Nicotinic receptor activation on primary sensory afferents modulates autorhythmicity in the mouse renal pelvis

<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The modulation of the spontaneous electrical and <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> signals underlying pyeloureteric peristalsis upon nicotinic receptor activation located on primary sensory afferents (<jats:styled-content style="fixed-case">PSAs</jats:styled-content>) was investigated in the mouse renal pelvis.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>Contractile activity was followed using video microscopy, electrical and <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> signals in typical and atypical smooth muscle cells (<jats:styled-content style="fixed-case">TSMCs</jats:styled-content> and <jats:styled-content style="fixed-case">ASMCs</jats:styled-content>) within the renal pelvis were recorded separately using intracellular microelectrodes and Fluo‐4 <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> imaging.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Nicotine and carbachol (<jats:styled-content style="fixed-case">CCh</jats:styled-content>; 1–100 μM) transiently reduced the frequency and increased the amplitude of spontaneous phasic contractions in a manner unaffected by muscarininc antagonists, 4‐<jats:styled-content style="fixed-case">DAMP</jats:styled-content> (1,1‐dimethyl‐4‐diphenylacetoxypiperidinium iodide) and pirenzipine (10 nM) or L‐<jats:styled-content style="fixed-case">NAME</jats:styled-content> (<jats:styled-content style="fixed-case">L</jats:styled-content>‐<jats:styled-content style="fixed-case">N</jats:styled-content>ω‐nitroarginine methyl ester; 200 μM), inhibitor of <jats:styled-content style="fixed-case">NO</jats:styled-content> synthesis, but blocked by the nicotinic antagonist, hexamethonium or capsaicin, depletor of <jats:styled-content style="fixed-case">PSA</jats:styled-content> neuropeptides. These negative chronotropic and delayed positive inotropic effects of <jats:styled-content style="fixed-case">CCh</jats:styled-content> on <jats:styled-content style="fixed-case">TSMC</jats:styled-content> contractions, action potentials and <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> transients were inhibited by glibenclamide (<jats:styled-content style="fixed-case">G</jats:styled-content>lib; 1 μM), blocker of <jats:styled-content style="fixed-case">ATP</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">K</jats:styled-content> (<jats:styled-content style="fixed-case">KATP</jats:styled-content>) channels. Nicotinic receptor‐evoked inhibition of the spontaneous <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> transients in <jats:styled-content style="fixed-case">ASMCs</jats:styled-content> was prevented by capsaicin but not <jats:styled-content style="fixed-case">G</jats:styled-content>lib. In contrast, the negative inotropic and chronotropic effects of the non‐selective <jats:styled-content style="fixed-case">COX</jats:styled-content> inhibitor indomethacin were not prevented by <jats:styled-content style="fixed-case">G</jats:styled-content>lib.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>The negative chronotropic effect of nicotinic receptor activation results from the release of calcitonin gene‐related peptide (<jats:styled-content style="fixed-case">CGRP</jats:styled-content>) from <jats:styled-content style="fixed-case">PSAs</jats:styled-content>, which suppresses <jats:styled-content style="fixed-case"><jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> signalling in <jats:styled-content style="fixed-case">ASMCs</jats:styled-content>. <jats:styled-content style="fixed-case">PSA</jats:styled-content>‐released <jats:styled-content style="fixed-case">CGRP</jats:styled-content> also evokes a transient hyperpolarization in <jats:styled-content style="fixed-case">TSMCs</jats:styled-content> upon the opening of <jats:styled-content style="fixed-case">KATP</jats:styled-content> channels, which reduces contraction propagation but promotes the recruitment of <jats:styled-content style="fixed-case">TSMC <jats:roman>Ca<jats:sup>2+</jats:sup></jats:roman></jats:styled-content> channels that underlie the delayed positive inotropic effects of <jats:styled-content style="fixed-case">CCh</jats:styled-content>.</jats:p></jats:sec>