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Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission.
Am J Physiol Cell Physiol. 2015 Jul 15; 309(2):C107-16.AJ

Abstract

Hydrogen sulfide (H2S) is a key signaling molecule regulating important physiological processes, including smooth muscle function. However, the mechanisms underlying H2S-induced detrusor smooth muscle (DSM) contractions are not well understood. This study investigates the cellular and tissue mechanisms by which H2S regulates DSM contractility, excitatory neurotransmission, and large-conductance voltage- and Ca(2+)-activated K(+) (BK) channels in freshly isolated guinea pig DSM. We used a multidisciplinary experimental approach including isometric DSM tension recordings, colorimetric ACh measurement, Ca(2+) imaging, and patch-clamp electrophysiology. In isolated DSM strips, the novel slow release H2S donor, P-(4-methoxyphenyl)-p-4-morpholinylphosphinodithioic acid morpholine salt (GYY4137), significantly increased the spontaneous phasic and nerve-evoked DSM contractions. The blockade of neuronal voltage-gated Na(+) channels or muscarinic ACh receptors with tetrodotoxin or atropine, respectively, reduced the stimulatory effect of GYY4137 on DSM contractility. GYY4137 increased ACh release from bladder nerves, which was inhibited upon blockade of L-type voltage-gated Ca(2+) channels with nifedipine. Furthermore, GYY4137 increased the amplitude of the Ca(2+) transients and basal Ca(2+) levels in isolated DSM strips. GYY4137 reduced the DSM relaxation induced by the BK channel opener, NS11021. In freshly isolated DSM cells, GYY4137 decreased the amplitude and frequency of transient BK currents recorded in a perforated whole cell configuration and reduced the single BK channel open probability measured in excised inside-out patches. GYY4137 inhibited spontaneous transient hyperpolarizations and depolarized the DSM cell membrane potential. Our results reveal the novel findings that H2S increases spontaneous phasic and nerve-evoked DSM contractions by activating ACh release from bladder nerves in combination with a direct inhibition of DSM BK channels.

Authors+Show Affiliations

Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina.Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina.Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina petkov@cop.sc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25948731

Citation

Fernandes, Vítor S., et al. "Novel Mechanism of Hydrogen Sulfide-induced Guinea Pig Urinary Bladder Smooth Muscle Contraction: Role of BK Channels and Cholinergic Neurotransmission." American Journal of Physiology. Cell Physiology, vol. 309, no. 2, 2015, pp. C107-16.
Fernandes VS, Xin W, Petkov GV. Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. Am J Physiol Cell Physiol. 2015;309(2):C107-16.
Fernandes, V. S., Xin, W., & Petkov, G. V. (2015). Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. American Journal of Physiology. Cell Physiology, 309(2), C107-16. https://doi.org/10.1152/ajpcell.00021.2015
Fernandes VS, Xin W, Petkov GV. Novel Mechanism of Hydrogen Sulfide-induced Guinea Pig Urinary Bladder Smooth Muscle Contraction: Role of BK Channels and Cholinergic Neurotransmission. Am J Physiol Cell Physiol. 2015 Jul 15;309(2):C107-16. PubMed PMID: 25948731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. AU - Fernandes,Vítor S, AU - Xin,Wenkuan, AU - Petkov,Georgi V, Y1 - 2015/05/06/ PY - 2015/01/23/received PY - 2015/05/02/accepted PY - 2015/5/8/entrez PY - 2015/5/8/pubmed PY - 2015/9/29/medline KW - Ca2+ transients KW - GYY4137 KW - acetylcholine KW - detrusor smooth muscle SP - C107 EP - 16 JF - American journal of physiology. Cell physiology JO - Am J Physiol Cell Physiol VL - 309 IS - 2 N2 - Hydrogen sulfide (H2S) is a key signaling molecule regulating important physiological processes, including smooth muscle function. However, the mechanisms underlying H2S-induced detrusor smooth muscle (DSM) contractions are not well understood. This study investigates the cellular and tissue mechanisms by which H2S regulates DSM contractility, excitatory neurotransmission, and large-conductance voltage- and Ca(2+)-activated K(+) (BK) channels in freshly isolated guinea pig DSM. We used a multidisciplinary experimental approach including isometric DSM tension recordings, colorimetric ACh measurement, Ca(2+) imaging, and patch-clamp electrophysiology. In isolated DSM strips, the novel slow release H2S donor, P-(4-methoxyphenyl)-p-4-morpholinylphosphinodithioic acid morpholine salt (GYY4137), significantly increased the spontaneous phasic and nerve-evoked DSM contractions. The blockade of neuronal voltage-gated Na(+) channels or muscarinic ACh receptors with tetrodotoxin or atropine, respectively, reduced the stimulatory effect of GYY4137 on DSM contractility. GYY4137 increased ACh release from bladder nerves, which was inhibited upon blockade of L-type voltage-gated Ca(2+) channels with nifedipine. Furthermore, GYY4137 increased the amplitude of the Ca(2+) transients and basal Ca(2+) levels in isolated DSM strips. GYY4137 reduced the DSM relaxation induced by the BK channel opener, NS11021. In freshly isolated DSM cells, GYY4137 decreased the amplitude and frequency of transient BK currents recorded in a perforated whole cell configuration and reduced the single BK channel open probability measured in excised inside-out patches. GYY4137 inhibited spontaneous transient hyperpolarizations and depolarized the DSM cell membrane potential. Our results reveal the novel findings that H2S increases spontaneous phasic and nerve-evoked DSM contractions by activating ACh release from bladder nerves in combination with a direct inhibition of DSM BK channels. SN - 1522-1563 UR - https://www.unboundmedicine.com/medline/citation/25948731/Novel_mechanism_of_hydrogen_sulfide_induced_guinea_pig_urinary_bladder_smooth_muscle_contraction:_role_of_BK_channels_and_cholinergic_neurotransmission_ L2 - https://journals.physiology.org/doi/10.1152/ajpcell.00021.2015?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -