Time-dependent changes in pulmonary vascular responses to acute hypoxia during and after cold exposure in rats.

This study evaluated time-dependent alterations in pulmonary vascular reactivity to acute hypoxia and to the administration of angiotensin II (AT-II) during and after chronic exposure to cold using isolated perfused lung specimens from rats. Animals were exposed to a cold environment (3.5 (mean) +/- 1.0 (SD) degrees C) or to a normal temperature (24.0 +/- 1.0 degrees C) for 7 days. The isolated lungs were taken serially and pulmonary vascular responses to acute hypoxia and AT-II were examined. Both the pulmonary vascular responses to acute hypoxia and to AT-II were significantly reduced 9 h after the exposure to cold. The diminished vascular response to AT-II was restored to the pre-exposure level after 5 days of cold exposure and then sustained. On the other hand, the reduced response to acute hypoxia was sustained for the first 7 days during exposure to cold and then returned to the pre-exposure level during sustained exposure to cold. After removal from the 7 days of cold exposure, the pulmonary vascular response to acute hypoxia was immediately restored. Thus, during exposure to cold, pulmonary vascular response to acute hypoxia was more sustained than the AT-II-induced vasoconstriction. We concluded that cold exposure alters pulmonary vascular responses to acute hypoxia and AT-II in rats, but that the response to acute hypoxia is more sustained than that of AT-II.

Reduced pulmonary vascular reactivity after cold exposure to acute hypoxia: a role of nitric oxide (NO).

Exposure to high altitude causes pulmonary hypertension and alterations in pulmonary vascular reactivity. Among the environmental factors, cold exposure has been suggested to be involved in the development of pulmonary hypertension. However, little information is available about pulmonary vascular reactivity after cold exposure. We examined whether cold exposure can cause changes in pulmonary vascular reactivity to acute hypoxia and the possible participation of endogenous nitric oxide. We measured mean systemic (Psa) and pulmonary artery pressures (Ppa) in conscious rats after 1-week cold exposure (3.5 +/- 1.0 degrees C). Subsequently, we investigated hypoxic pulmonary vasoconstriction (HPV) with and without endogenous NO inhibition using N(G)-nitro-L-arginine methyl ester (3 mg/kg) or 7-nitroindazole (1 mg/kg). Cold exposure for 1 week caused a small but significant increase in Ppa, but not in Psa. Neither Ppa nor Psa showed significant changes after both NO inhibitions in rats exposed to cold. However, cold exposure caused a blunted HPV and an increase in plasma nitrite-nitrate concentration compared with rats kept in a neutral environment (24.0 +/- 1.0 degrees C). In addition, NO inhibition by N(G)-nitro-L-arginine methyl ester partially restored the blunted HPV in rats exposed to cold, but not 7-nitroindazole, a selective inhibitor of neuronal NO synthase. We concluded that cold exposure alters pulmonary vascular reactivity to acute hypoxia, and augmented endothelial NO bioactivity plays a counterregulatory role in response to acute hypoxia during cold exposure in rats.

The sinusoidal pressure during ischemia-reperfusion injury in perfused mouse liver pretreated with or without L-NAME.

