Double Occlusion Technique Research Articles

Ventilator-derived dynamic respiratory system compliance: Comparison with static compliance in children

Measurement of dynamic lung compliance during breathing requires measurement of esophageal pressure, whereas static respiratory system compliance (Crs) method requires several airway occlusions. Despite their precision these compliance methods are cumbersome and not suitable for evaluation of pulmonary system in intensive care. The current ventilators display dynamic Crs, which, however, is seldom utilized in clinical practice. We studied the feasibility of ventilator-derived dynamic Crs measurement in pulmonary evaluation after congenital cardiac surgery in children. In 50 children static Crs was measured by double-occlusion technique, and compared with simultaneous ventilator-derived dynamic Crs values. The early postoperative dynamic and static Crs showed a correlation (r = 0.57, p < 0.0001), but static Crs was 48% higher than dynamic (p < 0.0001). Dynamic Crs measurement showed no correlation with radiographic lung edema findings, whereas the static Crs showed a negative correlation with radiographic lung edema scoring (r = −0.50, p = 0.0002). Thus ventilator-derived dynamic Crs seems less reliable in postoperative pulmonary evaluation than static Crs.

Effects of Constant Flow vs. Constant Pressure Perfusion on Fluid Filtration in Severe Hypothermic Isolated Blood-Perfused Rat Lungs.

Victims of severe accidental hypothermia are prone to fluid extravasation but rarely develop lung edema. We hypothesize that combined hypothermia-induced increase in pulmonary vascular resistance (PVR) and a concomitant fall in cardiac output protect the lungs against edema development. Our aim was to explore in hypothermic-isolated blood-perfused rat lungs whether perfusion at constant pressure influences fluid filtration differently from perfusion at constant flow. Isolated blood-perfused rat lungs were hanging freely in a weight transducer for measuring weight changes (ΔW). Fluid filtration coefficient (Kfc), was determined by transiently elevating left atrial pressure (Pla) by 5.8 mmHg two times each during normothermia (37°C) and during hypothermia (15°C). The lung preparations were randomized to two groups. One group was perfused with constant flow (Constant flow group) and the other group with constant pulmonary artery pressure (Constant PPA group). Microvascular pressure (Pmv) was determined before and during elevation of Pla (ΔPmv) by means of the double occlusion technique. Kfc was calculated with the formula Kfc = ΔW/ΔPmv/min. All Kfc values were normalized to predicted lung weight (PLW), which was based on body weight (BW) according to the formula: PLW = 0.0053 BW - 0.48 and presented as KfcPLW in mg/min/mmHg/g. At cessation, bronchoalveolar lavage (BAL) fluid/perfusate protein concentration (B/P) ratio was determined photometrically. Data were analyzed with parametric or non-parametric tests as appropriate. p < 0.05 considered as significant. Perfusate flow remained constant in the Constant flow group, but was more than halved during hypothermia in the Constant PPA group concomitant with a more fold increase in PVR. In the Constant flow group, KfcPLW and B/P ratio increased significantly by more than 10-fold during hypothermia concerted by visible signs of edema in the trachea. Hemoglobin and hematocrit increased within the Constant flow group and between the groups at cessation of the experiments. In hypothermic rat lungs perfused at constant flow, fluid filtration coefficient per gram PLW and B/P ratio increased more than 10-fold concerted by increased hemoconcentration, but the changes were less in hypothermic lungs perfused at constant PPA.

Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice.

BackgroundInhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it’s biochemical mechanisms and effects on inflammatory reactions.MethodsMice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured.ResultsHPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3rd and 6th hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines.ConclusionLow-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.

