Effects of the dual endothelin receptor antagonist tezosentan and hypertonic saline/dextran on porcine endotoxin shock

Aim: To evaluate the haemodynamic effects of the dual endothelin receptor antagonist tezosentan, both alone and combined with hypertonic saline/dextran (HSD), on porcine endotoxin shock, with focus on cardiopulmonary circulation. The effects on gas exchange and short‐term survival were also studied. Methods: A prospective, randomized experimental study was carried out. Thirty‐two anaesthetized pigs underwent pulmonary and carotid artery catheterization. Following haemodynamic stabilization and baseline measurements, endotoxaemia was induced by an Escherichia coli‐endotoxin infusion over 180 min and the animals observed another 120 min. After 60 min of endotoxaemia, directly before intervention, animals were randomized into four groups: a tezosentan group, an HSD group, a combined tezosentan/HSD group and a control group. The consequent haemodynamic effects and blood gas results were recorded. Results: The endotoxin infusion reduced mean arterial blood pressure from 111 ± 14 (mean ± standard deviation) to 77 ± 27 mmHg and cardiac index from 126.9 ± 27.2 to 109.3 ± 22.6 mL min^?1 kg^?1 within 90 min in the control group. In addition, endotoxin simultaneously increased mean pulmonary artery pressure from 24 ± 17 to 38 ± 19 mmHg and reduced arterial oxygenation from 18.9 ± 2.0 to 12.2 ± 5.3 kPa. Tezosentan, alone and combined with HSD, reversed the pulmonary hypertension and prevented the reduction in cardiac index and arterial oxygenation, resulting in reduced metabolic acidosis. Additionally, in the tezosentan group, the mean arterial blood pressure was reduced to the same level as in controls, an effect not prevented by the addition of HSD. It was found that all three interventions improved survival rates. Conclusion: Tezosentan, alone and in combination with HSD, improved cardiac index and arterial oxygenation. The addition of HSD to tezosentan treatment did not improve the endotoxin‐induced hypotension, but beneficial effects on microcirculation and systemic oxygenation were seen despite low perfusion pressure, as indicated by increased SvO₂ and reduced metabolic acidosis.     

P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate-induced pulmonary vasoconstriction in vivo in the pig

Purpose

To investigate the role of P2Y₁ and P2Y₁₂ receptors in hypoxia- and adenosine diphosphate (ADP)-induced pulmonary vasoconstriction.

Methods

19 anaesthetized, mechanically ventilated pigs (31.3 ± 0.7 kg) were evaluated in normoxia and hypoxia, without (n = 6) or with P2Y₁ receptor antagonist MRS2500 (n = 7) or P2Y₁₂ receptor antagonist cangrelor (n = 6) treatment. 12 pigs (29.3 ± 0.4 kg) were evaluated before and during ADP infusion, without and with MRS2500 (n = 6) or cangrelor (n = 6) pre-treatment.

Results

Hypoxia increased (p < 0.05) mean pulmonary artery pressure (MPAP) by 14.2 ± 1.1 mmHg and pulmonary vascular resistance (PVR) by 2.7 ± 0.4 WU. Without treatment MPAP and PVR remained unaltered (p = ns) for 90 min hypoxia. During hypoxia MRS2500 decreased (p < 0.013) MPAP by 4.3 ± 1.2 mmHg within 15 min. Cangrelor decreased (p < 0.036) MPAP to be 3.3 ± 0.4 and 3.6 ± 0.6 mmHg lower than hypoxia baseline after 10 and 30 min. PVR was, however, unaltered (p = ns) by MRS2500 or cangrelor during hypoxia. ADP increased (p < 0.001) MPAP and PVR to stabilize 11.1 ± 1.3 mmHg and 2.7 ± 0.3 WU higher than baseline. MRS2500 or cangrelor pre-treatment totally abolished the sustained MPAP- and PVR-increases to ADP.

Conclusions

ADP elicits pulmonary vasoconstriction through P2Y₁ and P2Y₁₂ receptor activation. ADP is not a mandatory modulator, but may still contribute to pulmonary vascular tone during acute hypoxia. Further investigations into the mechanisms behind ADP-induced pulmonary vasoconstriction and the role of ADP as a modulator of pulmonary vascular tone during hypoxia are warranted.     

Effect of chronic hypoxia on pulmonary artery blood velocity in rats as assessed by electrocardiography-triggered three-dimensional time-resolved MR angiography

Pulmonary arterial hypertension (PAH) is a severe disease that leads to increased pulmonary vascular resistance and right heart failure. Noninvasive methods are needed to detect changes in the pulmonary artery circulation during PAH establishment and/or treatment. Pulmonary blood flow velocity can be evaluated by dynamic MR angiography, although the relevance of such data in the context of PAH remains to be demonstrated. A novel dynamic MR angiography technique was used in this work to measure blood flow velocity in the pulmonary arteries of the same living animals, before and after the establishment of chronic hypoxia‐induced PAH. Chronic hypoxia decreased significantly the blood flow velocity (43.8 ± 4.9 vs 24.3 ± 8.7 cm/s) on electrocardiography‐triggered time‐resolved angiograms. In parallel, chronic hypoxia‐induced PAH was confirmed from invasive measurements of the mean pulmonary arterial pressure (32.1 ± 4.8 vs 12.5 ± 2.2 mmHg) and the ratio of the right ventricle weight to the left ventricle plus septum weight (Fulton index: 0.54 ± 0.06 vs 0.27 ± 0.04). This study demonstrates the potential interest of dynamic MR angiography for the investigation of experimental models and for the evaluation of treatment efficacy. Copyright © 2010 John Wiley & Sons, Ltd.     

Effect of alveolar hypoxia on segmental pulmonary vascular resistance and lung fluid balance in dogs

In a biventricular bypass preparation with constant-flow perfusion, pulmonary arterial pressure (P_pa), average pulmonary capillary pressure (P_pc), venous pressure (P_v), extravascular lung water volume (EVW_d) and capillary permeability-surface area product for urea (PS) were determined in control animals and in animals subjected to alveolar hypoxia. During hypoxia, P_pa increased in a biphasic manner, the site of hypoxic pulmonary vasoconstriction being located in the arterial upstream segment. At baseline, P_pc values were identical in control and experimental animals (3.4 ± 0.4 vs. 3.6 ± 0.2 mmHg). During 150 min of airway hypoxia, the rise in P_pc (5.1 ± 0.3mmHg) did not exceed the rise in P_pc (4.9 ± 0.5mmHg) recorded in control animals at same time interval during normoxic ventilation. EVW_d increased during hypoxia to values significantly higher than those obtained in control animals (0.559 ± 0.036 vs. 0.466 ± 0.027 mL water g^?1 lung). PS remained unchanged at baseline level throughout experiments in both groups of animals. Present data suggest that lung oedema formation during alveolar hypoxia may be caused by increased transcapillary fluid loss preferentially through transcellular hydraulic pathways in capillary endothelial cells.     

Endogenous NO does not regulate baseline pulmonary pressure,but reduces acute pulmonary hypertension in dogs

