The spectral fingerprint of sleep problems in post-traumatic stress disorder.

STUDY OBJECTIVES: Sleep problems are a core feature of post-traumatic stress disorder (PTSD). The aim of this study was to find a robust objective measure for the sleep disturbance in patients having PTSD. METHODS: The current study assessed EEG power across a wide frequency range and multiple scalp locations, in matched trauma-exposed individuals with and without PTSD, during rapid eye movement (REM) and non-REM (NREM) sleep. In addition, a full polysomnographical evaluation was performed, including sleep staging and assessment of respiratory function, limb movements, and heart rate. The occurrence of sleep disorders was also assessed. RESULTS: In patients having PTSD, NREM sleep shows a substantial loss of slow oscillation power and increased higher frequency activity compared with controls. The change is most pronounced over right-frontal sensors and correlates with insomnia. PTSD REM sleep shows a large power shift in the opposite direction, with increased slow oscillation power over occipital areas, which is strongly related to nightmare activity and to a lesser extent with insomnia. These pronounced spectral changes occur in the context of severe subjective sleep problems, increased occurrence of various sleep disorders and modest changes in sleep macrostructure. CONCLUSIONS: This is the first study to show pronounced changes in EEG spectral topologies during both NREM and REM sleep in PTSD. Importantly, the observed power changes reflect the hallmarks of PTSD sleep problems: insomnia and nightmares and may thus be specific for PTSD. A spectral index derived from these data distinguishes patients from controls with high effect size, bearing promise as a candidate biomarker.

Sleep Fosters Insight Into Real-Life Problems.

Anecdotal reports recount of individuals obtaining insights during sleep. For instance, various acclaimed scientists have attributed some of their greatest insights to sleep-related mentation. To date, this phenomenon has not been systematically investigated. The current study explored the occurrence and characteristics of Sleep-Related Insights (SRIs) in a large population sample, using a questionnaire approach. We found that a large majority of participants (~80%) experienced SRIs at some point in their lives and about 40% obtained SRIs regularly. Most of these subjects could link SRIs to remembered sleep mentation. SRIs were reported to occur in both sleep and half-sleep states, and at any point of the sleep period. Furthermore, SRIs regarded emotional preoccupations about twice as often as theoretical problems. Finally, SRIs were not robustly related to subjective sleep-quality, but small positive correlations with insomnia and narcolepsy-like symptoms were observed. In conclusion, SRIs are much more common than might have been expected, manifest in several forms and appear to be part of normal, healthy sleep. Importantly, the strong link of SRIs with sleep mentation suggests they result from some form of higher-order information processing during sleep, rather than being (fully) secondary to general restorative effects of sleep. Finally, our findings show that a large portion of the sampled population is aware of sleep's benefits for real life problem solving and experiences such benefits on a regular basis.

Vascular recruitment increases evidence of lung injury.

OBJECTIVE: Changes in pulmonary blood flow rate can alter the size of the perfused pulmonary capillary surface area. We tested the hypothesis that full recruitment of the pulmonary vascular bed may decrease evidence of lung injury by recruiting less injured capillaries. We also tested the hypothesis that endothelial ectoenzyme activity is an earlier indicator of lung injury than are permeability measures. DESIGN: Isolated canine lung lobes were perfused with autologous blood at constant blood flows of either 2.05+/-0.04 L/min (SEM) (high flow, full recruitment, n = 12) or 0.600 +/- 0.004 L/min (low flow, 33% full recruitment, n = 12) after lung injury to determine the effect of vascular recruitment on measures of injury. SETTING: Research laboratory at a medical university. SUBJECTS: Lung lobes were obtained from 36 mongrel dogs of either gender. INTERVENTIONS: Lung injury was induced by adding phorbol myristate acetate (PMA) to the blood perfusing the isolated lung. MEASUREMENTS AND MAIN RESULTS: Indicator dilution methods were used to measure single pass hydrolysis of 3[H]-benzoyl-Phe-Ala-Pro, a synthetic substrate for angiotensin converting enzyme, and calculate the modified first order kinetic parameter corresponding to the ratio of a normalized maximal enzymatic conversion rate (A(max)) to the Michaelis-Menten constant (K(m)), i.e., A(max)/K(m), before and after PMA. At a given flow rate, the decrease in A(max)/K(m)serves as an index of vascular injury. PMA decreased A(max)/K(m), percent metabolism, and fractional substrate utilization, and increased permeability, vascular resistance, and vascular pressures regardless of flow rate. The decrease in enzyme activity was detected earlier than the increase in permeability. CONCLUSION: The greater percentage decrease in percent metabolism and fractional substrate utilization and the earlier appearance of increased permeability during high flow indicates that increasing blood flow three-fold recruited injured vessels and/or increased vascular injury by increasing vascular perfusion pressures.

