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The role of vascular smooth muscle Kv7 channels in renal perfusion

Stocker, Felix

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Abstract

Vascular smooth muscle cell membranes contain potassium channels that by influencing membrane potential importantly contribute to the regulation of arterial tone. The KCNQ gene encodes for 5 different K+ channel subunits forming homo- or heteromeric Kv7, which are a family of voltage-dependent K+ channels functionally expressed in various vascular beds that can be activated by depolarizing stimuli and inactivated upon prolonged depolarization. In this thesis, the contribution of Kv7 to the regulation of renal arterial tone was studied, testing the hypotheses that (i) the Kv7.1-specific activator R-L3 is effective in causing reversible vasodilation of the entire renal arterial vasculature and that (ii) the endogenous vasodilators atrial natriuretic peptide (ANP) and Urocortin either attenuate or enhance the therapeutically intended vasodilatory effect of subunit-specific activation of Kv7.1 or Kv7.2-5 in small renal resistance arteries. Isometric wire myography was used to examine the contractile responses of short preglomerular resistance artery segments. A novel isolated perfused rat kidneys setup was introduced to investigate renal perfusion pressure as an indicator of arterial contractility on a whole-organ level. It was shown that pharmacological activation of Kv7.2-5 channels produces a strong anticontractile effect in agonist-induced vasoconstriction of renal resistance arteries. Specific activation of Kv7.1 was found to decrease sensitivity to vasoconstrictive agonists in small interlobar artery segments as well as to decrease perfusion pressure of intact perfused rat kidneys in a manner reversible by specific pharmacological Kv7.1 channel blockade. Unspecific blockade of all Kv7 was demonstrated to enhance arterial contractility in both isolated vessels and isolated perfused kidneys, whereas specific blockade of Kv7.1 was without either of these effects, indicating a contribution of homo- or heteromeric Kv7.4 and Kv7.5, but not homomeric Kv7.1, to resting tone of the renal arterial vasculature. Experiments on isolated interlobar vessels displayed dose-dependent vasorelaxations in response to the cGMP-coupled hormone ANP and the cAMP-dependent autocrine and paracrine vasodilator Urocortin in both agonist-induced and depolarization-induced vasoconstriction. Further experiments revealed that Kv7 contribute to vascular reactivity independently of the anticontractile effect induced by both ANP and Urocortin. The results presented here confirm our first hypothesis that R-L3 is effective in causing reversible vasorelaxation of the entire renal arterial bed, undermining a previously unappreciated role for Kv7.1 in regulating renal arterial contractility and renal perfusion pressure. By demonstrating the possibility to influence vascular tone through specific Kv7 modulators independently of both cGMP- and cAMP-dependent endogenous vasodilators and thus negating our second hypothesis, this thesis stresses the importance of Kv7 as potential therapeutic targets in the treatment of renovascular pathology.

Item Type: Dissertation
Supervisor: Schubert, Prof. Dr. med. Rudolf
Place of Publication: Heidelberg
Date of thesis defense: 15 September 2020
Date Deposited: 20 Nov 2020 11:19
Date: 2020
Faculties / Institutes: Medizinische Fakultät Mannheim > Zentrum für Biomedizin und Medizintechnik (CBTM)
Subjects: 610 Medical sciences Medicine
Controlled Keywords: Kv7, KCNQ, Kaliumkanal, Nierenperfusion, Arteria renalis, Isoliert perfundiertes Organ, Vasokonstriktion, Vasodilatation
Uncontrolled Keywords: Kv7 KCNQ Isometrische Myographie Isoliert perfundierte Niere Kardiovaskuläre Physiologie
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