It has remained unclear whether endogenous production of nitric oxide (NO) plays an important role in the regulation of physiologically normal pulmonary pressures. Severe alveolar hypoxia is accompanied by decreased pulmonary NO production, which could contribute to the development of hypoxic pulmonary hypertension. On the other hand, pharmacological NO inhibition further augments this hypertensive response. Aims: The aims of the present study were to test: (a) whether NO contributes importantly in the maintenance of baseline pulmonary pressure; and (b) to which degree NO is involved in the pulmonary haemodynamic adjustments to alveolar hypoxia. Methods: In anaesthetized dogs (n = 37), the systemic and pulmonary haemodynamic effects of the NO synthase inhibitor, N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME, 20 mg kg^?1) and substrate, l ‐arginine (200–500 mg kg^?1), were determined at baseline and during alveolar hypoxia. Constant blood flows were accomplished by biventricular bypass, and systemic normoxaemia was maintained by extracorporeal oxygenation. Results: The primary findings were: (a) l ‐NAME failed to increase baseline mean pulmonary arterial pressure (10.1 ± 0.7 vs. 10.5 ± 0.5 mmHg, P = ns), despite effective NO synthase inhibition as evidenced by robust increases in systemic arterial pressures; (b) l ‐NAME augmented the pulmonary hypertensive response to alveolar hypoxia (10.2 ± 0.7 to 19.5 ± 1.7 with l ‐NAME vs. 9.9 ± 1.1 to 15.5 ± 1.0 mmHg without l ‐NAME, P < 0.05); and (c) l ‐arginine failed to decrease baseline or elevated pulmonary pressures. Instead, prolonged l ‐arginine caused increases in pulmonary pressure. Conclusion: These findings suggest that NO plays no significant role in the tonic physiological control of pulmonary pressure, but endogenous NO becomes an important vasodilatory modulator during elevated pulmonary pressure.     

Pulmonary ischemia/reperfusion injury: A quantitative study of structure and function in isolated heart‐lungs of the rat

Early graft dysfunction after lung transplantation is a significant and unpredictable problem. Our study aimed at a detailed investigation of structure‐function correlations in a rat isolated heart‐lung model of ischemia/reperfusion injury. Variable degrees of injury were induced by preservation with potassium‐modified Euro‐Collins solutions, 2 hr of cold ischemia, and 40 min of reperfusion. Pulmonary artery pressure (P_pa), pulmonary vascular resistance (PVR), peak inspiratory pressure (PIP), and perfusate gases (ΔP_O2, ΔP_CO2) were recorded during reperfusion. Right lungs were used to calculate W/D‐weight ratios. Nineteen experimental and six control left lungs were fixed for light and electron microscopy by vascular perfusion. Systematic random samples were analyzed by stereology to determine absolute and relative volumes of lung structures, the amount of interstitial and intraalveolar edema, and the extent of epithelial injury. Lectin‐ and immunohistochemistry using established epithelial cell markers were performed in three animals per group to reveal sites of severe focal damage. Experimental lungs showed a wide range in severity of ischemia/reperfusion injury. Intraalveolar edema fluid amounted to 77–909 mm³ with a mean of 448±250 mm³ as compared with 22±22 mm³ in control lungs (P<0.001). Perfusate oxygenation (ΔP_O2) decreased from 30.5±15.2 to 21.7±15.2 mm Hg (P=0.05) recorded after 5 and 40 minutes of reperfusion. In experimental lungs, a surface fraction of 1% to 58% of total type I pneumocyte surface was damaged. Intraalveolar edema per gas exchange region (Vv ape,P) and ΔP_O2 were related according to ΔP_O2 = 96 − 60 × log₁₀(Vv ape,P) [mm Hg]. The extent of epithelial injury did not correlate with ΔP_O2 nor with intraalveolar edema, but increased significantly with PVR. Lectin‐ and immunohistochemistry revealed focal severe damage to the alveolar epithelium at the border of perivascular cuffs. We conclude that ischemia/reperfusion‐associated respiratory compromise is a direct function of the amount of intraalveolar edema, however, it is not determined by the actual extent of diffuse alveolar epithelial damage at the air‐blood‐barrier but by the presence of focal severe epithelial damage at the perivascular/alveolar interface. Anat Rec 255:84–99, 1999. © 1999 Wiley‐Liss, Inc.     