Age differences in sleep-wake behavior under natural conditions.

Differences in lifestyle may account for a considerable portion of the reported age-related changes in overt circadian rhythmicity. By instructing a group of healthy, noninstitutionalized, elderly subjects and a group of young adults to keep a sleep-wake log for a period of two weeks, and to wear an activity monitor for an overlapping period of 11 days, we attempted to assess age-related differences in the habitual sleep-wake behavior, in particular its day-to-day variability. Four clusters of coherent variables were constructed, reflecting (1) circadian phase, (2) variability of sleep-wake behavior, (3) sleep-wake continuity and (4) subjective sleep-wake quality. The results showed that, in comparison with the young subjects, the elderly had a relatively advanced and more regular sleep-wake pattern, reported more midnight awakening and did not differ in their subjective sleep evaluation. In spite of a greater regularity in their lifestyle (which would favor a larger amplitude of the overt circadian rhythmicity) oral temperature measurements showed some evidence of a weakened 24-h periodicity in the elderly.

Endothelial ectoenzyme assays estimate perfused capillary surface area in the dog lung.

Whether the pulmonary vascular bed accommodates flow-induced increases in blood volume mainly through recruitment of previously unperfused capillaries or distension of already perfused vessels remains controversial. The modified first order reaction parameter of an enzyme and substrate, Amax/K(m), is, under nontoxic conditions, proportional to enzyme mass. Thus for ACE, an endothelium-bound ectoenzyme uniformly distributed along the luminal surface of the pulmonary capillary bed, Amax/K(m) is proportional to the dynamically perfused capillary surface area (PCSA). We estimated single-pass translobar hydrolysis and calculated the corresponding Amax/K(m) values of the synthetic ACE substrate 3H-benzoyl-Phe-Ala-Pro (BPAP), under first-order reaction conditions, in isolated blood-perfused dog lung lobes. We additionally studied blood flow distribution using radioactive microsphere techniques. Experiments were performed under zone III conditions over a wide range of lobar blood flow rates (Qb). As Qb was increased, Amax/K(m) rose linearly, while lobar vascular resistance (LVR) decreased, suggesting capillary recruitment rather than distension. Single pass BPAP hydrolysis (v approximately 2.9 at resting Qb) was not altered over a wide range of Qb, indicative of unchanging capillary transit times. When full capillary recruitment was achieved (at Qb > 70 ml/min/g lung wet weight), further Qb elevations failed to increase Amax/K(m), but decreased BPAP hydrolysis, denoting shorter transit times through the fully recruited capillary bed. Our data indicate that, as previously shown for rabbit lung, in this canine model, increases in pulmonary blood volume are mainly accommodated through recruitment of previously unperfused capillaries throughout the entire lung.

Methylene blue restores vasodilation to bradykinin after inhibition of nitric oxide production in the isolated dog lung.

