Guanylate cyclase activators influence reactivity of human mesenteric superior arteries retrieved and preserved in the same conditions as transplanted kidneys.
BACKGROUND
This study sought to investigate the mechanisms of relaxation induced by the (nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulators 3-[5'-hydroxymethyl-2'-furyl]-1-benzylindazole (YC-1) in human mesenteric arteries relaxed and precontracted with 1 micromol/L 5-hydroxytryptamine (serotonin).


METHODS
Human mesenteric arteries obtained during kidney retrieval were preserved in the same conditions as transplanted kidneys. All experiments were performed after reperfusion with Krebs buffer in 37 degrees C and 100% oxygen exposure.


RESULTS
In endothelium-intact rings, YC-1 (0.001 to 30 mmol/L) caused concentration-dependent relaxation (pEC(50): 6.59 +/- 0.12), which shifted to the right in endothelium-denuded rings. The sGC inhibitor 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ 10 mmol/L) partially attenuated the maximal responses to YC-1 (E(max) = 51.30% +/- 3.70%; n = 6) and displaced its curve to the right in intact and denuded vessels. Both, the NO synthesis inhibitor N-nitro-L-arginine methyl ester (100 mmol/L) and the NO scavenger carboxy-2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 mmol/L) significantly reduced YC-1 relaxation. The sodium pump inhibitor ouabain (1 micromol/L) produced a greater decrease in the vasodilator response of YC-1 (E(max) = 18.7% +/- 4.55%; n = 9). ODQ (10 micromol/L) plus 1 mumol/L ouabain abolished the relaxant response of YC-1 (E(max) = 9.4% +/- 2.94%, n = 9).


CONCLUSIONS
This study demonstrated that sodium pump stimulation by YC-1 as an additional mechanism of sGC activation independent of cGMP relaxed human mesenteric artery, including blockade of Ca(2+) influx. Furthermore, this study suggested an ability of NO to mediate relaxation of resistance-like arteries through the activation of soluble guanylate cyclase and K(+) channels.
Slupski
M
M
Department of Transplantation and General Surgery, Nicolaus Copernicus University, Curi-Sklodowskiej 9, Bydgoszcz, Kuj-Pom, Poland. maciejslupski@wp.pl
Szadujkis-Szadurski
L
L
Grześk
G
G
Szadujkis-Szadurski
R
R
Szadujkis-Szadurska
K
K
Wlodarczyk
Z
Z
Masztalerz
M
M
Piotrowiak
I
I
Jasiński
M
M
D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000502:physiology*; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D009926:Organ Preservation; D010069:Oxadiazoles / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use; D012189:Retrospective Studies; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000627:therapeutic use
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D007191:Indazoles; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; D014665:Vasodilator Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D019331:NG-Nitroarginine Methyl Ester