Pressure/flow relation in the peripheral pulmonary vascular bed in dogs: a preliminary study

In order to test a technique for the determination of the pressure/flow relationship in the peripheral pulmonary vascular bed, the perfusion pressure changes with increasing and then decreasing flow in a small part of the lung (around 1 ml) were studied in anaesthetized supine dogs, after insertion of a specially designed double distal lumen Swan–Ganz catheter. One lumen was used for the pressure measurement, one for infusion of saline by a pump with variable flow, from 0.1 to 1.0 ml s^-1. A conventional thermodilution Swan–Ganz catheter was also advanced in the pulmonary artery, to measure pressures in the pulmonary circulation as well as cardiac output. During infusion in the wedged catheter, right atrial, pulmonary arterial and balloon occlusion wedge pressures did not change. The pressure/flow curve of the occluded vascular bed showed a shape similar to that of collapsible tubes, with a pressure plateau at high flow, but this could also be due to vascular recruitment. The curve exhibited hysteresis, with a lower pressure when flow decreased. The slope of the initial part of the curve increased, on average, from 54±9 during normoxia to 91±27 mmHg s ml^-1during hypoxia (FIO₂= 0.10); this difference was not significant, but the perfusion pressure at high flow was significantly higher during hypoxia (P < 0.05). Using blood instead of saline would allow the determination of the peripheral pulmonary vascular resistance under physiological conditions, and further work is needed to estimate the sensitivity and the reproducibility of this technique.     

Acute effects of pulmonary artery banding in sheep on right ventricle pressure–volume relations: relevance to the arterial switch operation

The first stage of the two‐stage arterial switch operation (ASO) for transposition of the great arteries (TGA) is associated with depressed ventricular function and an unstable immediate post‐operative course. It is unclear if this is because of the acute increase in afterload of the thin‐walled, low‐pressure ventricle by pulmonary artery banding (PAB). To determine the acute effects of afterload increase on the contractile function of thin‐walled ventricles, we studied the right ventricular pressure–volume relations of seven sheep before and 30 min after PAB using combined pressure–conductance catheters during inflow reduction. Load independent indices of systolic and diastolic performance were derived from these relations. Pulmonary artery banding increased the mean ratio between right and left ventricular systolic pressure from 0.34 ± 0.05 to 0.64 ± 0.10, P < 0.05 (mean ± SD). There were no significant changes in heart rate and end‐systolic volume after banding although there was an incremental trend in the end‐diastolic volume and stroke volume. Right ventricular output (530 ± 163–713 ± 295 mL min^–1, P < 0.05), slope of the end‐systolic pressure–volume relation (ESPVR) (3.7 ± 2.8–10.0 ± 4.8 mmHg mL^–1, P < 0.05) and slope of the pre‐load recruitable stroke work (PRSW) relation (9.6 ± 1.8–15.0 ± 3.1 mmHg, P < 0.05) were significantly increased indicating improved contractile state after banding. The diastolic function curve was unchanged after banding although the right ventricle (RV) was operating at a larger end‐diastolic volume. Hence, the RV of sheep responded to acute pressure overload by demonstrating enhanced contractility and evidence of the Frank–Starling mechanism without associated change in right ventricular diastolic performance.     

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-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.     

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.     

Intravenous injection of AlbunexR microspheres causes thromboxane mediated pulmonary hypertension in pigs,but not in monkeys or rabbits

østensen , J., Hede , R., Myreng , Y., Ege , T. & Holtz , E. 1992. Intravenous injection of Albunex^R microspheres causes thromboxane-mediated pulmonary hypertension in pigs, but not in monkeys or rabbits. Acta Physiol Scand 144 , 307–315. Received J April 1991, accepted 7 October 1991. ISSN 0001–6772. Nycomed AS Research and Development, Oslo, Norway. Intravenous injection of the ultrasound contrast agent Albunex^R (manufactured by Nycomed AS, Oslo, Norway; 400 million air-filled albumin microspheres per ml, mean diameter 4 ± 1 μm) caused a dose-dependent increase of mean pulmonary arterial pressure in nine pigs. The highest dose (0.014 ± 0.002 ml kg^-1) increased mean pulmonary arterial pressure from 17± mmHg to 42 ± 3 mmHg and decreased mean systemic arterial pressure from 111±9 to 93± 12 mmHg. The pressure responses began 22 ± 1 s after particle injection, and reached maximum after 51 ±3 s. No changes in mean pulmonary arterial pressure or mean systemic arterial pressure were observed after Albunex^R injections during treatment with indomethacin (10 mg kg^-1+ 5 mgkg^-1 h-1 i.v., n= 6) or the thromboxane A2 receptor antagonist HN-11500 (10 mg kg^-1+ 5 mg kg^-1 h^-l i.v., n= 3). No Doppler enhancement could be detected in a carotid artery following injection of 0.12 ml kg^-1 Albunex^R during indomethacin treatment. In five rabbits, Albunex^R caused Doppler enhancement in a carotid artery, and 0.48 ml kg^-1 did not affect mean pulmonary arterial pressure or other haemodynamic parameters in five rabbits or in three cynomolgus monkeys. The pressure response in pigs may be explained by release of thromboxane A2 from the pulmonary intravascular macrophages during phagocytosis of the microspheres. This response to Albunex^R was totally absent in rabbits and monkeys.     