Methylene blue (MB) is a widely used putative inhibitor of nitric oxide (NO)-dependent responses, particularly in cell culture and vascular ring studies. MB is postulated to diminish vasodilation to NO either by preventing activation of guanylate cyclase by NO or by oxidizing NO formed by NO synthase. In the present study we examined whether MB inhibited vasodilation to bradykinin (BK) in the cyclooxygenase-inhibited, isolated canine lung lobe perfused with blood at constant flow. One group of lobes (n = 5) was challenged with BK at baseline vascular tone, after tone was doubled by infusion of serotonin (5-HT), and again after MB treatment. Bradykinin challenge failed to evoke a depressor response at baseline vascular tone but induced marked vasodilation after vascular tone was increased by 5-HT. Subsequent treatment with MB, however, failed to significantly diminish vasodilation to BK (p > 0.05). A second group of lobes (n = 4) was challenged with BK after cyclooxygenase inhibition and the doubling of vascular tone with serotonin infusion. The dose-dependent vasodilation to BK was diminished (p < 0.01) after treatment with 1.8 mM N omega-nitro-L-arginine (L-NA), a potent inhibitor of nitric oxide synthase. However, subsequent treatment with MB restored the vasodilator response to bradykinin to pre-L-NA values (p < 0.01). While our results suggest that vasodilation to bradykinin is mediated in part by NO formation, MB treatment does not appear to alter BK-induced vasodilation, and even enhanced vasodilation to bradykinin after L-NA. MB appears to have some nonspecific effects on vascular tone and reactivity that are unrelated to NO formation.

Effect of high blood flow on pulmonary vascular permeability to protein.

The elevated cardiac output associated with exercise increases lung lymph flow and may increase extravascular lung water. However, it is not known if extremely elevated cardiac output alters pulmonary vascular permeability. The hematocrit-protein method was used to determine the solvent drag reflection coefficient, an index of vascular permeability to proteins, in the isolated blood-perfused canine lung lobe. Microvascular pressure was obtained by double vascular occlusion. Lobes filtered fluid during perfusion at normal flow, 0.451 +/- 0.005 l/min (LF; n = 8), or high flow, 2.319 +/- 0.080 l/min (HF; n = 7). In the LF, venous pressure was elevated to 19.0 +/- 0.5 Torr to induce filtration, whereas Pv was 3.3 +/- 0.1 Torr in the HF. In HF vs. LF, respectively, arterial pressure was 61.4 +/- 7.1 vs. 28.0 +/- 1.0 Torr (P < 0.05), microvascular pressure was 31.9 +/- 3.0 vs. 22.2 +/- 0.9 Torr (P < 0.05), and sigma was 0.52 +/- 0.07 vs. 0.51 +/- 0.02 (P > 0.05). The fivefold increase in blood flow did not alter pulmonary vascular permeability to proteins; however, the capillary filtration coefficient was fivefold greater in the HF vs. LF group (0.328 +/- 0.059 vs. 0.067 +/- 0.007; P < 0.002). These data are compatible with enzyme activity measures indicating a direct linear relationship between blood flow rate and perfused pulmonary microvascular surface area. Although the data do not rule out the possibility of increased pulmonary vascular permeability to water during very elevated blood flow rates, the greater filtration rate during elevated flow is more likely related to increases in both microvascular pressure and surface area.

Segmental vascular pressures in lung embolism.

Average microvascular filtration pressure and vascular permeability measures were obtained in 100-microns glass bead-embolized dog lung lobes randomly assigned to groups in which isolated perfusion was designed to produce weight gain (edema groups) or no weight gain (isogravimetric groups). The solvent drag reflection coefficient (sigma), an index of vascular permeability, was obtained during edema formation, whereas isogravimetric capillary pressure was obtained during isogravimetry. Vascular permeability increased in response to embolism, because sigma was 0.53 +/- 0.03 vs. 0.80 +/- 0.05 (P < 0.005) in embolized and control lobes, respectively. Vascular occlusion methods indicated the greatest resistance increase in response to embolism in the vascular segment represented by Pao--Pdo (arterial occlusion pressure--double occlusion pressure). Because papaverine vasodilation reduced total vascular resistance (RT; P < 0.05) by decreasing Pao (P < 0.01) without altering Pdo, the RT increase in response to embolism was likely due to both vasoconstriction and obstruction. Because Pdo approximated capillary pressure at isogravimetry, Pdo appears to estimate average filtration pressure in both embolized (n = 6) and control lungs (n = 6). Arterial pressure was 56.2 +/- 13.6 vs. 17.6 +/- 1.5 cmH2O (P < 0.01) in embolized (n = 5) and control lobes (n = 6), respectively, whereas Pdo values of 16.1 +/- 1.5 vs. 12.4 +/- 0.8 (P < 0.05) suggested relatively little increase in filtration pressure in response to embolism. If the beads obstructed 100-microns vessels, the vascular segment represented by Pao--Pdo, the major site of vasoconstriction as well as mechanical obstruction, likely includes 100-microns arteries.

