Zonghai Ruan

Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats.

We investigated whether nicorandil might prevent and reverse monocrotaline (MCT)-induced pulmonary arterial hypertension. Rats were injected with 50 mg/kg of MCT subcutaneously and randomized to either 7.5 mg/kg/d of nicorandil in drinking water or placebo for 3 weeks. Animals that were treated with MCT and survived for 3 weeks were assigned to either nicorandil or placebo. Nicorandil markedly attenuated pulmonary arterial hypertension with severe structural remodeling of the pulmonary vessels. The survival rate at 3 weeks after treatment was significantly increased in the nicorandil group compared with the placebo group (73% versus 39%, P < 0.05). In the placebo group, endothelial nitric oxide synthase (eNOS) protein was significantly decreased, the numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen-positive cells were increased in the lung tissue, and P-selectin was intensely expressed on the endothelium of the pulmonary arteries. These features were prevented by nicorandil. Late treatment with nicorandil did not palliate established pulmonary arterial hypertension nor improved survival. Thus, nicorandil inhibited development of MCT-induced pulmonary arterial hypertension but failed to reverse it. These effects were associated with marked up-regulation of diminished lung eNOS protein along with improvement of pulmonary vascular endothelial activation and anti-inflammatory and anti-proliferative effects in the lung tissue.

Contribution of nitric oxide to adaptation of tibetan sheep to high altitude

We examined the effects of endogenous nitric oxide synthase (NOS) inhibition on pulmonary hemodynamics in awake sheep living at low and high altitudes to evaluate the role of NO in adaptation to an hypoxic environment. Unanaesthetized male sheep in three places--Matsumoto, Japan (680 m above sea level), Xing, China (2300 m) and Maxin, China (3750 m)--were prepared for measurements of pulmonary artery (Ppa) and pulmonary vascular resistance (PVR) before and after the NOS inhibition. The non-selective NOS inhibitor, Nw-nitro-l-argine (NLA, 20 mg/kg) was used. Baseline Ppa became elevated with an increase in altitude. After NLA administration, PVR significantly increased in animals of all groups. However, the increase in PVR after NLA in tibetan sheep at 3750 m was significantly higher than those in other groups. We conclude that augmented endogenous NO production may contribute to regulating the pulmonary vascular tone in tibetan sheep (3750 m) adapted to high altitude.

Effect of ONO1714, a Specific Inducible Nitric Oxide Synthase Inhibitor, on Lung Lymph Filtration and Gas Exchange during Endotoxemia in Unanesthetized Sheep

Background:The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial. The current study was designed to examine effects of a newly synthesized and selective inducible nitric oxide synthase inhibitor, ONO1714, on endotoxin-induced lung injury in unanesthetized sheep. Methods:Thirteen unanesthetized sheep chronically instrumented with a lung lymph fistula and vascular catheters for monitoring were prepared. Animals were randomly allocated into two experimental groups. In experiment 1, sheep (n = 6) were infused only with endotoxin (1 &mgr;g/kg) for 30 min. In experiment 2, sheep (n = 7) were pretreated with ONO1714 (0.1 mg/kg) before 30 min of endotoxin administration, and the endotoxin was infused in the same manner as in experiment 1. Mean pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow were measured. Observation was continued over 5 h after endotoxin administration. Results:ONO1714 did not cause any pulmonary hemodynamic changes at baseline or exert any influences on transient pulmonary hypertension and increased pulmonary vascular resistance during endotoxemia. However, inducible nitric oxide synthase inhibition with ONO1714 significantly reduced lung lymph filtration and improved abnormal oxygenation during endotoxemia. In addition, increased nitrate–nitrite in plasma and lung lymph in response to endotoxin was prevented by treatment with ONO1714. Conclusions:These findings suggest that nitric oxide release by the inducible nitric oxide synthase pathway partially contributes to the increased permeability of pulmonary edema and decreased oxygenation during endotoxemia in sheep.

Nitric oxide inhibitor altitude-dependently elevates pulmonary arterial pressure in high-altitude adapted yaks

We studied the effect of N(w)-nitro-L-arginine (NLA) on yak pulmonary vascular tone in a climatic (hypobaric/hyperbaric adjusted) chamber. Five young male yaks that had been born and reared at an altitude greater than 3800 m a.s.l. were used. After measuring control values, 20 mg/kg of NLA was administered via the jugular vein to each animal, and pulmonary hemodynamics and blood gases were repeatedly measured at simulated altitudes of 0, 2260 and 4500 m. The mean PaO2 decreased in an altitude-dependent manner, whereas there was no change in mean pulmonary arterial pressure (mPAP) or mean cardiac output (mCO). NLA significantly increased mPAP, and mean pulmonary vascular resistance (mPVR), and decreased CO at each tested altitude, and greater increases in mPAP and mPVR by NLA were observed at the higher elevations. We conclude that augmented endogenous NO production, especially at higher altitudes, accounts for the low pulmonary vascular tone observed in high-altitude adapted yaks.

Blunted effect of the Kv channel inhibitor on pulmonary circulation in Tibetan sheep: A model for studying hypoxia and pulmonary artery pressure regulation

Objective:   The aim of this study was to assess the effect of 4‐aminopyridine, a Kv channel inhibitor, on the pulmonary circulation of Tibetan sheep. It has been reported that chronic hypoxia downregulates the 4‐aminopyridine (4AP)‐sensitive Kv channel (which governs the membrane potential (Em) of pulmonary vascular smooth muscle cells in pulmonary vessels) without a change in 4AP sensitivity.

Oxygen consumption, assessed with the oxygen absorption spectrophotometer, decreases independently of venoconstriction during hepatic anaphylaxis in perfused rat liver

ABSTRACT Anaphylactic shock is accompanied by a decrease in oxygen consumption. However, it is not well known whether oxygen consumption decreases during local anaphylactic reaction in liver. We determined the effects of anaphylaxis and norepinephrine on oxygen consumption in isolated rat livers perfused portally and recirculatingly at constant flow with blood (hematocrit, 12%). Oxygen consumption was continuously measured by monitoring the portal-hepatic venous oxygen saturation differences using the absorption spectrophotometer, the probes of which were built in perfusion lines. Hepatic anaphylaxis was induced by an injection of ovalbumin (0.01 or 0.1 mg) into the perfusate of the isolated liver of the rat sensitized with subcutaneous ovalbumin (1 mg). Hepatic venoconstriction and liver weight loss were similarly observed in response to norepinephrine (0.01-10 &mgr;mol L−1) and anaphylaxis. However, hepatic anaphylaxis reduced oxygen consumption, whereas norepinephrine increased it. There was a possibility that anaphylactic venoconstriction could reduce the perfused surface area, resulting in decreased oxygen consumption. However, pretreatment with a vasodilator of sodium nitroprusside substantially attenuated venoconstriction but not the decrease in oxygen consumption during anaphylaxis. Thus, we conclude that local hepatic anaphylaxis decreases oxygen consumption independently of venoconstriction in isolated blood-perfused rat livers.

Anaphylactic hepatic venoconstriction is attenuated by nitric oxide released via shear stress-dependent and -independent mechanisms in Guinea pig.

1. The role of shear stress in nitric oxide (NO)‐mediated attenuation of anaphylactic venoconstriction was studied using an isolated ovalbumin‐sensitized guinea pig liver.