PS-109 B-lines In Lung Ultrasound In Newborns: Comparison With Static Lung Compliance

Background and aims Vertical artefacts (B-lines) in lung ultrasound have been shown to correlate with lung liquid. In neonates the abundance of B-lines decreases after birth reflecting the decrease in the liquid content of the lungs. Static lung compliance, a sign of the elasticity of the lungs, improves after birth. Our aim was to study the correlation between static lung compliance and lung ultrasound in neonates. Methods 24 healthy term infants were studied. Static lung compliance was measured by the double occlusion technique at the age of 0–4 h during silent sleep and regular respiration. Lung ultrasound was performed immediately after the compliance measurement. B-lines in ultrasound from six designated areas on the chest were scored on a 5-step scale to yield the US score. Results Static lung compliance correlated significantly (p = 0,043, Pearson Correlation) with the abundance of B-lines in ultrasound. Conclusion Our result supports the utility of lung ultrasound in estimating lung liquid.

The key or just a cog in the wheel to operability assessment?

The ability to measure the hydrostatic pressure in a capillary bed ( P c) was an impetus for the development of the arterial occlusion method [1]. The relevance of P c in pulmonary circulation is its role in pulmonary oedema formation. In order to accurately measure P c, the isogravimetric method and the double occlusion technique have served as standards [2, 3]. However, both techniques require surgical isolation of the organ. The pulmonary artery occlusion technique was developed for in vivo use with a standard fluid-filled pulmonary artery catheter. When incorporated, the technique enabled P c measurements as part of a standard right heart catheterisation procedure. But interest in this technique appeared to wane after discovering that the pulmonary artery occlusion technique, rather than measuring P c, was measuring a pre-capillary pressure in the >80–100 μm calibre range [1, 4]. Although this limited its application in pulmonary oedema research, the technique would later find renewed interest in the field of pulmonary hypertension (PH) [4, 5]. Of the …

Hepatic pre‐sinusoidal vessels contract in anaphylactic hypotension in rabbits

The purpose of this study was to determine whether anaphylactic hypotension in rabbits is accompanied by hepatic venoconstriction, and the effects of anaphylaxis on hepatic segmental vascular resistances and liver weight in isolated perfused rabbit livers. The rabbits were sensitized by subcutaneous injection of antigen of 2.5 mg ovalbumin with complete Freund's adjuvant three times at 1 week interval. One week after sensitization, anaphylaxis was induced by an injection of 2.5 mg ovalbumin into the jugular vein of pentobarbital anaesthetized rabbits or the perfusate of rabbit livers perfused via the portal vein at a constant flow. Using the double occlusion technique to estimate the hepatic sinusoidal pressure, pre- (R(pre)) and post-sinusoidal (R(post)) resistances were calculated for the isolated perfused livers. An antigen injection into the sensitized rabbits caused not only a decrease in systemic arterial pressure from 79 +/- 2 to 40 +/- 4 mmHg, but also an increase in portal venous pressure (P(pv)) from 9.5 +/- 2.2 to 24.1 +/- 3.9 cmH(2)O. Portal hypertension persisted for 8 min after the antigen injection. An injection of antigen into the perfusate caused a marked increase in P(pv) from 5.4 +/- 0.1 to 28.6 +/- 2.4 cmH(2)O at 6 min, but only a slight increase in double occlusion pressure from 2.2 +/- 0.2 to 3.8 +/- 0.2 cmH(2)O, resulting in a selective increase in R(pret) rather than R(post). Concomitant with the hepatic pre-sinusoidal constriction, liver weight loss occurred. Anaphylactic hypotension in rabbits is accompanied by hepatic venoconstriction which is characterized by pre-sinusoidal contraction.

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.

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.

Atrial natriuretic factor increases splenic microvascular pressure and fluid extravasation in the rat.

