Potassium channels mediate hydrogen sulfide- induced cutaneous...

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Thermoregulatory & Microvascular Physiology, Noll Laboratory

Potassium channels mediate hydrogen sulfide-induced cutaneous vasodilation in healthy young adults.

Jessica L. Kutz, Jody L. Greaney, Lacy M. Alexander, FACSM

Department of Kinesiology, The Pennsylvania State University, University Park, PA


Preclinical models suggest hydrogen sulfide modulates vascular function.

Zhao W, Zhang J, Lu Y, and Wang R. The vasorelaxant effect of H(2)S as a novel endogenous

gaseous K(ATP) channel opener. The EMBO journal 20: 6008-6016, 2001.

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Endogenous hydrogen sulfide production.

Cystathionine-β-synthase (CBS) Cystathionine-ϒ-lyase (CSE) 3-mercaptopyruvate sulfurtransferase (3-MST)

H2S


CSE and 3-MST are expressed in the cutaneous circulation of humans.

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CSE and 3-MST are expressed in the cutaneous circulation of humans.


Hydrogen sulfide elicits vasodilation in the cutaneous circulation in a dose-dependent manner.

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Hydrogen sulfide elicits vasodilation in the cutaneous circulation in a dose-dependent manner.

n = 6


ACh

Endoplasmic

Reticulum

Ach

Receptor

IP3R

Calmodulin

CSE/ 3-MST H2S

KATP

channel

ATP

PtdIns(4,5)P2 ATP

PtdIns(4,5)P2

SKCa & IKCa

Hyperpolarization Vasodilation

K+

K+

K+ K+

? ?

Tetraethylammonium (TEA) all KCa channels

Senicapoc (SENI) IKCa3.1 channels

Glybenclamide (GLY) KATP channels

Hypothesis: Exogenous H2S-induced cutaneous vasodilation is mediated by KATP channels.

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Protocol

Site 1

Site 2

Site 3

Site 4

Site 5

Insert Fibers 20 min

Hyperemia 60-90 min

Baseline 30 min

5 mM Na2S 15 min

Flush Ringers 5 min

SNP + 43°C 5 min

Ringers

Ringers

Ringers

Ringers

Ringers

Control: Ringers

KCa Inhibited

IKCa Inhibited

KATP Inhibited

Triple Blockade

+ Na2S

+ Na2S

+ Na2S

+ Na2S

+ Na2S

Ringers

Ringers

Ringers

Ringers

Ringers

SNP

SNP

SNP

SNP

SNP

0 500 1000 1500 20000

50

100

150

Time(sec)

Flux(P

U)Na₂S

Infusion

SNPInfusion


Na 2

S

Na 2

S+Tea

Na 2

S+Gly

Na 2

S+Seni

Na 2

S+Tea

+Gly

+Seni

0

10

20

30

40

* *

Δb

ase

(%

CV

Cm

ax)

Exogenous H2S-induced cutaneous vasodilation is mediated, in part, by TEA-sensitive KCa channels.

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Both NO and by-products of COX contribute, in part, to exogenous hydrogen sulfide-mediated cutaneous vasodilation.

Wang R. (2009). Hydrogen sulfide: a new EDRF.

Kidney international 76, 700-704


-3 -2 -1 0 1 20

20

40

60

80

100CONTROL

L-NAME

*

B

log [Na2S] (mM)

%C

VC

ma

x (

flu

x •

mm

Hg

-1)

Both NO and by-products of COX contribute, in part, to exogenous hydrogen sulfide-mediated cutaneous vasodilation.

-3 -2 -1 0 1 20

20

40

60

80

100CONTROL

KETO

*

B

log [Na2S] (mM)

%C

VC

ma

x (

flu

x •

mm

Hg

-1)

-3 -2 -1 0 1 20

20

40

60

80

100CONTROL

KETO + L-NAME

*

B

log [Na2S] (mM)

%C

VC

ma

x (

flu

x •

mm

Hg

-1)

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In the cutaneous circulation of humans…

• CSE and 3-MST are expressed

• Exogenous H2S donors elicit vasodilation in a dose-dependent manner

• KCa channels, at least in part, mediate H2S induced vasodilation

• NO and downstream product of COX contribute to exogenous H2S-mediated vasodilation

Potassium channels mediate hydrogen sulfide- induced cutaneous...

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