Hypoxic pulmonary vasoconstriction (HPV), a unique response of pulmonary circulation, is critical to prevent hypoxemia under local hypoventilation. Hypoxic inhibition of K+ channel is known as an important O2-sensing mechanism in HPV. Carbon monoxide (CO) is suggested as a positive regulator of Ca2+-activated K+ channel (BK(Ca)), a stimulator of guanylate cyclase, and an O2-mimetic agent in heme moiety-dependent O2 sensing mechanisms. Here we compared the effects of CO on the HPV (Po2, 3%) in isolated pulmonary artery (HPV(PA)) and in blood-perfused/ventilated lungs (HPV(lung)) of rats. A pretreatment with CO (3%) abolished the HPV(PA) in a reversible manner. The inhibition of HPV(PA) was completely reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. In contrast, the HPV(lung) was only partly decreased by CO. Moreover, the partial inhibition of HPV(lung) by CO was affected neither by the pretreatment with ODQ nor by NO synthase inhibitor (L-NAME). The CO-induced inhibitions of HPV(PA) and HPV(lung) were commonly unaffected by tetraethylammonium (TEA, 2 mM), a blocker of BK(Ca). As a whole, CO inhibits HPV(PA) via activating guanylate cyclase. The inconsistent effects of ODQ on HPV(PA) and HPV(lung) suggest that ODQ may lose its sGC inhibitory action when applied to the blood-containing perfusate.
Animals ; Anoxia/*physiopathology ; Carbon Monoxide/*pharmacology ; Guanylate Cyclase/antagonists & inhibitors/metabolism ; NG-Nitroarginine Methyl Ester/chemistry/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors/metabolism ; Oxadiazoles/chemistry/pharmacology ; Pulmonary Artery/*physiopathology ; Quinoxalines/chemistry/pharmacology ; Rats ; Tetraethylammonium/chemistry/pharmacology ; Vasoconstriction/*drug effects/physiology

OBJECTIVETo identify and elucidate the vasorelaxant activity of homoisoflavonoids, the main chemical components from Lignum Sappan (the stems of Caesalpinia sappan), in isolated rat thoracic aortic rings pre-contracted with phenylephrine (PE, 1 micromol x L(-1)) and KCl (60 mmol x L(-1)).

METHODThe tension of rat thoracic aorta rings was used to evaluated the vasorelaxant activities of four homoisoflavonoids, brazlin (1), (E)-3-(3,4-dihydroxybenzylidene)-7-hydroxychroman-4-one (2), sappanone B (3), 3-deoxysappanone B (4).

RESULTCumulative addition of homoisoflavonoids (2, 3 and 4) (50-1000 micromol x L(-1)) exhibited an acute relaxation either in endothelium-intact or endothelium-denuded rings in a concentration-dependent manner. However, this relaxation was significantly inhibited in endothelium-denuded condition and in the presence of endothelial nitric oxide synthase (eNOS) inhibitor, N(W)-nitro-L-arginine methyl ester (L-NNA, 100 micromol x L(-1)), and a soluble guanylate cylcase (sGC) inhibitor, methylene blue (MB, 10 micromol x L(-1)) when addition of variation homoisoflavonoids brazlin (1) (50-1000 micromol x L(-1)).

CONCLUSIONThese results indicate that normo-homoisoflavonoids (2, 3 and 4) from Caesalpinia sappan mediates endothelium-independent vasodilator action in rat thoracic aortic rings, while the variation homoisoflavonoids brazlin elicits endothelium-dependent relaxation might via nitric oxide (NO)-cGMP pathway. This research could explain the pharmacological activities of homoisoflavonoids to a certain degree.

Animals ; Aorta, Thoracic ; drug effects ; physiology ; Caesalpinia ; chemistry ; Endothelium ; metabolism ; Enzyme Inhibitors ; pharmacology ; Flavonoids ; chemistry ; pharmacology ; Guanylate Cyclase ; antagonists & inhibitors ; Male ; Muscle Contraction ; drug effects ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide Synthase Type III ; antagonists & inhibitors ; Phenylephrine ; pharmacology ; Potassium Chloride ; pharmacology ; Rats ; Receptors, Cytoplasmic and Nuclear ; antagonists & inhibitors ; Soluble Guanylyl Cyclase ; Vasodilation ; drug effects ; Vasodilator Agents ; chemistry ; pharmacology