Effect of aspirin on vascular tone and reactivity to vasoactive amines in the dog lung.

The effect of increasing blood levels of aspirin on pulmonary hemodynamics and pressor response to vasoactive amines was examined in the isolated canine lung lobe, blood perfused at constant flow. At steady state lobar vascular resistance (LVR), lobes were challenged with either 250 micrograms serotonin (5-HT; n = 4), 5.0 mumol acetylcholine (ACh; n = 4) or 50 micrograms norepinephrine (NE; n = 4) before and after blood aspirin concentration [ASA] was incrementally increased from 17 to 3140 microM. LVR was partitioned into arterial (Ra) and venous (Rv) segments by venous outflow occlusions 20 min after each ASA addition and at the peak of the pressor response to each amine. ASA treatment was associated with a dose-related 105% increase in LVR (P < 0.01) accounted for by a 154% increase in Ra (P < 0.01) and a 70% increase in Rv (P < 0.01) at 3150 microM ASA (n = 12). In spite of increased vascular tone, higher [ASA] also potentiated increases in both pulmonary arterial pressure and LVR to both 5-HT and NE whereas only Ra increased with ACh challenge. Thus, the increase in pulmonary vascular tone and reactivity to vasoactive amines is positively correlated with blood aspirin levels in the dog.

Effect of methylene blue on vasoreactivity in dog lung.

We examined the effect of methylene blue (MB), a putative inhibitor of guanylate cyclase (GC) activation by endothelium-derived relaxing factor (EDRF) and nitrovasodilator compounds, on vascular tone and reactivity to vasoactive substances in the isolated, blood-perfused canine lower left lung lobe. Lobar vascular resistance was partitioned into arterial and venous segments by venous outflow occlusion. Because MB did not alter vasoconstriction to either serotonin or acetylcholine (P greater than 0.05) except after cyclooxygenase inhibition (COI), we determined the effectiveness of MB as an inhibitor of GC activation by nitrovasodilators. Lobes were given graded bolus doses of nitroglycerin (GTN), sodium nitroprusside (SNP), and bradykinin (BK) at baseline vascular tone, after COI, and after vascular tone was raised by either U-46619, a thromboxane analogue, or MB infusion. GTN and BK but not SNP induced dose-dependent vasodilation when vascular tone was raised by U-46619. However, when vascular tone was increased to a similar level by 30 mg MB and 0.5 mg/min infusion, vasodilation to GTN, SNP, and BK was enhanced from U-46619 infusion. In contrast to MB, NG-nitro-L-arginine, a putative inhibitor of EDRF synthesis, diminished vasodilation to BK in cyclooxygenase-inhibited lobes with elevated vascular tone. Because MB potentiated vasodilation to GTN, SNP, and BK, it is questionable whether MB is an effective inhibitor of vasodilation to nitrovasodilators or BK in the isolated, blood-perfused canine lung.

Effects of different cyclooxygenase inhibitors on the segmental distribution of pulmonary vascular resistance in the dog.