The spleen is an important site of atrial natriuretic factor (ANF)-induced fluid extravasation into the systemic lymphatic system. The mechanism underlying this process was studied in a blood-perfused (1 ml min(-1)) rat spleen using the double occlusion technique. To ensure that our observations were spleen specific, a similar protocol was repeated in the hindquarters. Rat ANF(1-28), infused into the splenic artery of anaesthetized male rats, caused a dose-dependent (0.3-59 pmol min(-1)) increase in microvascular pressure from 11.3 +/- 0.7 to 14.9 +/- 0.5 mmHg and in post-capillary resistance from 7.2 +/- 0.6 to 10.1 +/- 1.1 mmHg ml(-1). ANF elicited no change in splenic pre-capillary resistance or in hindquarter haemodynamics. Intrasplenic ANF (6.5 pmol min(-1)) caused a sustained increase in intrasplenic fluid efflux from 0.1 +/- 0.1 to 0.3 +/- 0.1 ml min(-1), and in capillary filtration coefficient (Kf) from 1.2 +/- 0.5 to 2.4 +/- 0.6 ml mmHg-1 min-1 (100 g tissue)-1. Mechanical elevation of splenic intravascular pressure (from 11.3 +/- 0.7 to 22.4 +/- 0.2 mmHg) significantly increased intrasplenic fluid extravasation (from 0.4 +/- 0.3 to 1.4 +/- 0.3 ml min(-1)). The natriuretic peptide receptor-C (NPRC)-specific agonist C-ANF(4-23) (12.5 and 125 pmol min(-1)) did not alter splenic intravascular pressure or pre-/post-capillary resistance. The ANF antagonist A71915 (8.3 and 83 pmol min-1), which blocks ANF-stimulated cGMP production via natriuretic peptide receptor-A (NPRA), inhibited the ANF-induced changes in splenic microvascular pressure and post-capillary resistance. It is concluded that ANF enhances the extravasation of isoncotic fluid from the splenic vasculature both by raising intrasplenic microvascular pressure (increased post-capillary resistance) and by increasing filtration area. The constrictive activity of ANF on the splenic vasculature is mediated through NPRA.

PII: S0003-4975(99)01541-6

This study by Tanita and coworkers adds to a growing body of literature implicating activation of polymorphonuclear leukocytes (PMNs) as a contributing factor to pulmonary dysfunction. Using an isolated perfused rat lung model, the authors have investigated the impact of perfusion with human PMNs mechanically stimulated by gentle agitation in a glass vial. This resulted in increased CD18 integrin expression, assessed by immunofluorescence. The authors attempted to quantify capillary leak by modifying a method originally described by Aubrey Taylor’s group at the University of South Alabama. Capillary filtration coefficient has been used to quantify capillary leak in isolated perfused lung models for many years. It is based on the assumption that fluid leak into the lung interstitium is related to changes in intravascular pressure at the capillary level and the integrity of the endothelial membrane. In the classic model described by Taylor, isolated lung blocks are perfused while suspended from a force transducer until a steady state (constant weight) is achieved. Elevation of the venous reservoir results in increasing “back pressure” in the capillary circulation. Because the entire hydrostatic column may not be transmitted directly to the capillary bed (due to venous resistance), a double occlusion technique is generally used to quantify the increase in capillary pressure. In extensive studies in a variety of animals, Taylor’s group has demonstrated the reliability and reproducibility of the model.

Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia.

We previously demonstrated augmented endothelium-derived nitric oxide (EDNO)-dependent pulmonary arterial dilation and increased arterial endothelial nitric oxide synthase (eNOS) levels in chronic hypoxic (CH) and monocrotaline (nonhypoxic) models of pulmonary arterial hypertension. Therefore, we hypothesized that the long-term elevation of arterial eNOS levels associated with CH is related to pulmonary hypertension or some factor(s) associated with hypertension and not directly to hypoxia. To test this hypothesis, we examined responses to the EDNO-dependent dilator ionomycin in U-46619-constricted, isolated, saline-perfused lungs from control rats, CH (4 wk at 380 mmHg) rats, and rats previously exposed to CH but returned to normoxia for 4 days or 2 wk. Microvascular pressure was assessed by double-occlusion technique, allowing calculation of segmental resistances. In addition, vascular eNOS immunoreactivity was assessed by quantitative immunohistochemistry, and eNOS mRNA abundance was determined by RT-PCR assays. Our findings indicate that 4-day and 2-wk posthypoxic rats exhibit persistent pulmonary hypertension, likely due to maintained arterial remodeling and polycythemia associated with prior exposure to CH. Furthermore, arterial dilation to ionomycin was augmented in lungs from each experimental group compared with controls. Finally, arterial eNOS immunoreactivity and whole lung eNOS mRNA levels remained elevated in posthypoxic animals. These findings suggest that altered vascular mechanical forces or vascular remodeling contributes to enhanced EDNO-dependent arterial dilation and upregulation of arterial eNOS in various models of established pulmonary hypertension.

