most likely by normalizing renal microvascular reactivity to P2X1 receptor activation.
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and zrguan@uab.edu.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia;
authors.forename: Sean T
authors.initials: ST
authors.lastname: Singletary
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and School of Natural Sciences, University of California, Merced, California.
authors.forename: Haword
authors.initials: H
authors.lastname: Cha
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Van Beusecum
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Anthony K
authors.initials: AK
authors.lastname: Cook
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.affiliation: Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, Georgia; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Inscho
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure; D018932:Chemokine CCL2 / Q000652:urine; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology / Q000627:therapeutic use; D014661:Vasoconstriction
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D058474:Receptors, Purinergic P2X1; D006852:Hydrochlorothiazide; D006830:Hydralazine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D010426:Pentosan Sulfuric Polyester; D012110:Reserpine; D000255:Adenosine Triphosphate
keywords: afferent arteriole; hypertension; inflammation; purinoceptors; triple therapy