Distinct effects of CGRP on typical and atypical  smooth muscle cells involved in generating  spontaneous contractions in the mouse renal pelvis.
OBJECTIVE
We investigated the cellular mechanisms underlying spontaneous contractions in the mouse renal pelvis, regulated by calcitonin gene-related peptide (CGRP).


METHODS
Spontaneous contractions, action potentials and Ca2+ transients in typical and atypical smooth muscle cells (TSMCs and ATSMCs) within the renal pelvis wall were recorded separately using tension and intracellular microelectrode recording techniques and Fluo-4 Ca2+ imaging. Immunohistochemical and electron microscopic studies were also carried out.


RESULTS
Bundles of CGRP containing transient receptor potential cation channel, subfamily V, member 1-positive sensory nerves were situated near both TSMCs and ATSMCs. Nerve stimulation reduced the frequency but augmented the amplitude and duration of spontaneous phasic contractions, action potentials and Ca2+ transients in TSMCs. CGRP and agents increasing internal cyclic adenosine monophosphate (cAMP) mimicked the nerve-mediated modulation of TSMC activity and suppressed ATSMCs Ca2+ transients. Membrane hyperpolarization induced by CGRP or cAMP stimulators was blocked by glibenclamide, while their negative chronotropic effects were less affected. Glibenclamide enhanced TSMC Ca2+ transients but inhibited ATSMC Ca2+ transients, while both 5-hydroxydecanoate and diazoxide, a blocker and opener of mitochondrial ATP-sensitive K+ channels, respectively, reduced the Ca2+ transient frequency in both TSMCs and ATSMCs. Inhibition of mitochondrial function blocked ATSMCs Ca2+ transients and inhibited spontaneous excitation of TSMCs.


CONCLUSIONS
The negative chronotropic effects of CGRP result primarily from suppression of ATSMC Ca2+ transients rather than opening of plasmalemmal ATP-sensitive K+ channels in TSMCs. The positive inotropic effects of CGRP may derive from activation of TSMC L-type Ca2+ channels. Mitochondrial Ca2+ handling in ATSMCs also plays a critical role in generating Ca2+ transients.
Hashitani
Hikaru
H
Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. hasitani@med.nagoya-cu.ac.jp
Lang
Richard J
RJ
Mitsui
Retsu
R
Mabuchi
Yoshio
Y
Suzuki
Hikaru
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D054086:KATP Channels / Q000378:metabolism; D007682:Kidney Pelvis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008839:Microelectrodes; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism
D020746:Calcium Channels, L-Type; D054086:KATP Channels; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium