title: Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.
abstract: The purpose of this study was to assess, in the murine kidney, the mechanisms underlying the endothelium-dependent control of vascular tone and whether or not, in a severe model of hypertension and renal failure, KCa channels contribute to its regulation. Wild-type (BL) and double-transgenic female mice expressing human angiotensinogen and renin (AR) genes received either control or a high-salt diet associated to a nitric oxide (NO) synthase inhibitor treatment (BLSL and ARSL). Changes in renal perfusion pressure (RPP) were measured in isolated perfused kidneys. BLSL and AR were moderately hypertensive without kidney disease while ARSL developed severe hypertension and renal failure. In the four groups, methacholine induced biphasic endothelium-dependent responses, a transient decrease in RPP followed by a cyclooxygenase-dependent increase in RPP. In the presence or not of indomethacin, the vasodilatations were poorly sensitive to NO synthase inhibition. However, in the presence of cyclooxygenase and NO synthase inhibitors, apamin, and/or TRAM-34, blockers of KCa2.3 and KCa3.1, respectively, abolished the decrease in RPP in response to either methacholine or the two activators of KCa2.3/KCa3.1, NS309, and SKA-31. Thus, KCa2/3 channels play a major role in the regulation of murine kidney perfusion and this mechanism is maintained in hypertension, even when severe and associated with kidney damage.
authors.affiliation: Unité de Recherches et de Découvertes Cardiovasculaires, Institut de Recherches Servier, 11 rue des Moulineaux, 92150, Suresnes, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Waeckel
authors.forename: Florence
authors.initials: F
authors.lastname: Bertin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Clavreul
authors.forename: Thibaut
authors.initials: T
authors.lastname: Damery
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.forename: Jérôme
authors.initials: J
authors.lastname: Paysant
authors.forename: Patricia
authors.initials: P
authors.lastname: Sansilvestri-Morel
authors.forename: Serge
authors.initials: S
authors.lastname: Simonet
authors.forename: Christine
authors.initials: C
authors.lastname: Vayssettes-Courchay
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Verbeuren
authors.forename: Michel
authors.initials: M
authors.lastname: Félétou
mesh_terms: D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D006978:Hypertension, Renovascular / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D012083:Renin / Q000235:genetics / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012982:Sodium, Dietary / Q000009:adverse effects; D014664:Vasodilation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D012982:Sodium, Dietary; D016210:Methacholine Chloride; D000808:Angiotensinogen; D019001:Nitric Oxide Synthase; D012083:Renin; D007213:Indomethacin