An increase in pulmonary vascular resistance (PVR) after cyclooxygenase inhibition (COI) is well documented in the dog, but the site of vasoconstriction to chemically distinct cyclooxygenase inhibitors is largely unknown. The purpose of the present study was to examine and compare equimolar concentrations of three chemically unrelated cyclooxygenase inhibitors, indomethacin (INDO; n = 6), meclofenamate (MECLO; n = 6) and ibuprofen (IBU; n = 5), upon the longitudinal distribution of PVR in the isolated canine lower left lung lobe perfused at constant flow with autologous blood. At successive increases in the blood concentration of each cyclooxygenase inhibitor, PVR was partitioned into upstream (arterial, Ra), middle (Rm) and downstream (venous, Rv) resistance by arterial and venous flow occlusion with capillary pressure estimated by a double flow occlusion technique. All three cyclooxygenase inhibitors produced significant pulmonary vasoconstriction with the largest increase in PVR after INDO (104 +/- 21%) and the smallest after IBU (69 +/- 10%). The PVR increase in the INDO and MECLO group was related to an elevation in both Ra (p less than 0.01) and Rv (p less than 0.01), whereas only Rv was increased by IBU (p less than 0.01). While none of the cyclooxygenase inhibitors increased Rm (p greater than 0.05), capillary pressure was increased from pretreatment levels by each cyclooxygenase inhibitor. Although each of the three chemically distinct cyclooxygenase inhibitors raised PVR, the segmental distribution of PVR and the magnitude of the capillary pressure increase varied at equimolar blood concentration.

Pressure-dependent increase in lung vascular permeability to water but not protein.

Simultaneous measures of vascular permeability to fluid (capillary filtration coefficient, Kf) and to plasma proteins (solvent drag reflection coefficient, sigma) were obtained over venous pressures (Pv) from 14 to 105 Torr in the isolated ventilated canine lung lobe (n = 70) pump perfused with autologous blood. The sigma was obtained from the relative increase in the concentration of plasma proteins vs. erythrocytes during fluid filtration. Kf's were obtained from two gravimetric methods as well as from change in hematocrit. All Kf's increased (P less than 0.05) as Pv was increased. However, sigma averaged 0.59 +/- 0.01 (range 0.54-0.67) and was unchanged (P greater than 0.05) by elevation of Pv over 20-105 Torr. In 44 lobes where all three Kf measures were obtained, gravimetric measures of Kf did not differ (P greater than 0.05) and were highly correlated with Kf obtained from hematocrit change, Vf Kf (P less than 0.001). However, both weight-based Kf's exceeded Vf Kf (P less than 0.05), suggesting that fluid filtration was overestimated by rate of lung weight gain or underestimated by hematocrit change. Increased permeability to water but not to protein over Pv from 20 to 105 Torr indicates that permeability to both can change independently and is counter to the theory that elevated vascular pressure "stretches" vascular pores.

Multiple muscarinic receptor subtypes in the canine pulmonary circulation.

The vascular response to the muscarinic receptor agonist acetylcholine (ACh) in the presence of selected antagonists was examined in the isolated blood-perfused canine left lower lung lobe under conditions of normal (resting) and elevated vascular tone. At normal vascular tone, ACh (1-5 mumol) produced a dose-dependent increase in pulmonary arterial pressure (Ppa), total pulmonary vascular resistance (PVR), and downstream resistance (Rds) without altering upstream resistance (Rus). Pirenzepine (50 and 100 nM), the prototype M1-selective antagonist, and gallamine, an M2-selective antagonist, as well as atropine (50 nM) and secoverine (100 nM), nonselective antagonists, attenuated (P less than 0.05) the ACh-induced increase in Ppa and Rds. With elevated vascular tone induced by serotonin infusion, ACh produced a dose-dependent increase in Ppa in 19 of 25 lobes, although Rus decreased while Rds increased in all lobes. At high vascular tone, pirenzepine or gallamine attenuated the ACh-induced increase in Rds, whereas Rus was not affected. Secoverine and atropine antagonized ACh-induced increases in both Rds and Rus. The pA2 values (i.e., the negative log antagonist concentration requiring a doubling of ACh dose for an equivalent increase in Rds) for gallamine, pirenzepine, secoverine, and atropine were 6.1 +/- 0.1, 7.4 +/- 0.1, 8.3 +/- 0.2, and 10.2 +/- 0.3, respectively. These results suggest that 1) ACh increases PVR in the dog by constricting the venous segments (downstream) of the pulmonary circulation via activation of pulmonary vascular muscarinic receptors under conditions of both normal and elevated vascular tone, 2) both M1- and non-M1-muscarinic receptor subtypes appear to participate in mediating the ACh-induced increase in Rds, and 3) ACh moderately relaxes the upstream (arterial) vessels, especially under conditions of elevated tone.

