TY - JOUR
T1 - Distinct effects of CGRP on typical and atypical smooth muscle cells involved in generating spontaneous contractions in the mouse renal pelvis
AU - Hashitani, Hikaru
AU - Lang, Richard John
AU - Mitsui, Retsu
AU - Mabuchi, Yoshio
AU - Suzuki, Hikaru
PY - 2009
Y1 - 2009
N2 - BACKGROUND AND PURPOSE: We investigated the cellular mechanisms underlying spontaneous contractions in the mouse renal pelvis, regulated by calcitonin gene-related peptide (CGRP). EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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.
AB - BACKGROUND AND PURPOSE: We investigated the cellular mechanisms underlying spontaneous contractions in the mouse renal pelvis, regulated by calcitonin gene-related peptide (CGRP). EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20050194
U2 - 10.1111/j.1476-5381.2009.00514.x
DO - 10.1111/j.1476-5381.2009.00514.x
M3 - Article
SN - 0007-1188
VL - 158
SP - 2030
EP - 2045
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -