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 demonstrate the vasodilatation activity of the coumarin-containing Angelica dahurica var. formosana and to further analyze active components in the herb extracts.

METHODS(1) The vasodilatation effects induced by different extracts (cyclohexane, ethyl acetate, acetone, methanol, 95 % ethanol and water) of Angelica dahurica var. formosana on mouse thoracic aorta pre-contracted with phenylephrine were investigated. (2) The amount of imperatorin and isoimperatorin in each extract was measured by high-performance liquid chromatography. (3) The vasodilatation effects of imperatorin and isoimperatorin on mouse thoracic aorta were compared using the same in vitro method. (4) The vasodilatation mechanism of imperatorin in the mouse thoracic aorta pre-contracted with phenylephrine was studied using the methods of denuded endothelium, NG-nitro-L-arginine methylester (L-NAME, a nitric oxide synthase inhibitor), and propranolol.

RESULTS(1) The cyclohexane and ethyl acetate extracts of Angelica dahurica var. formosana decreased the maximal response of phenylephrine-induced mouse thoracic aorta contraction dose-dependently, with 50% inhibiting concentration (IC(50)) values of 35.3+/-12.4 mg/L and 40.5+/-12.0 mg/L, respectively. The vasodilatation effect of imperatorin and isoimperatorin was dose-dependent. (2) The cyclohexane extract, showing the strongest vasodilatation effect, possessed the highest contents of imperatorin (4.09%) and isoimperatorin (0.27%, w/w). There was a correlation between the vasodilatation activity and the contents of imperatorin and isoimperatorin in the extracts. (3) The vasodilatation effect of imperatorin was about 4-fold stronger than that of isoimperatorin. (4) The vasodilatation effect of imperatorin was signifificantly attenuated to 24.88%+/-4.06% in the denuded endothelium group compared with the intact endothelium group. And 1 mmol/L L-NAME reduced the imperatorin-induced vasorelaxation by 32.18 %+/-11.29 %.

CONCLUSIONSThe principal effective component of Angelica dahurica var. Formosana was found to be imperatorin. Imperatorin-induced vasodilatation is at least partially regulated by nitric oxide, and has no correlation to beta-receptor.

Angelica ; chemistry ; Animals ; Chromatography, High Pressure Liquid ; Endothelium, Vascular ; physiology ; Furocoumarins ; analysis ; pharmacology ; Male ; Mice ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; physiology ; Phenylephrine ; pharmacology ; Plant Extracts ; pharmacology ; Propranolol ; pharmacology ; Vasodilation ; drug effects

The present experiments were done to determine the effectiveness of a non-specific nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on oxidative stress parameters induced by aluminium chloride (AlCl3) intrahippocampal injections in Wistar rats. Animals were sacrificed 3 h and 30 d after treatments, heads were immediately frozen in liquid nitrogen and forebrain cortices were removed. Crude mitochondrial fraction preparations of forebrain cortices were used for the biochemical analyses: nitrite levels, superoxide production, malondialdehyde concentrations, superoxide dismutase (SOD) activities and reduced glutathione contents. AlCl3 injection resulted in increased nitrite concentrations, superoxide anion production, malondialdehyde concentrations and reduced glutathione contents in the forebrain cortex, suggesting that AlCl3 exposure promoted oxidative stress in this brain structure. The biochemical changes observed in neuronal tissues showed that aluminium acted as a pro-oxidant. However, the non-specific nitric oxide synthase (NOS) inhibitor, L-NAME, exerted anti-oxidant actions in AlCl3-treated animals. These results revealed that NO-mediated neurotoxicity due to intrahippocampal AlCl3 injection spread temporally and spatially to the forebrain cortex, and suggested a potentially neuroprotective effect for L-NAME.
Aluminum Compounds/*toxicity ; Animals ; Chlorides/*toxicity ; Glutathione/metabolism ; Male ; Malondialdehyde ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide Synthase/*antagonists & inhibitors ; Nitrites/chemistry/metabolism ; Prosencephalon/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Superoxides/metabolism

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

OBJECTIVETo investigate whether the methanol extract of Berberis amurensis Rupr. (BAR) augments penile erection using in vitro and in vivo experiments.

METHODSThe ex vivo study used corpus cavernosum strips prepared from adult male New Zealand White rabbits. In in vivo studies for intracavernous pressure (ICP), blood pressure, mean arterial pressure (MAP), and increase of peak ICP were continuously monitored during electrical stimulation of Sprague-Dawley rats.

RESULTSPreconstricted with phenylephrine (PE) in isolated endotheliumintact rabbit corus cavernosum, BAR relaxed penile smooth muscle in a dose-dependent manner, which was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one, a soluble guanylyl cclase inhibitor. BAR significantly relaxed penile smooth muscles dose-dependently in ex vivo, and this was inhibited by pretreatment with L-NAME H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one. BAR-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA, P<0.01), a nonselective K channel blocker, 4-aminopyridine (4-AP, P<0.01), a voltage-dependent K channel blocker, and charybdotoxin (P<0.01), a large and intermediate conductance Ca sensitive-K channel blocker, respectively. BAR induced an increase in peak ICP, ICP/MAP ratio and area under the curve dose dependently.

CONCLUSIONBAR augments penile erection via the nitric oxide/cyclic guanosine monophosphate system and Ca sensitive-K (BK and IK) channels in the corpus cavernosum.

Animals ; Area Under Curve ; Berberis ; chemistry ; Blood Pressure ; drug effects ; Cyclic GMP ; metabolism ; Epoprostenol ; pharmacology ; In Vitro Techniques ; Indomethacin ; pharmacology ; Male ; Models, Biological ; Muscle Relaxation ; drug effects ; Muscle, Smooth ; drug effects ; physiology ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; metabolism ; Penile Erection ; drug effects ; Phenylephrine ; pharmacology ; Plant Extracts ; pharmacology ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; metabolism ; Pressure ; Rabbits

The purpose of this study was to determine if mild hypoxia alters the responsiveness to vasoactive agents in the renal and the femoral arteries in the fetal sheep. Ten pregnant sheep were operated under halothane anesthesia at 116 to 124 days' gestation. A maternal tracheal catheter was placed for infusing compressed air (control group, n=5) or nitrogen (hypoxia group, n=5) starting on post operative day 6 and maintained for 5 days. Femoral and renal arteries were harvested from the fetus to study the constriction response to phenylephrine (PE 10(-9) to 10(-5) mol/L). To determine the involvement of nitric oxide as a modulator of vessel constriction, N-nitro-Larginine methyl ester (L-NAME) was used at a concentration of 10(-4) mol/L in parallel chambers. In the hypoxia group, maternal Pao2 significantly decreased from a base-line of 110.4 +/-1.4 to 80.5 +/-1.6 (mmHg, p <0.01), fetal Pao2 significantly decreased from a baseline of 20.9 +/-0.3 to 15.5 +/-0.1 (mmHg, p <0.01). Hypoxia was associated with a significant increase in PE maximal response in the absence (184.5 +/-6.6 vs. 146.2 +/-4.3) and presence (166.9 +/-6.3 vs. 145.0 +/-4.5) of L-NAME, and a decrease in EC50 in the absence (6.0 +/-1.1 vs. 27.0 +/-4.1) of L-NAME of femoral arteries. However, there were no significant differences in PE maximal response and EC50 in the absence and presence of L-NAME of renal arteries. We concluded that mild chronic hypoxia seems to increase the fetal femoral artery response to PE, but not in the fetal renal artery. This observation is consistent with a redistribution of cardiac output away from the carcass.
Animals ; *Anoxia ; Blood Glucose/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Femoral Artery/*embryology/*pathology ; Hematocrit ; Hydrogen-Ion Concentration ; Kidney/blood supply ; Lactates/blood/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/metabolism ; Nitric-Oxide Synthase/antagonists & inhibitors ; Phenylephrine/chemistry/metabolism/pharmacology ; Renal Artery/pathology ; Sheep/*embryology ; Time Factors ; Vasoconstrictor Agents/*pharmacology