BACKGROUND: Hepatic ischemia-reperfusion (I/R) is accompanied by liver weight gain and ascites formation possibly caused by an increase in the sinusoidal pressure, a determinant of hepatic transvascular fluid movement. However, changes in the sinusoidal pressure during hepatic I/R in mice are not known. It is also controversial whether nitric oxide (NO) exerts a beneficial or detrimental effect on hepatic I/R injury. We determined the changes in hepatic sinusoidal pressure and liver weight, and the effect of a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) on I/R injury of isolated mouse liver. MATERIALS AND METHODS: Isolated liver from 20 male outbred ddY mice was perfused portally with diluted blood (Hct 3%). After pretreatment with L-NAME (100 microm) or D-NAME (100 microm), ischemia was induced at room temperature by occlusion of the inflow line of the portal vein for 1 h followed by 1-h reperfusion in a recirculating manner. The sinusoidal pressure was assessed by the double vascular occlusion pressure (Pdo), and pre- and postsinusoidal resistance was determined. Liver injury was assessed by blood levels of alanine aminotransferase (ALT). RESULTS: In the d-NAME group (n=7), immediately after reperfusion, the portal pressure increased by 2.8 +/- 0.1 (SE) mmHg, which was accompanied by an increase in Pdo of 1.5 +/- 0.1 mmHg, indicating increases in pre- and postsinusoidal resistance to a similar degree. Then, presinusoidal, but not postsinusoidal, resistance sustained increased until 60 min after reperfusion. Liver weight increased to 0.14 +/- 0.04 g/g liver after reperfusion, followed by a gradual return to baseline. Blood ALT levels increased at 60 min after reperfusion. There were no significant differences in changes in the variables between the D- and L-NAME (n=7) groups. In the time-matched non- I/R control group (n=6), no changes in variables were observed for 2 h. CONCLUSIONS: Mouse hepatic I/R causes marginal liver weight gain associated with a small and transient increase in the sinusoidal pressure, and nitric oxide does not play any significant roles in this injury.

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

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 micromol 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.

Involvement of platelet-activating factor and leukotrienes in anaphylactic segmental venoconstriction in ovalbumin sensitized guinea pig livers.

The hepatic anaphylactic venoconstriction is partly involved in anaphylactic hypotension, and is characterized by significant post-sinusoidal constriction and liver congestion in guinea pigs. We determined what chemical mediators are involved in anaphylaxis-induced segmental venoconstriction and liver congestion in perfused livers isolated from ovalbumin sensitized guinea pigs. Livers were perfused portally and recirculatingly at constant flow with diluted blood. The sinusoidal pressure was measured by the double occlusion pressure (Pdo), and was used to determine the pre-sinusoidal (Rpre) and post-sinusoidal (Rpost) resistances. An antigen injection increased both the portal vein pressure and Pdo, resulting in 4.1- and 2.3-fold increases in Rpre and Rpost, respectively. Hepatic congestion was observed as reflected by liver weight gain. Pretreatment with TCV-309 (10microM, platelet-activating factor (PAF) receptor antagonist) or ONO-1078 (100microM, human cysteinyl-leukotriene (Cys-LT) receptor 1 antagonist), but not indomethacin (10microM, cyclooxygenase inhibitor), ketanserin (10microM, serotonin receptor antagonist), or diphenhydramine (100microM, histamine H1 antagonist), significantly attenuated this anaphylactic hepatic venoconstriction. Anaphylaxis-induced increases in Rpre and Rpost were significantly inhibited by TCV-309 (by 48%) and ONO-1078 (by 36%), respectively. Combined TCV-309 and ONO-1078 pretreatment exerted additive inhibitory effects on anaphylactic hepatic venoconstriction. Anaphylactic hepatic weight gain was converted to weight loss when post-sinusoidal constriction was attenuated. It is concluded that anaphylaxis-induced pre-sinusoidal constriction is mainly caused by PAF and the post-sinusoidal constriction by Cys-LTs in guinea pig livers.

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.

Hepatic venoconstriction is involved in anaphylactic hypotension in rats.

We determined the roles of liver and splanchnic vascular bed in anaphylactic hypotension in anesthetized rats and the effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused rat livers. In anesthetized rats sensitized with ovalbumin (1 mg), an intravenous injection of 0.6 mg ovalbumin caused not only a decrease in systemic arterial pressure from 120 +/- 9 to 43 +/- 10 mmHg but also an increase in portal venous pressure that persisted for 20 min after the antigen injection (the portal hypertension phase). The elimination of the splanchnic vascular beds, by the occlusions of the celiac and mesenteric arteries, combined with total hepatectomy attenuated anaphylactic hypotension during the portal hypertension phase. For the isolated perfused rat liver experiment, the livers derived from sensitized rats were hemoperfused via the portal vein at a constant flow. Using the double-occlusion technique to estimate the hepatic sinusoidal pressure, presinusoidal (R(pre)) and postsinusoidal (R(post)) resistances were calculated. An injection of antigen (0.015 mg) caused venoconstriction characterized by an almost selective increase in R(pre) rather than R(post) and liver weight loss. Taken together, these results suggest that liver and splanchnic vascular beds are involved in anaphylactic hypotension presumably because of anaphylactic presinusoidal contraction-induced portal hypertension, which induced splanchnic congestion resulting in a decrease in circulating blood volume and thus systemic arterial hypotension.

