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.

Nonlinear effects of potassium channel blockers on endothelium-dependent hyperpolarization

“…, Waeckel et al . ). Along these lines, the possibility of an allosteric interaction between the two toxins is raised by the observation that apamin increases [ 125 I]‐ChTx binding (Zygmunt et al .…”

“…, Waeckel et al . ), although as a cautionary note, the activators SKA‐31 and NS309 can have other effects (Wong et al . , Waeckel et al .…”

“…, Waeckel et al . ). This, together with its contribution to endothelium‐dependent vasorelaxation being greatest in arterioles and small resistance arteries, means that EDH has the potential to play a significant role in tissue perfusion and blood pressure regulation (Parkington et al .…”

Vascular Reactivity Profile of Novel KCa3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed

“…Altered function of the intermediate‐conductance calcium‐activated potassium channels (K Ca 3.1) has been suggested to accompany endothelial dysfunction observed in many cardiovascular disease states including diabetes (for extensive review, see ). However, preserved K Ca 3.1 functions and ensuing EDH‐mediated relaxations have also been reported . So, regardless of whether the EDH system is impaired or preserved, pharmacological activation of K Ca 3.1 might constitute a therapeutic strategy to improve endothelial function in diseased coronary arteries and other vascular beds and may provide cardiovascular protection .…”

Functional Interaction among KCa and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease

“…The majority of the work delineating the individual contributions of SK Ca and IK Ca channels to vasodilation and tissue hyperemia was performed using mesenteric (gut) arteries as an accessible and abundant source of resistance arteries in the body [56,57,58]. However, to a lesser extent, studies also resolved clear contributions of respective K Ca channel subtypes in the microcirculation of the eye [59], brain [60,61,62], heart [63,64], lung [65,66], skeletal muscle [8,67], and kidney [68,69,70]. While it is clear that both SK Ca and IK Ca channels are integral to overall cardiovascular health (systemic vascular resistance and blood pressure control), respective K Ca contributions underlying hyperemia throughout organs may vary.…”