Segmental vasodilatory effectiveness of inhaled NO in lungs from chronically hypoxic rats

Inhaled nitric oxide (iNO) is being used to treat pulmonary hypertension in a variety of chronic lung diseases associated with pulmonary vascular remodeling. We hypothesized that chronic hypoxia (CH)-induced vascular remodeling decreases the vasodilatory effectiveness of iNO due to a thickened diffusional barrier. We therefore examined segmental vasodilatory responses to iNO in U-46619-constricted lungs isolated from control and CH (4 weeks at 0.5 atm) rats using double occlusion technique. We further measured lung fluid flux and vascular wall thickness in lungs from each group to provide an index of vascular permeability and vascular remodeling, respectively. CH was associated with decreased venous, but not arterial, responsiveness to iNO in saline-perfused lungs. In addition, the presence of red blood cells (RBC) within the perfusate greatly reduced venodilation in both groups of lungs, indicating that venous responsiveness to iNO in saline-perfused lungs is largely dependent upon transport of NO from an upstream site. In contrast, RBC had no effect on arterial dilation in control lungs, but attenuated arterial dilation to iNO in lungs from CH rats. Finally, fluid flux and arterial wall thickness were greater in lungs from CH rats. We conclude that arterial remodeling associated with CH may limit venous dilation to iNO. Furthermore, the decreased arterial responsiveness to iNO following CH is consistent with extravasation of hemoglobin within the arterial vasculature.

Relative effects of cyclooxygenase and nitric oxide synthase inhibition on vascular resistances in neonatal lamb lungs.

Effective attenuation of pulmonary vasoconstriction is essential during early postnatal development when increased pulmonary vascular resistance (PVR) may lead to a resumption of right-to-left shunting across fetal channels. In addition, modulation of venous resistance contributes to normal lung fluid balance. This study was designed to identify the relative modulating effects of endothelium-derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were measured using inflow-outflow and double occlusion techniques in isolated lungs of 6-h-old lambs studied under control conditions or after blocking PG and/or EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively. During normoxia, both indomethacin and N omega-nitro-L-arginine were required to increase total PVR, but EDNO appeared to have the greater modulating effect. Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser, but significant, increase in hypoxic pulmonary vasoconstriction of small arteries and veins, suggesting that dilator PG played the dominant modulating role during hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance, suggesting that constrictor prostanoids had a greater effect than dilator PG on this segment. EDNO had a modest modulating effect on venous resistance in these lungs. These data suggest that dilator PG and EDNO exert complementary effects in attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb lungs.

Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension.

We have previously demonstrated that arterial, but not venous, vasodilatory responses to endothelium-derived nitric oxide (EDNO)-dependent agonists are enhanced in lungs isolated from rats with chronic hypoxia (CH)-induced pulmonary arterial hypertension. These data suggest that CH is associated with increased endothelial nitric oxide synthase (eNOS) activity within the pulmonary arterial vasculature. In addition, the correlation of increased pulmonary arterial pressure with selectively enhanced arterial responsiveness to EDNO-mediated agonists suggests that arterial hypertension, rather than hypoxia per se, is a contributing factor in this response. Therefore, we hypothesized that 1) CH selectively upregulates eNOS within the pulmonary arterial vasculature and 2) monocrotaline (MC)-induced pulmonary arterial hypertension selectively enhances pulmonary arterial dilation to EDNO-dependent dilators and upregulates arterial eNOS. We examined the responses to the EDNO-dependent dilators arginine vasopressin and ionomycin in U-46619-constricted isolated perfused lungs from control and MC-treated rats. Microvascular pressure was assessed by the double-occlusion technique, allowing calculation of segmental resistances. Lungs from MC-treated rats exhibited augmented arterial dilation to arginine vasopressin compared with control lungs. However, the responses to ionomycin were not different between the two groups. Quantitative immunocytochemistry was used to compare pulmonary eNOS immunoreactivity in vessels from control, CH, and MC-treated rats. eNOS staining was more intense in the arteries of CH and MC-treated rats compared with those of control animals, whereas CH and MC treatment had no effect on eNOS staining in veins. We conclude that pulmonary arterial hypertension, or altered vascular mechanical forces associated with hypertension, may be responsible for the augmented EDNO-dependent arterial dilation and upregulation of arterial eNOS in lungs from CH and MC-treated rats.

