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12/10/2014
1
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
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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.
12/10/2014
2
Thermoregulatory & Microvascular Physiology, Noll Laboratory
Endogenous hydrogen sulfide production.
Cystathionine-β-synthase (CBS) Cystathionine-ϒ-lyase (CSE) 3-mercaptopyruvate sulfurtransferase (3-MST)
H2S
Thermoregulatory & Microvascular Physiology, Noll Laboratory
CSE and 3-MST are expressed in the cutaneous circulation of humans.
12/10/2014
3
Thermoregulatory & Microvascular Physiology, Noll Laboratory
CSE and 3-MST are expressed in the cutaneous circulation of humans.
Thermoregulatory & Microvascular Physiology, Noll Laboratory
Hydrogen sulfide elicits vasodilation in the cutaneous circulation in a dose-dependent manner.
12/10/2014
4
Thermoregulatory & Microvascular Physiology, Noll Laboratory
Hydrogen sulfide elicits vasodilation in the cutaneous circulation in a dose-dependent manner.
n = 6
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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.
12/10/2014
5
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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.
12/10/2014
6
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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
Thermoregulatory & Microvascular Physiology, Noll Laboratory
-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)
12/10/2014
7
Thermoregulatory & Microvascular Physiology, Noll Laboratory
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