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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2006
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
The heme-enzyme soluble guanylyl cyclase (sGC) is an ubiquitous NO receptor, which mediates NO downstream signaling by the
generation of cGMP. We studied the mechanism of action of the anthranilic acid derivatives 5-chloro-2-(5-chloro-thiophene-2-sulfonylamino- N -(4-(morpholine-4-sulfonyl)-phenyl)-benzamide sodium salt (HMR1766) (proposed international nonproprietary name, ataciguat
sodium) and 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy- N -(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (S3448) as a new class of sGC agonists. Both compounds activated different
sGC preparations (purified from bovine lung, or crude from human corpus cavernosum) in a concentration-dependent and quickly
reversible fashion (EC 50 = 0.5â10 μM), with mixed-type activation kinetics. Activation of sGC by these compounds was additive to activation by NO
donors, but instead of being inhibited, it was potentiated by the heme-iron oxidants 1 H -[1,2,4]-oxdiazolo[3,4- a ]quinoxalin-1-one (ODQ) and 4 H -8-bromo-1,2,4-oxadiazolo(3,4- d ) benz( b )(1,4)oxazin-1-one (NS2028), suggesting that the new compounds target the ferric heme sGC isoform. Protoporphyrin IX acted
as a competitive activator, and zinc-protoporphyrin IX inhibited activation of heme-oxidized sGC by HMR1766 and S3448, whereas
heme depletion of sGC by Tween 20 treatment reduced activation. Both compounds increased cGMP levels in cultured rat aortic
smooth muscle cells; induced vasorelaxation of isolated endothelium-denuded rat aorta, porcine coronary arteries, and human
corpus cavernosum (EC 50 1 to 10 μM); and elicited phosphorylation of the cGMP kinase substrate vasodilator-stimulated phosphoprotein at Ser239. HMR1766
intravenous bolus injection decreased arterial blood pressure in anesthetized pigs. All of these pharmacological responses
to the new compounds were enhanced by ODQ and NS2028. Our findings suggest that HMR1766 and S3448 preferentially activate
the NO-insensitive heme-oxidized form of sGC, which exists to a variable extent in vascular tissues, and is a pharmacological
target for these new vasodilator drugs.