ANP gene expression in rat hearts during hypoxia

 It is unclear whether the increase in plasma atrial natriuretic peptide (ANP) concentration during hypoxia is due to direct, hypoxia-induced upregulation of ANP secretion in the heart, or to pressure overload of the right ventricle (RV) following hypoxia-induced pulmonary hypertension. To test the hypothesis that hypoxia leads to an early upregulation of the ANP gene, we examined the influence of acute and prolonged inspiratory hypoxia (6 h, 1 or 3 weeks) on the expression of ANP messenger ribonucleic acid (mRNA) in rat heart and compared the results with the expression of the ANP gene after acute pressure overload induced by experimental coarctation of the main pulmonary artery. As a molecular marker for hypertrophy we determined the ratio of α- and β-myosin gene expression. Hypoxia increased systolic RV pressure from 20.0 ± 1.6 mmHg to 27.8 ± 1.6 mmHg (P < 0.01) and 41.6 ± 2.1 mmHg (P < 0.05) after 1 and 3 weeks hypoxia respectively. The ANP plasma concentration did not change significantly after 6 h or 1 week: 232 ± 21 pg/ml (control), 246 ± 25 pg/ml (6 h), 268 ± 25 pg/ml (1 week), but increased significantly after 3 weeks hypoxia (446.8 ± 99.56 pg/ml; P < 0.05). ANP mRNA levels in different regions of the heart did not change after 6 h or 1 week hypoxia. After 3 weeks hypoxia ANP mRNA had increased 2.7-fold in the RV (P < 0.05), 4.2-fold in the left ventricle (LV, P < 0.05), 3.5-fold in the septum (S, P < 0.05) and about 1.4-fold in the right (n.s.) and left atrium (n.s.). Relative ventricular masses increased significantly only for the RV (190%, P < 0.05) during hypoxia. The β/α-myosin mRNA ratio did not change after 6 h hypoxia but, contrary to ANP gene expression, increased after just 1 week (6.1-fold in RV, 7.8-fold in LV, 6-fold in S; P < 0.05) and was more pronounced in the RV after 3 weeks (9.4-fold in RV, 7.6-fold in LV, 9.1-fold in S; P < 0.05). The increase in the β/α-myosin mRNA ratio in the LV contrasts with a lack of increase in relative ventricular mass. Acute pressure overload in the RV after pulmonary arterial banding significantly increased ANP-mRNA and the β/α-myosin mRNA ratio after 1 day in the RV. In the LV ANP mRNA was unchanged. The delayed upregulation of the ANP gene suggests that hypoxia per se is not a significant stimulus for ANP gene expression in the heart and that hypoxia-induced ANP-gene expression in the heart is regulated predominantly by the increase in RV afterload due to hypoxia-induced increased pulmonary pressure. The upregulation of ANP and β-myosin mRNA in the LV during chronic hypoxia has yet to be elucidated. Received: 5 November 1996 / Received after revision and accepted: 24 January 1997     

Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism

 Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO₂ threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO₂ levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O₂, 5% CO₂) was 15.2±1.8 mmHg, and hypoxia (2% O₂, 5% CO₂) produced a ΔPAP of 6.3±0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the ΔPAP by 88.3±2.7% and 78.2±6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the ΔPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5·10^–5 M) or methylene blue (1.4·10^–4 M). It was found that both inhibitors more than doubled the hypoxic ΔPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4±0.2 (normoxia), 2.5±0.3 (hypoxia) and 3.3±0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O₂-sensing in PSMC. Received: 17 March 1997 / Received after revision: 10 June 1997 / Accepted: 11 July 1997     

Regulation of alveolar gas conductance by NO in man,as based on studies with NO donors and inhibitors of NO production

Aim: Nitric oxide (NO) is a mediator of the pulmonary vessel tone and permeability. We hypothesized that it may also regulate the alveolar‐capillary membrane gas conductance and lung diffusion capacity. Methods: In 20 healthy subjects (age = 23 ± 3 years) we measured lung diffusion capacity for carbon monoxide (DLco), its determinants (membrane conductance, D_m, and pulmonary capillary blood volume, V_c), systolic pulmonary artery pressure (PAPs) and pulmonary vascular resistance (PVR). Measurements were performed before and after administration of N^g ‐monomethyl‐l ‐arginine (l ‐NMMA, 0.5 mg kg^?1 min^?1), as a NO production inhibitor, and l ‐arginine (l ‐Arg, 0.5 mg kg^?1 min¹) as a NO pathway activator. The effects of l ‐NMMA were also tested in combination with active l ‐Arg and inactive stereoisomer d ‐Arg vehicled by 150 mL of 5%d ‐glucose solution. For l ‐Arg and l ‐NMMA, saline (150 mL) was also tested as a vehicle. Results: l ‐NMMA reduced D_m (?41%P < 0.01), DLco (?20%, P < 0.01) and cardiac output (CO), and increased PAPs and PVR. In 10 additional subjects, a dose of l ‐NMMA of 0.03 mg kg^?1 min¹ infused in the main stem of the pulmonary artery was able to lower D_m (?32%, P < 0.01) despite no effect on PVR and CO. D_m depression was significantly greater when l ‐NMMA was vehicled by saline than by glucose. l ‐Arg but not d ‐Arg abolished the effects of l ‐NMMA. l ‐Arg alone increased D_m (+14%, P < 0.01). Conclusion: The findings indicate that NO mediates the respiratory effects of l ‐NMMA and l ‐Arg, and is involved in the physiology of the alveolar‐capillary membrane gas conductance in humans. NO deficiency may cause an excessive endothelial sodium exchange/water conduction and fluid leakage in alveolar interstitial space, lengthening the air–blood path and depressing diffusion capacity.     

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (P_max), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6–24 h to measure spontaneous diurnal variations in P_max and cardiac output. Cardiac output varied by up to ~2.5 l/min; P_max varied little with cardiac output [0.61±0.74 (SD) mmHg min l^–1]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal ) for 8 h. In this group P_max rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in P_max during air breathing with changes in P_max during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in P_max during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of P_max to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.     

Effects of lactoferrin on rat dermal interstitial fluid pressure (Pif) and in vitro endothelial barrier function

We recently demonstrated that intravenous (i.v.) injection of the iron‐binding protein lactoferrin (Lf) followed by antilactoferrin (aLf) antibodies or iron‐saturated Lf alone increased albumin extravasation in vivo in several tissues including skin. Increased driving pressure for blood‐tissue exchange or direct effects of Lf on the endothelial barrier are possible mechanisms. We therefore, firstly, measured interstitial fluid pressure (P_if) in dermis of rats given 1 mg Lf i.v. followed 30 min later by aLf or saline and circulatory arrest 1 or 5 min thereafter and compared with controls. Secondly, transmonolayer passage of Evans blue labelled albumin (EB‐albumin) was evaluated in porcine pulmonary artery endothelial cells exposed to iron‐free or iron‐saturated Lf (both 100 μg mL^–1) in the absence and presence of 0.5 mM hydrogen peroxide. P_if increased significantly at 11–30 min following Lf to +2.1 ± 0.3 and +1.7 ± 0.2 mmHg at 11–20 and 21–30 min, respectively, compared with +0.1 ± 0.2 mmHg before Lf (P < 0.05, n=25). Endothelial transmonolayer passage of EB‐albumin during 3 h was not affected by iron‐free or iron‐saturated Lf neither in the absence nor presence of hydrogen peroxide that increased passage 3.5 times compared with controls. In conclusion, Lf‐induced increase in albumin extravasation in rat skin is not explained by changes in P_if (because Lf raised P_if significantly) or direct effects of Lf on the endothelial barrier.     

