Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA367

Poster Communications

Renal resistance arteries are sensitized to L-type Ca2+ channel activation in response to renal denervation

S. Pfannkuch1, J. Witte1, R. Rettig1, R. Schubert2, O. Grisk1

1. Physiology, University of Greifswald, Karlsburg, Germany. 2. Cardiovascular Physiology, Medical Faculty of Mannheim, Mannheim, Germany.

Perivascular innervation is a determinant of vascular smooth muscle cell (VSMC) phenotype.We tested if local renal denervation in young adult rats sensitizes renal resistance arteries to L-type Ca2+ channel activation and if increased sensitivity to L-type Ca2+ channel activation or noradrenaline (NA) supersensitivity can be abolished by KATP channel activation. We further investigated the effects of L-type Ca2+ channel activation on basal vascular tone and of KATP channel activation on NA-induced vascular tone in human renal resistance arteries. Eight-week-old rats underwent bilateral renal denervation or sham denervation under ketamine/xylazine anesthesia (100/10 mg*kg-1, i.p.). At the age of 12 weeks, kidneys were removed under pentobarbital anesthesia (60 mg/kg, i.p.) and third generation renal artery branches were dissected for myography and mRNA expression studies. Tissue samples from human kidneys were obtained from patients who underwent nephrectomy. L-type Ca2+ channel activator (S-(-)-BayK8644)-induced tension was higher in arteries from denervated rat kidneys than in arteries from sham-denervated kidneys (60 vs. 30% of K+-induced tension; p < 0.01). The KATP channel activator levcromakalim blocked S-(-)-BayK8644-induced vasoconstriction in arteries from denervated and sham-denervated rats. S-(-)-BayK8644 increased vascular tension to 100% of K+-induced tension in human renal resistance arteries which was blocked by levcromakalim. Arteries from denervated kidneys showed higher NA sensitivity than arteries from sham-denervated kidneys (logEC50 -6.62 vs. -6.12 mol/l; p < 0.01). In both groups, levcromakalim similarly shifted the NA concentration response curves to the right. Levcromakalim also shifted the NA concentration-response curves to the right in human renal resistance arteries. KATP channel blockade did not affect basal or NA-induced vascular tone in rat and human intrarenal arteries. Transcriptome analyses did not reveal statistically significant effects of renal denervation on K+ channel mRNA abundances. PCR analyses showed that mRNAs of all KATP channel constituents are present in human renal resistance arteries. Local renal denervation sensitizes renal resistance arteries to L-type Ca2+ channel activation suggesting that VSMC membrane potential (MP) is depolarized compared to the VSMC MP of innervated intrarenal arteries. A depolarized MP does not contribute to NA supersensitivity in denervated renal resistance arteries. KATP channels are functional in rat and human renal resistance arteries. They do not contribute to basal or NA-induced vascular tone.

Where applicable, experiments conform with Society ethical requirements