Modulation of vascular reactivity to serotonin in the dog lung.

Experiments were conducted to compare the effects of cyclooxygenase inhibition (COI) on vascular reactivity to serotonin (5-HT) in the isolated blood-perfused canine left lower lung lobe (LLL) and in isolated canine intrapulmonary lobar artery rings with and without a functional endothelium. LLLs (n = 6), perfused at constant blood flow, were challenged with bolus doses of 50, 100, and 250 micrograms 5-HT before COI, after COI with 45 microM meclofenamate, and after infusion of prostacyclin (PGI2) during COI. Lobar vascular resistance was segmentally partitioned by venous occlusion. Pulmonary arterial pressure increased from 13.5 +/- 1.0 to 16.3 +/- 0.8 cmH2O (P less than 0.01) after COI but declined to 13.1 +/- 1.1 cmH2O (P less than 0.01) subsequent to PGI2 infusion (91.3 +/- 14.5 ng.min-1.g LLL-1). The pulmonary arterial pressure changes were related to changes in postcapillary resistance. The dose-dependent pressor response to 5-HT was potentiated by COI (P less than 0.01) but reversibly attenuated (P less than 0.05) by PGI2 infusion. Isolated intrapulmonary artery rings (2-4 mm diam) exhibited a dose-related increase in contractile tension to 5-HT. The response to 5-HT was enhanced (P less than 0.05) in rings devoid of a functional endothelium. However, COI (10 microM indomethacin) did not alter (P greater than 0.05) the dose-related increase in contractile tension to 5-HT in rings with an intact endothelium. Our results suggest that both PGI2 and endothelium-derived relaxing factors modulate pulmonary vascular reactivity to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of fluid filtration to lung vascular pressure during edema.

Effect of edema on the relationship between rate of fluid filtration and vascular pressure was studied in ventilated isolated dog lung lobes blood-perfused at constant flow. Constant rate of lobe weight gain (S), representing transvascular fluid flux, was obtained at different venous pressures (Pv) as Pv was increased stepwise from 2 to 40 and then similarly decreased from 40 to 2 Torr (n = 6). In another group (n = 6), edema was maximized by reversing the sequence of Pv change; S was obtained during similar Pv steps as Pv was decreased from 40 to 2 and then returned to 40 Torr. In both groups, delta S was disproportionately greater for delta Pv at higher Pv's, with S vs. Pv fit by an exponential curve (P less than 0.001). The exponential relationship was independent of lung hydration inasmuch as greater edema on the second limb of Pv change did not alter the curve (P greater than 0.05). At 144% weight gain, interstitial compliance was 55.5 +/- 26.8 ml.100 g-1.Torr-1 (n = 10). Interstitial pressure reportedly remains constant, i.e., fails to increase to further buffer fluid filtration, after transition of the lung interstitium from low to high compliance at approximately 40% lung weight gain. If so, then the exponential S vs. Pv relationship observed in the present study at elevated interstitial compliance does not appear related to tissue pressure-buffering effects.

Pulmonary vascular reactivity and permeability to alveolar hypoxia in the dog.