Acute hypothyroidism has no effect on pulmonary vascular resistance

Summary The effect of acute hypothyroidism on the pulmonary circulation was studied in 9 nonobese athyreotic patients by right heart catheterization at rest and during exercise. The patients were studied while they were hypothyroid 2 weeks after ceasing triiodothyronine treatment and while they were euthyroid on replacement therapy. At rest, pulmonary blood flow [4.0±0.6 l/min vs 5.8±1.0 l/min,p<0.01] and systolic pulmonary artery pressure [18±3 mmHg vs 23±2 mmHg,p<0.01] were lower when the patients were hypothyroid than when they were euthyroid. The mean and diastolic pressures in the pulmonary artery and the pulmonary capillary pressures were not different among the groups. Likewise, thyroid hormone levels had no significant effect on pulmonary vascular resistance [100±25 dyn-s-cm^–5 vs 90±23 dyn-s-cm^–5]. With supine exercise, pulmonary blood flow [10.1±1.6 l/min vs. 13.2±2.0 l/min,p<0.01], mean pulmonary artery pressure [25±6 mmHg vs 30±6 mmHg,p<0.02], and systolic pulmonary artery pressure [36±6 mmHg vs 44±8 mmHg,p<0.01] were lower when the patients were hypothyroid. The diastolic pulmonary artery pressure and the pulmonary capillary pressure were similar in both thyroid states. Again, thyroid deficiency had no effect on pulmonary vascular resistance [81±23 dyn-s-cm^–5 vs 76±24 dyn-s-cm^–5]. The lower systolic pressures in the pulmonary artery seen in hypothyroidism are probably due to the decreased systolic volume load of the pulmonary circulation. The data do not suggest that thyroid hormones play a role in the regulation of pulmonary vascular resistance.Abbreviations PVR pulmonary vascular resistance - PAP_M mean pulmonary artery pressure - PCP_M mean pulmonary capillary pressure - PBF pulmonary blood flow     

Non-contact determination of arterial blood pressure alterations induced by blood loss using laser irradiation on the common carotid artery

In order to avoid the secondary exposure of medical personnel to toxic materials under biochemical hazard conditions, we have reported a method for non-contact monitoring of heart and respiratory rates, using microwave radar or laser irradiation. In large-scale disasters, it is important to be able to diagnose shock without touching patients. We evaluated a non-contact method of monitoring arterial blood pressure alterations of New Zealand rabbits induced by blood loss, using He-Ne laser reflection on the common carotid artery. PVR was significantly correlated with systolic blood pressure (r = 0.95, p < 0.01), where PV = peak voltage of reflected laser amplitude, and PVR = PV(present moment state)/PV(normal state). The following formula was derived using the least-squares linear fitting: SBP = 69.6 PVR + 8.2, in which SBP is the systolic blood pressure. Before blood withdrawal, the mean blood pressure, heart rate and haematocrit were 68 ± 3 mmHg, 154 ± 10 bpm and 40 ± 2%, respectively. After intervention, the mean blood pressure, heart rate and haematocrit were 38 ± 5 mmHg, 197 ± 25 bpm and 30 ± 2%, respectively. The proposed non-contact method appears promising for future clinical application in determining arterial blood pressure alterations. It is likely to be useful in reducing the risk of secondary exposure to toxic chemicals or infectious organisms in the case of large-scale disasters.     

