Signaling mechanisms involved in the intestinal pro-secretory actions of hydrogen sulfide.
BACKGROUND
H(2) S actions in the gut involve neural activation. This study aimed to reveal the signaling mechanisms responsible for the pro-secretory effect of H(2) S by using TRPV1 and unselective TRP blockers and inhibitors of other signaling cascades hitherto described to be targeted by H(2) S elsewhere.


METHODS
Ussing chamber voltage clamp technique was used to study actions of the H(2) S donor NaHS on secretion in guinea-pig and human colon. NaHS effects on guinea-pig primary afferents were also evaluated.


RESULTS
NaHS evoked secretion was significantly reduced in guinea-pig and human tissue by the selective TRPV1 blockers capsazepine, AMG9801, SB705498, BCTC; LY294002 (Phosphatidylinositol-3 kinase (PI3K) inhibitor), SKF96365 (store operated calcium channel blocker), 2-APB (inositol triphosphate blocker), and atropine but not by HC030031 (TRPA1 blocker) or L- and T-type calcium channel antagonists. Actions of TRPV1 antagonists suggested non-competitive inhibition at multiple sites. In guinea-pig colon, Gd(3+) and La(3+) (unselective TRP blockers) had no effects while ruthenium red reduced NaHS effects; in human colon Gd(3+) attenuated NaHS response. NaHS response was inhibited by neurokinin-1 and -3 receptor blockers in guinea-pig and neurokinin-1 and -2 receptor blockade in human tissue. There was cross-desensitization between NaHS and capsaicin responses. NaHS induced capsazepine and LY294002 sensitive afferent discharge.


CONCLUSIONS
H(2) S evokes mucosal secretion by targeting TRPV1 expressing afferent nerves which activate cholinergic secretomotor neurons via release of substance P acting in a species dependent manner on neurokinin-1, -2 or -3 receptors. Besides TRPV1 signaling H(2) S may target intracellular calcium dependent pathways and PI3K.
Krueger
D
D
Human Biology, Technische Universität München, Freising, Germany.
Foerster
M
M
Mueller
K
K
Zeller
F
F
Slotta-Huspenina
J
J
Donovan
J
J
Grundy
D
D
Schemann
M
M
D000368:Aged; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects* / Q000294:innervation; D007583:Jejunum / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009475:Neurons, Afferent / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000502:physiology; D013440:Sulfides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology
D002121:Calcium Channel Blockers; D018377:Neurotransmitter Agents; D013440:Sulfides; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013373:Substance P; C025451:sodium bisulfide; D002118:Calcium; D006862:Hydrogen Sulfide