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. 2. Guinea pigs were actively sensitized by a subcutaneous injection of 1 mg ovalbumin. Two weeks after sensitization, the livers were perfused with diluted blood under constant flow or constant perfusion pressure. The constant flow could result in increased shear stress during constriction, while the constant perfusion pressure could prevent changes in shear stress. Using the double occlusion technique to estimate the hepatic sinusoidal pressure, pre- and postsinusoidal constriction was evaluated. Hepatic anaphylaxis was induced by an injection of ovalbumin (4 microg) into the perfusate, the volume of which was 40 mL. 3. Under either constant flow or pressure, anaphylaxis caused venoconstriction of predominantly presinusoids over postsinusoids, although anaphylactic venoconstriction under constant pressure was significantly greater than that under constant flow. When shear stress was held constant by maintaining constant perfusion pressure, a NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME, 100 micromol/L), potentiated similarly both pre- and postsinusoidal constriction induced by anaphylaxis. This suggests that hepatic anaphylaxis shear stress-independently generates NO, resulting in dilatation of both pre- and postsinusoidal vessels in a similar magnitude. In contrast, when shear stress was allowed to rise under constant flow, anaphylactic presinusoidal constriction was preferentially potentiated by L-NAME. 4. Hepatic anaphylaxis can increase NO production in a shear stress-independent manner and dilates similarly both pre- and postsinusoids, while NO produced in a shear stress-dependent manner attenuates predominantly venoconstriction of the presinusoids where shear stress is preferentially increased.

Effects of norepinephrine and histamine on vascular resistance in isolated perfused mouse liver.

Mice have frequently been used for a variety of physiological studies because of the development of genetic engineering. However, the characteristics of hepatic vessels such as the vascular resistance distribution and the reactivity to various vasoconstrictors are not known in mice. We therefore determined the basal levels of segmental vascular resistances and the effects of histamine and norepinephrine on the vascular resistance distribution of mice. The liver of male non-inbred ddY mice was excised and perfused via the portal vein with 5% bovine albumin-Krebs solution at a constant flow rate. The sinusoidal pressure was measured by the double occlusion pressure and used to determine the presinusoidal (R(pre)) and postsinusoidal (R(post)) resistances. The basal R(post) comprised 53 +/- 1% of the total hepatic vascular resistance. The norepinephrine and histamine increased R(pre) in a greater magnitude than R(post) with liver weight loss. However, the response to histamine was weaker than that to norepinephrine. Moreover, histamine-induced vasoconstriction showed tachyphylaxis. In conclusion, the presinusoidal and postsinusoidal resistances of mouse livers were similar in magnitude. The presinusoidal vessels predominantly contract in response to norepinephrine and histamine in mouse livers.

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.

Comparison of cardiopulmonary response to endogenous nitric oxide inhibition in pigs inhabited at three levels of altitude.