Longitudinal Distribution of Pulmonary Vascular Compliance in Dogs.

The longitudinal distribution of pulmonary vascular compliance was evaluated in isolated canine lung lobes using arterial-(AO), venous-(VO), and double-occlusion (DO) techniques. Total vascular compliance (Ctau) was separated into pulmonary arterial (Ca) and venous compliance (Cv) in lumped model of pulmonary circulation. Under constant pulmonary venous pressure (Pv) at 5 mmHg, blood inflow to the lobe (Q) was gradually increased by changing pulmonary arterial pressure (Pa) from 10 to 22 mmHg at 4 mmHg ranges. Changes in vascular blood volume (deltaV) with each increment in Q were determined by decreased reservoir blood volume of perfusion system. DO was performed at each level of Q and allowing all vascular pressures to equilibrate at the same static pressure (Ps), which was equal to the compliance-weighted average pressure in the circulation. Ctau was obtained from the slope of the relationship between Ps and deltaV. When Pa and Pv were 14 and 5 mmHg, AO, VO, and DO were performed to measure pressures at Ca (Pca) and Cv (Pcv) and Ps. The arterial-to-venous compliance ratio (Ca/Cv) was evaluated using Pca, Pcv, and Ps measurements. Ctau was 0.113 +/- 0.012 ml/kg/mmHg. Ca/Cv was 0.30. Ca and Cv were 0.026 +/- 0.013 and 0.087 +/- 0.007 ml/kg/mmHg, respectively. These data demonstrated the usefulness of AO, VO, and DO techniques in evaluating the longitudinal distribution of compliance in canine pulmonary vasculature.

Local delivery of antithrombotic drug prevents restenosis after balloon angioplasty in atherosclerotic rabbit artery.

We investigated the ability of various antithrombotic drugs, delivered locally, to prevent restenosis after angioplasty in hypercholesterolemic rabbits. After dilating atherosclerotic iliac stenoses by balloon angioplasty, a low dose of heparin or a new antithrombotic drug, such as low molecular weight heparin (fragmin), argatroban, or batroxobin, was delivered locally using the balloon double-occlusion technique. In 1 group, high-dose heparin was administered intravenously. Animals that received no drugs served as a control group. After angioplasty, the stenotic segment was dilated and the mean percentage luminal stenosis fell from 89% to 9% in the group that received locally delivered heparin, from 88% to 7% in the group that received locally delivered argatroban, from 87% to 11% in the group that received locally delivered fragmin, from 88% to 15% in the group that received locally delivered batroxobin, from 82% to 18% in the group that received i.v. heparin (p < 0.0001 compared with before angioplasty in each case), and from 84% to 17% in the control group (p < 0.005 compared with before angioplasty). Twenty-eight days after angioplasty, the percentage luminal stenosis remained at 14% in the group that received locally delivered argatroban, 15% in the group that received locally delivered fragmin, and 28% in the group that received locally delivered batroxobin, whereas it increased to 45% in the group that received i.v. heparin, 30% in the group that received locally delivered heparin and 72% in the control group (p < 0.05 compared with after angioplasty in each case). Thus, local delivery low doses of new antithrombotic drugs prevents restenosis after angioplasty without affecting systemic coagulability; heparin, whether administered locally or intravenously, was less effective than the new drugs in preventing restenosis.