Hemodynamics and vascular permeability were studied during acute alveolar hypoxia in isolated canine lung lobes perfused at constant flow with autogenous blood. Hypoxia was induced in the presence (COI + Hypox, n = 6) or absence (Hypox, n = 6) of cyclooxygenase inhibition (COI) with indomethacin or meclofenamate. Hypoxic ventilation reduced blood PO2 from 143 to 25-29 Torr without a change in PCO2. During hypoxia a capillary filtration coefficient (Kf) was obtained gravimetrically as an index of vascular permeability to water. In COI + Hypox, pulmonary arterial pressure (Pa) increased from 11.5 +/- 0.7, post-COI normoxia, to a peak of 22.1 +/- 2.3 during hypoxia (P less than 0.01) without a change in capillary pressure (Pc). In contrast, hypoxia changed neither Pa nor Pc in Hypox relative to an untreated normoxic control group (Normox, n = 6, P greater than 0.05). Kfs (means +/- SE in ml.min-1.Torr-1.100 g-1) for Normox (0.070 +/- 0.014), Hypox (0.082 +/- 0.024), and COI + Hypox (0.057 +/- 0.017) did not differ from one another (P greater than 0.05). Although COI markedly enhanced the pressor response to acute alveolar hypoxia, hypoxia increased neither Pc nor vascular permeability regardless of COI.

Prostacyclin production with serotonin, increased flow, or elevated venous pressure in dog lung.

The lung may release prostacyclin (PGI2) in response to humoral or mechanical stimuli. We measured 6 keto-PGF1 alpha as an index of PGI2 production during serotonin (5-HT) infusion, elevated venous pressure (Pv), or increased blood flow (Q) in the isolated canine lower left lung lobe (LLL). Lobar vascular resistance (LVR) was partitioned into arterial (Ra), middle (Rm), and venous (Rv) components by arterial and venous occlusions. The infusion of 55-210 micrograms/min 5-HT (n = 9) was associated with concomitant increases in PGI2 production and dose-related increases in pulmonary arterial pressure (Pa) and LVR. 5-HT increased Ra at each infusion rate, whereas Rm was not changed and Rv was increased only at the highest infusion rate. When Pa was increased by stepwise elevations in Pv from 3.7 to 19.1 cmH2O (n = 8) or by increases in Q from 250 to 507 ml/min (n = 5) to match the Pa increase observed during 5-HT infusion, PGI2 production was not altered. Increases in Pv reduced LVR largely by decreasing Ra, whereas increases in Q reduced LVR without changing Ra, Rm, or Rv. Infusion of 5-HT when Pa was held constant by reduction in blood flow (n = 6) did not increase PGI2. Thus infusion of 5-HT at a normal blood flow rate increased PGI2 formation in the isolated blood-perfused dog lung lobe. The results also suggest that sustained mechanical effects related to increased venous pressure or elevated blood flow are not associated with a sustained elevation of PGI2 formation.

Hemodynamic and vascular permeability effects of lipid emulsion in the isolated canine lung lobe.

The isolated canine right lower lung lobe (RLL) perfused with autogenous blood at constant flow was used to study the effects of a parenteral lipid emulsion, Liposyn 10%, on pulmonary hemodynamics and vascular permeability. Lobes were placed into four groups: (1) control lobes (C; n = 6), which were infused via the lobar artery with normal saline at 1 ml.min-1 for 30 min; (2) lipid emulsion lobes (L; n = 6), which were infused via the lobar artery with Liposyn 10% at 1 ml.min-1 for 15 min; (3) lobes infused with both Liposyn 10% and 0.25 to 6.0 mg of lipoprotein lipase (LL; n = 4); and (4) lobes infused with 0.13 to 6.0 mg of lipoprotein lipase alone (LP; n = 6). Liposyn infusion alone caused no changes in lobar hemodynamics compared to group C. Over time there were no differences between groups C and L on venous PO2, PCO2, or pH. Post-infusion weight gain (over 10 to 14 min) averaged 0.23 +/- 0.08, 0.19 +/- 0.07, 0.66 +/- 0.23, and 3.00 +/- 1.46 g.min-1.100 g-1 RLL for groups C, L, LP, and LL, respectively (p less than 0.05, for group LL compared to Group C). The pulmonary filtration coefficient (Kf) was determined as an index of vascular permeability. Groups C and L had Kf values of 0.07 +/- 0.01 and 0.28 +/- 0.22 ml.min-1.mm Hg-1.100 g-1 (mean +/- SE), respectively, which did not differ significantly (p greater than 0.05). Liposyn 10%, given in a concentration larger than that used clinically, produced no untoward pulmonary vascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil inhibition of serotonin-induced vasoconstriction in dog lung.