Pulmonary vascular resistance as a potential marker of reactive pulmonary hypertension reduction following sildenafil therapy in patients disqualified from orthotopic heart transplantation

PurposeWe sought to determine the predictors of restoration of heart transplantation (HTx) candidacy in patients with systolic heart failure (HF) and reactive fixed pulmonary hypertension (RFPH) defined as pulmonary vascular resistance (PVR) > 2.5 Wood units (WU), transpulmonary gradient (TPG) > 12 mmHg or ≤2.5 WU with systolic arterial pressure ≤85 mmHg during vasoreactivity test, following sildenafil therapy.Material and methodsBetween 2007 and 2018 1136 patients were evaluated at our department as candidates for HTx. Thirty-five of them, who presented with systolic HF and were not eligible for HTx due to RFPH, were included in the study (31 men aged 55.1 ± 7.4 years). In all the patients sildenafil was introduced and up-titrated to a maximal tolerated dose in addition to optimal medical therapy. Patients were assessed at 3–6 months intervals.ResultsDuring median 11 months (interquartile range 6–18 months) reduction of RFPH enabling qualification for HTx was observed in 62.9% patients. Higher baseline PVR (OR 0.32; 95% CI (0.14–0.74) p < 0.001), pulmonary artery systolic pressure (PASP) (OR 0.94, 95% CI (0.88–0.99) p = 0.05), mean artery pulmonary pressure (mPAP) (OR 0.87, 95% CI (0.77–0.98) p = 0.02) and TPG (OR 082, 95% CI (0.70–0.96) p = 0.003) were negative predictors of RFPH reduction with sildenafil therapy. In multivariable analysis, lower PVR (p = 0.02) was identified as an independent predictor of RFPH reduction following sildenafil therapy.ConclusionSildenafil therapy can support PH reduction in systolic HF patients uneligible for HTx due to RFPH. Lower baseline PVR was identified as an independent predictor of PH reversibility with sildenafil enabling restoration of HTx candidacy.     

Endothelin infusion reduces hypoxic pulmonary hypertension in pigs in vivo

Previous work has shown that the plasma levels of the potent vasoactive peptide endothelin (ET) are increased in pathophysiological conditions with increased pulmonary vascular resistance and it has been speculated that ET may play some part in hypoxic pulmonary hypertension. We have therefore evaluated the effects of ET-infusion in the porcine pulmonary circulation after hypoxia-induced hypertension. Pigs under general anaesthesia were artificially ventilated through an endotracheal tube and hypoxia was induced by decreasing the fraction inhaled 0₂ from 0.21 to 0.10. Haemodynamic parameters were continuously recorded using a Swan-Ganz catheter in combination with thermodilution for cardiac output measurements. ET-1 or ET-3 was given as an i.v. infusion through the Swan-Ganz catheter in the right ventricle. Hypoxia induced a reproducible increase in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP) and right ventricular stroke work (RVSW) while the systemic vascular resistance (SVR) slightly decreased. Cumulative infusion of ET-1 (10, 25 and 50 ng kg^-1 min^-1) dose-dependently decreased MPAP and PVR; at a higher dose (100 ng kg^-1min^-1), the PVR returned to the level observed at hypoxia. ET-infusions at 50 and 100 ng kg^-1 min^-1 evoked an increase in SVR and a decrease in cardiac output (CO) and stroke volume (SV). RVSW also gradually decreased during ET-1 infusion. Infusion of ET-3 evoked effects similar to those of ET-1 infusions, although the response to ET-3 was not that rapid in onset. In a second series of animals, repeated 15 min periods of hypoxia evoked a stable, reproducible response with a consistent increase in PVR, MPAP and RVSW which returned to baseline values during normoxia. Infusion of ET-1 (25 ng kg^-1 min^-1) evoked a rapidly developing decrease in PVR and MPAP which was quickly normalized upon cessation of the ET-infusion. ET-1 infusion at this concentration did not per se influence the haemodynamic parameters during normoxia. It is concluded that in the pig, short-term ET-infusion reduces the pulmonary hypertension associated with acute hypoxia.