Evidence for uneven distribution of L-type calcium channels in rat pulmonary circulation.

Experiments were performed on isolated, perfused rat lungs to determine the segmental sites of vasoconstriction in response to factors that open voltage-sensitive, L-type calcium channels on vascular smooth muscle cells. Lungs from male Sprague-Dawley rats were perfused at constant flow with a physiological saline solution (PSS) containing albumin. Measurements were made of pulmonary arterial and venous pressure, whereas capillary pressure was estimated by the double-occlusion technique. After equilibration, lungs were constricted with depolarizing PSS containing high K+ (35 or 45 mM). With both stimuli, approximately 80% of the observed increase in vascular resistance occurred on the arterial side of the circulation. Both nifedipine and verapamil reversed this response; however, reversal was more consistent in the arterial segment. In additional experiments, the L-type channel activator (-)BAY K 8644 caused increased resistance in the arterial but not the venous segment. Another group of lungs constricted with the thromboxane mimetic U-46619 demonstrated equal arterial and venous vasoconstriction. In U-46619-constricted lungs, nifedipine caused a 28% reversal of the agonist-induced increase in arterial resistance but was without effect on the venous circulation. These data suggest that a greater density of L-type calcium channels may exist within the arterial segment of the pulmonary circulation than in the veins.

Pressure-flow relationships in in vitro model of compartment syndrome.

Compartment syndrome is a condition in which an increase in intramuscular pressure decreases blood flow to skeletal muscle. According to the Starling resistor (i.e., vascular waterfall) model of blood flow, the decrease in flow could occur through an increase in arterial resistance (Rart) or an increase in the critical closing pressure (Pcrit). To determine which explains the decrease in flow, we pump perfused a canine gastrocnemius muscle placed within an airtight box, controlled box pressures (Pbox) so that flow ranged from 100 to 50%, and measured Pcrit, Rart, arterial compliance, small venular pressure (measured by the double-occlusion technique), and venous pressure. An increase in Pbox limited flow mainly through an increase in Pcrit (75-85%), with only small changes in Rart (15-25%) and no change in arterial compliance. Increases in Pbox also produced a vascular waterfall in the venous circulation, but small venular transmural pressure always remained less than control levels. We conclude that increases in Pbox mostly limit blood flow through increases in Pcrit and that Rart plays a minor role. Transmural pressure across the small venules decreases with increases in intramuscular pressure, which contradicts the currently held belief that compartment syndrome is due to a cycle of swelling-ischemia-swelling.

Site of pulmonary vasodilation by inhaled nitric oxide in the perfused lung.

To determine the site of inhaled nitric oxide (NO)-induced pulmonary vasodilation, a double vascular occlusion technique was used with rabbit lungs ventilated and perfused at 20 ml/min with Krebs solution containing 3% dextran and 30 microM indomethacin. Inhaled NO (120 ppm for 3 min) reduced pulmonary vasoconstriction produced by U-46619 infusion (0.5-1.2 nmol/min), significantly decreasing total resistance (RT) [1,080 +/- 51 (SE) vs. 1,545 +/- 109 mmHg.l-1.min; P < 0.01]. Acetylcholine infusion (ACh; 2-5 nmol/min) and nitroglycerin (NTG; 0.35 mumol) likewise decreased RT. Arterial resistance (Ra) was also significantly less with inhaled NO, ACh, and NTG compared with U-46619 alone. Venous resistance (Rv), however, was unchanged. When the direction of perfusion was reversed in the lung, inhaled NO, ACh, and NTG significantly decreased RT compared with U-46619 alone, and Rv was also reduced by all three agents. After electrolysis-induced acute lung injury, inhaled NO significantly reduced both RT and Ra compared with U-46619 alone, whereas Rv was unaffected. Our results demonstrate that inhaled NO gas affects primarily the arterial (precapillary) component of the pulmonary circulation but, under conditions of extreme venous constriction, may dilate the postcapillary component as well.