Nitric oxide (NO) plays an important role for the pulmonary circulation in normal and chronic hypoxia. We examined effects of endogenous nitric oxide synthase (NOS) inhibition on pulmonary and systemic vascular resistance in unanesthetized pigs living at three levels of altitude to evaluate the role of NO in adaptation to a hypoxic environment. Unanesthetized male adult pigs in three areas [Matsumoto, Japan (680 m above sea level, n = 5); Xing, China (2,300 m, n = 5); and Maxin, China (3,750 m, n = 5)] were prepared for vascular monitoring. Pulmonary (P(pa)), and systemic artery pressure (P(sa)) were monitored, and pulmonary artery wedge pressure (P(cwp)) and cardiac output (CO) were measured before and after treatment with a non-selective NOS inhibitor, N(w)-nitro-L-argine (NLA; 20 mg/kg). Pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were (P(pa)-P(cwp))/CO and P(sa)/CO, respectively. Related to altitude baseline P(pa) was elevated. After NLA administration, P(pa) and P(sa) increased and CO decreased in all animals, resulting in increases in PVR and SVR. However, there were no significant differences in the increase in PVR and SVR in the three groups of pigs. Thus, endogenous NO production contributes to regulate the basal pulmonary vascular tone, but the development of hypoxic pulmonary hypertension appears to be independent of the NO pathway in adult pigs.

Comparison of pulmonary vascular response to endogenous nitric oxide inhibition in sheep and pigs living at 2,300 m.

To compare the role of nitric oxide in an adaptive process to chronic hypoxia, we examined the effects of endogenous nitric oxide synthase inhibition on pulmonary vascular tone in conscious sheep and pigs living at high altitude. Unanesthetized male sheep (n = 6) and pigs (n = 5), born and residing in the highlands of Qinghai Province, China (2,300-3,000 m a.s.l.) were studied at that altitude. Pulmonary artery pressure (P(pa)), pulmonary artery wedge pressure (P(cwp)), and cardiac output (CO) were measured. Pulmonary vascular resistance (PVR) was calculated as (P(pa)- P(cwp))/ CO. Using a climatic chamber, hemodynamic measurements during exposures to atmospheric pressures corresponding to altitudes of 0, 2,300, and 4,500 m a.s.l. were performed with and without NO inhibition, using N(w)-nitro- L-argine (NLA; 20 mg kg(-1)), a potent stereospecific competitive inhibitor of nitric oxide synthase. P(pa) and PVR at baseline (2,300 m) and during hypoxic exposure (4,500 m) were significantly higher in pigs than in sheep. After NLA administration, P(pa) increased and CO decreased in both animals, resulting in significantly increased PVR at baseline and during hypoxic exposure. However, there were no significant differences in the percent increase in basal or hypoxic PVR after NLA administration between sheep and pigs. We conclude that augmented endogenous NO production could contribute to the regulation of pulmonary vascular tone at high altitude in sheep and pigs. However, it is unlikely that NO is responsible for the different pulmonary vascular tones between sheep and pigs at basal condition at moderately high altitude.

Endogenous nitric oxide and pulmonary circulation response to hypoxia in high-altitude adapted Tibetan sheep.

Nitric oxide (NO) is important for the pulmonary circulation response to acute and chronic hypoxia. We examined effects of endogenous nitric oxide synthase (NOS) inhibition on pulmonary vascular tone in response to hypoxia in Tibetan sheep dwelling at 3,000 m above sea level using a pressure chamber. Unanaesthetized male sheep living at 2,300 m above sea level ( n=7) were prepared for vascular monitoring. Pulmonary artery ( P(pa)), pulmonary artery wedge ( P(cwp)) and systemic artery pressures together with cardiac output (CO) were measured, and pulmonary vascular resistance (PVR) was calculated as ( P(pa)- P(cwp))/CO. A non-selective NOS inhibitor, N(omega)-nitro- l-arginine (NLA; 20 mg kg(-1)), and a selective NOS inhibitor, ONO-1714 (0.1 mg kg(-1)), were used and measurements were made at 0 m, 2,300 m, and 4,500 m, with and without the NOS inhibitors. After NLA, P(pa) increased slightly and CO decreased in animals at baseline (2,300 m). The increased PVR after NLA at 4,500 m was greater than that at 2,300 m ( P<0.05). Selective NOS inhibition increased PVR at baseline, but not at 4,500 m. The enhanced pulmonary vasoconstriction after NO inhibition at basal and hypoxic conditions suggests a modulating role of NOS bioactivity in the pulmonary circulation and that augmented endothelial NOS plays a counterregulatory role in the pulmonary vasoconstrictor response to acute hypoxia in high-altitude adapted Tibetan sheep.

