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20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 4A (CYP4A) metabolite of arachidonic acid (AA) in human and rabbit lung microsomes and is a dilator of isolated human pulmonary arteries (PA). However, little is known regarding the contribution of P-450 metabolites to pulmonary vascular tone. We examined 1) the effect of two mechanistically distinct omega- and omega1-hydroxylase inhibitors on perfusion pressures in isolated rabbit lungs ventilated with normoxic or hypoxic gases, 2) changes in rabbit PA ring tone elicited by 20-HETE or omega- and omega1-hydroxylase inhibitors, and 3) expression of CYP4A protein in lung tissue. A modest increase in perfusion pressure (55 +/- 11% above normoxic conditions) was observed in isolated perfused lungs during ventilation with hypoxic gas (FI(O(2)) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pressure above that of vehicle and amplified hypoxia-induced increases in perfusion pressures by 92 +/- 11% and 105 +/- 11% over baseline pressures, respectively. 20-HETE relaxed phenylephrine (PE)-constricted PA rings. Treatment with 17-ODYA enhanced PE-induced contraction of PA rings, consistent with inhibition of a product that promotes arterial relaxation, whereas 6-(20-propargyloxyphenyl)hexanoic acid (PPOH), an epoxygenase inhibitor, blunted contraction to PE. Conversion of AA into 20-HETE was blocked by 17-ODYA, DDMS, and hypoxia. CYP4A immunospecific protein confirms expression of CYP4A in male rabbit lung tissue. Our data suggest that endogenously produced 20-HETE could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.

This study was carried out to determine the influence and site of action of N omega-nitro-L-arginine methylester, an L-arginine analogue, on basal pulmonary vascular tone and hypoxic vasoconstriction in neonatal pig lungs. We studied isolated lungs from pigs, age 14.5 +/- 0.5 (SD) d and weight 3.6 +/- 0.7 kg, perfused with autologous blood at a constant flow rate. The arterial-venous occlusion method was used to determine sites of action upstream and downstream of the double occlusion pressure (Pd) during baseline, infusion of acetylcholine, and ventilation of the lung with a hypoxic gas mixture. The measurements were then repeated during the three conditions described above after adding N omega-nitro-L-arginine methylester, a competitive inhibitor of nitric oxide synthase, to the blood. During control conditions, the vascular resistance was almost evenly divided upstream and downstream of Pd. Infusion of acetylcholine resulted in downstream dilation, and hypoxia resulted in an increase in both upstream and downstream resistance. After adding N omega-nitro-L-arginine methylester to the blood, there was an increase in both upstream and downstream resistances; acetylcholine infusion resulted in an increase in total vascular resistance, which was entirely due to upstream constriction; and the hypoxia response was much larger both upstream and downstream of Pd. These results suggest that nitric oxide synthase helped maintain a low level of basal pulmonary vascular tone both upstream and downstream of Pd in these neonatal pig lungs; that the vascular effect of acetylcholine was changed from downstream dilation to upstream constriction by N omega-nitro-L-arginine methylester; and that nitric oxide synthase activity modulated both the upstream and downstream vasomotor response to hypoxia.

Recently, we presented a simple two-parameter distensible vessel model as a potential tool for characterizing pulmonary vascular pressure vs. flow curves under zone 3 conditions (Linehan et al. J. Appl. Physiol. 73: 987-994, 1992). One parameter, alpha, represents the distensibility of the resistance vessels as the fractional change in vessel diameter per Torr change in pressure, and the other parameter, R0, represents the vascular resistance that would exist if the resistance vessels were at their respective diameters obtained if the vascular pressure were zero. The objective of the present study was to determine whether this distensible vessel model was capable of describing the pressure vs. flow data obtained during hypoxia vasoconstriction and under control conditions in isolated lungs from neonatal pigs. The piglet lungs were perfused with autologous blood, and the pulmonary arterial pressure was measured over a range of flow rates from 15 to 250 ml.min-1 x kg-1 at constant left atrial (3 Torr) pressure. The model provided a reasonable fit to the data under both conditions. Hypoxia resulted in a significant increase in R0, from 0.39 +/- 0.10 Torr.ml-1 x min.kg during control conditions to 1.41 +/- 0.46 Torr.ml-1 x min.kg during hypoxia. alpha was 2.4 +/- 0.4%/Torr under control conditions and 2.0 +/- 0.4%/Torr during hypoxia, but this difference was not statistically significant. The results suggest that the distensible vessel model may be useful for interpreting pressure-flow data in terms of changes in geometry and distensibility of the resistance vessels in response to a vasoconstrictor stimulus such as hypoxia.

We used an improved version of the low-viscosity bolus method to evaluate longitudinal (arterial-to-venous) differences in the sensitivity of the dog lung lobe vasculature to selected vasoconstrictor stimuli, including hypoxia, and serotonin, histamine, and norepinephrine infusions. This method revealed a bimodal distribution of local vascular resistance vs. cumulative vascular volume under the zone 3 conditions studied. Our interpretation of the two modes of relatively high resistance is that they correspond to high resistance per unit volume segments of the arteries and veins upstream and downstream from the relatively low resistance per unit volume capillary bed. Thus an increase in the height of the upstream and downstream modes of the resistance distribution suggests constriction in small arteries and veins, respectively. Horizontal displacement of the modes along the cumulative volume axis suggests changes in the distribution of volume among the arteries, veins, and capillary bed. By use of these criteria, the results are consistent with the concept that each of the vasoconstrictor stimuli studied had a different longitudinal response pattern. Hypoxia constricted mainly small arteries, whereas serotonin constricted small and large arteries. Histamine constricted large and small veins, and norepinephrine constricted large and small veins and arteries.