The effect of the voltage-dependent calcium channel blocker verapamil on serotonin (5-HT)-induced vasoconstriction and segmental distribution of vascular resistance was examined in isolated, blood-perfused dog left lower lung lobe. 5-HT, 250 micrograms, increased lobar vascular resistance (LVR) by 47.3 +/- 6.5 cm H2O (n = 7), accounted for by a 30.8 +/- 4.3 and 16.4 +/- 2.8 cm H2O increase in upstream (Ra) and downstream (Rv) resistance, respectively. However, the increase in LVR, Ra, and Rv to 5-HT was significantly attenuated as verapamil concentration was increased from 1.2 to 100 microM. The verapamil concentration that inhibited 50% of LVR response (ED50) to 5-HT was 12.1 +/- 5.5 microM. The LVR response to 50, 100, and 250 micrograms 5-HT was reduced after 12.5 microM verapamil by 41 +/- 4.4, 43 +/- 3.8, and 43 +/- 5.0%, respectively. The increase in Ra to 50, 100, and 250 micrograms 5-HT was reduced by 57 +/- 6.7, 57 +/- 4.6, and 51 +/- 7.2%, respectively, by 12.5 microM verapamil, with Rv reduced by 32 +/- 3.9% only at 250 micrograms 5-HT. The alpha-adrenergic receptor antagonist, phentolamine (10 microM) reduced the pressor response to norepinephrine (NE) by 97% but reduced the Ppa increase to 250 micrograms 5-HT by only 29 +/- 10% and did not alter the pressor response to 5 mmol KCl. A verapamil concentration of 105 microM was required to inhibit 50% of the control pressor response to KCl. Our results suggest that the entry of extracellular calcium is important for 5-HT-evoked contractions of canine pulmonary vascular smooth muscle.

Reversal of tachyphylaxis to angiotensin II in dog lung.

Angiotensin II (ANG II) is a potent vasoconstrictor in most vascular beds. We studied the role of cyclooxygenase products and/or endothelium-derived relaxing factor (EDRF) in modulating the pressor response to ANG II in the isolated, blood perfused dog lung. ANG II was given as a bolus dose of 2, 4 and 8 micrograms before and after cyclooxygenase inhibition (COI) with either 40 mumol/l indometacin (INDO) or 45 mumol/l meclofenamate (MECLO), and before and after methylene blue (MB) infusion followed by MECLO or MECLO followed by MB infusion. ANG II produced an increase in lobar vascular resistance (LVR) that averaged 3.7 +/- 1.1 to 3.0 +/- 0.3 cm H2O/l/min (n = 30), but was not dose-related and exhibited marked tachyphylaxis. In contrast, after INDO, the increase in LVR to ANG II averaged 8.2 +/- 1.0 to 18.4 +/- 2.2 (n = 6) and 5.0 +/- 1.2 to 15 +/- 2.4 cm H2O/l/min after MECLO (n = 6) and both cyclooxygenase inhibitors increased (p less than 0.05) basal vascular tone. Infusion of MB did not alter baseline vascular tone, but prevented the tachyphylaxis to ANG II. Our results indicate that tachyphylaxis to ANG II-induced vasconstriction in the isolated, blood perfused dog lung lobe is not only reversed by COI, but potentiated and dose-related. Whereas MB diminished tachyphylaxis to ANG II, it failed to potentiate the pressor response to ANG II except with concurrent COI. Our findings suggest that vasodilator cyclooxygenase products are probably more important than EDRF in regulating both vascular tone and reactivity to ANG II in the dog lung.