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 microg/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.

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.

Effects of platelet-activating factor and thromboxane A2 on isolated perfused guinea pig liver.

Lipid mediators, thromboxane A2 (TxA2) and platelet-activating factor (PAF), are potent vasoconstrictors, and have been implicated as mediators of liver diseases, such as ischemic-reperfusion injury. We determined the effects of a TxA2 analogue (U-46619) and PAF on the vascular resistance distribution and liver weight (wt) in isolated guinea pig livers perfused with blood via the portal vein. The sinusoidal pressure was measured by the double occlusion pressure (P(do)), and was used to determine the pre- (R(pre)) and post-sinusoidal (R(post)) resistances. U-46619 and PAF concentration-dependently increased the hepatic total vascular resistance (R(t)). The minimum concentration at which significant vasoconstriction occurs was 0.001 microM for PAF and 0.1 microM for U-46619. Moreover, the concentration of U-46619 required to increase R(t) to the same magnitude is 100 times higher than PAF. Thus, the responsiveness to PAF was greater than that to U-46619. Both agents increased predominantly R(pre) over R(post). U-46619 caused a sustained liver weight loss. In contrast, PAF also caused liver weight loss at lower concentrations, but it produced liver weight gain at higher concentrations (2.5 +/- 0.3 per 10g liver weight at 1 microM PAF), which was caused by substantial post-sinusoidal constriction and increased P(do). In conclusion, both TxA2 and PAF contract predominantly the pre-sinusoidal veins. TxA2 causes liver weight loss, while PAF at high concentrations increases liver weight due to substantial post-sinusoidal constriction in isolated guinea pig livers.

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. METHODOLOGY: Pulmonary haemodynamic indices and blood gas analyses were measured in six young male animals in an altitude chamber that was adjusted to simulated altitudes of 0 m, 2260 m, and 4500 m. Drip infusion of 4AP, 10 mg/h for 3 h, was started and continued during the study. RESULTS: With the increase in altitude mean pulmonary artery pressure increased and mean PaO(2) decreased. 4AP had no effect on the levels of mean PPA, mean pulmonary artery wedge pressure, cardiac output, and mean PaO(2), mean PaCO(2), and mean pH at any altitude but tended to alter heart rate and mean arterial pressure at altitudes of 2260 m and 4500 m. CONCLUSION: It is concluded that the 4AP-sensitive Kv channel does not play a role in pulmonary vascular tone in high-altitude active Tibetan sheep. Their pulmonary vascular oxygen sensing appears not to involve Kv channels.

NO, but not CO, attenuates anaphylaxis-induced postsinusoidal contraction and congestion in guinea pig liver.

The pathophysiology of the hepatic vascular response to anaphylaxis in guinea pig is not known. We studied effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused livers derived from guinea pigs sensitized with ovalbumin. We also determined whether nitric oxide (NO) or carbon monoxide (CO) modulates the hepatic anaphylaxis. The livers were perfused portally and recirculatingly at constant flow with diluted blood. With the use of the double-occlusion technique to estimate the hepatic sinusoidal pressure (Pdo), portal venous resistance (Rpv) and hepatic venous resistance (Rhv) were calculated. An antigen injection caused venoconstriction characterized by an increase in Rpv greater than Rhv and was accompanied by a large liver weight gain. Pretreatment with the NO synthase inhibitor NG-nitro-l-arginine methyl ester, but not the heme oxygenase inhibitor zinc protoporphyrin IX, potentiated the antigen-induced venoconstriction by increasing both Rpv and Rhv (2.2- and 1.2-fold increase, respectively). In conclusion, anaphylaxis causes both pre- and postsinusoidal constriction in isolated guinea pig livers. However, the increases in postsinusoidal resistance and Pdo cause hepatic congestion. Endogenously produced NO, but not CO, modulates these responses.