Previously we found that raising cerebrospinal fluid pressure (PCSF) caused pulmonary vasoconstriction mediated by adrenal catecholamines. To localize the site of this vasoconstriction we used the outflow occlusion technique to divide changes in the pulmonary arteriovenous pressure gradient (Pa-v) into upstream and downstream pressure drops. Experiments were conducted in 10 dogs in which the animal's left lower lung lobe was denervated and perfused at constant flow and outflow pressure with blood pumped from the dog's pulmonary artery. Raising PCSF to 218 Torr caused Pa-v to rise from 9.0 to 12.5 Torr. Most (83%) of this increase resulted from an increase in the downstream pressure drop. Previous studies have indicated that changes in the upstream and downstream pressure drops, as measured by this technique, are highly correlated with changes in the resistance of the arterial and venous sides of the vascular bed. Thus, it appears that elevated PCSF caused primarily pulmonary venoconstriction. Similar results were obtained with norepinephrine and epinephrine infusion. This is consistent with previous studies, indicating that adrenal catecholamines are responsible for the increase in Pa-v in response to PCSF in this preparation.

To determine whether the site of serotonin-induced pulmonary vasoconstriction is influenced by serotonin uptake and inactivation within the lung, we utilized an isolated perfused left lower lobe of the dog lung, which could be perfused with flow in the normal direction (i.e., blood flowing into the lobar artery) or in the retrograde direction (i.e., blood flowing into the lobar vein). To localize the site of vasoconstriction, we utilized an outflow occlusion technique in which the changes in lobar vascular resistance were divided into changes in arterial and venous resistances. Serotonin infusion constricted vessels on the arterial side of the site of serotonin uptake during both forward and retrograde perfusion while having much less influence on the venous side. However, during retrograde perfusion the serotonin infusion rate required to produce a given increase in arterial resistance was approximately 85 micrograms/min greater than during forward perfusion. Thus, it would appear that serotonin was primarily an arterial constrictor in this preparation and that, although the lung removed a substantial quantity of serotonin, the uptake and inactivation within the lung had relatively little influence on the site of serotonin vasoconstriction.

Using the low-viscosity bolus method, we examined the influence of lung inflation on the longitudinal distribution of vascular resistance during hypoxia in isolated cat lungs. During hypoxia, increasing transpulmonary pressure decreased vascular resistance but did not change the volume into the lung at which the maximum local resistance was located. This was in contrast to the normoxic situation in which inflation caused an increase in resistance over much of the transpulmonary pressure range studied and moved the maximum local resistance downstream. These results indicate that during hypoxia the major increase in resistance was in extra-alveolar vessels and that distension of these vessels by lung inflation decreased the magnitude of the pressor response. The increase in resistance in alveolar vessels, which occurred on inflation, was similar during control and hypoxic conditions but was a smaller part of the total resistance during hypoxia because of the much larger extra-alveolar vessel resistance.

To determine the influence of pulmonary vasoconstriction on lung tissue perfusion, we examined the effects of hypoxia, sympathetic nerve stimulation, and histamine on vascular resistance, blood, and extravascular volumes, weight, and the distribution of vascular transit times in dog left lower lung lobes perfused in situ. Hypoxia, sympathetic stimulation, and histamine increased pulmonary vascular resistance by 1.96, 1.42, and 2.02 times and increased the relative dispersion of the transit time distributions by 1.49, 1.30, and 1.71 times the control values, respectively. Hypoxia and sympathetic stimulation tended to decrease the blood volume accessible to indocyanine green dye and the lobe weight. On the other hand, histamine infusion, which also decreased the volume accessible to the dye, increased the lobe weight. Despite this increase in weight, histamine infusion resulted in a decrease in the extra-vascular volume accessible to 3HOH. These results indicate that these vasoconstrictor stimuli increased the heterogeneity of transit times through the lung lobe and decreased the flowing blood volume. In addition, histamine decreased the size of the perfused microvascular bed, indicating that pulmonary vasoconstriction can influence the local pattern of microvascular perfusion.

The venous occlusion experiments provide sufficient data to permit the vascular bed of a dog lung lobe to be mathematically modeled as three serial compartments, each containing a quantifiable resistance separated by equal parallel compliances. To determine how these compartments are related to the sites of vasomotion in the pulmonary vascular bed we investigated the effects of various pulmonary vasomotor stimuli. We found that serotonin, sympathetic nerve stimulation, hypoxia, and prostaglandin F2 alpha increased the pressure drop upstream (arterial) from the site of major lobar compliance. On the other hand, histamine, norepinephrine, epinephrine, and elevation of the cerebrospinal fluid pressure increased the pressure drop downstream (venous) from the site of major lobar compliance. These stimuli either did not affect the pressure drop across the middle compartment or increased it slightly. Thus we conclude that the middle compartment represents vessels located between the muscular arteries and veins including the capillary bed and possibly other small nonmuscular vessels. Further, the average preocclusion pressure in the middle compartment is a microvascular pressure that can be used to evaluate the impact of vasoconstriction on the lobar microcirculation.