Anti-inflammatory treatment of meconium aspiration syndrome: Benefits and risks

Meconium aspiration syndrome (MAS) is a major cause of respiratory insufficiency in the term and post-term newborns. There are several pathomechanisms participating in this disorder, particularly the airway obstruction, surfactant dysfunction, inflammation, lung edema, pulmonary vasoconstriction and bronchoconstriction. Inflammatory changes resulting from meconium aspiration cause severe impairment of lung parenchyma and surfactant, and influence the reactivity of both vascular and airway smooth muscle. Therefore, anti-inflammatory drugs may be of benefit in the management of MAS. This article reviews the pharmacological actions and side effects of various anti-inflammatory drugs used up to now in the experimental models of MAS and in the treatment of newborns with meconium aspiration.     

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.     

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.     

硝基酪氨酸和诱导型一氧化氮合酶在大鼠胎粪吸入性肺损伤中表达的研究

目的：观察大鼠胎粪诱导肺损伤时肺组织硝基化酪氨酸和诱导型一氧化氮合酶（iNOS）表达的改变，探讨两者在此种损伤中的作用。 方法： 16只雄性SD大鼠，随机分为对照组和胎粪组，分别由气管插管注入生理盐水或20%胎粪生理盐水混悬液1 mL/kg。24 h后取材，观察支气管肺泡灌洗液（BALF）细胞计数，比色法检测肺组织匀浆髓过氧化物酶（MPO）活性、一氧化氮（NO）含量，Western blot法测定硝基酪氨酸和iNOS蛋白表达改变。 结果： 胎粪组BALF细胞计数、肺组织MPO活性、NO含量分别为(4.04±1.01)×109cells/L、(1.49±0.22)U/g wet lung tissue、(12.77±5.00)mmol/g protein，对照组BALF细胞计数、肺组织MPO活性、NO含量分别为(0.53±0.19)×109cells/L、(0.62±0.16)U/g wet lung tissue、(4.89±1.32)mmol/g protein，两组比较差异显著（均P<0.01）；Western blot结果显示胎粪组肺组织硝基酪氨酸和iNOS蛋白表达明显强于对照组，分别为0.46±0.19和1.49±0.60，与对照组（0.15±0.04和0.09±0.04）比较, 差异显著（均P<0.01）。 结论： 胎粪可诱导iNOS表达增强并产生过量的硝基酪氨酸，两者可能在胎粪性肺损伤发病机制中发挥重要作用。     

Central and peripheral cardiovascular adaptations to exercise in endurance‐trained children

Stroke volume (SV) response to exercise depends on changes in cardiac filling, intrinsic myocardial contractility and left ventricular afterload. The aim of the present study was to identify whether these variables are influenced by endurance training in pre‐pubertal children during a maximal cycle test. SV, cardiac output (Doppler echocardiography), left ventricular dimensions (time–movement echocardiography) as well as arterial pressure and systemic vascular resistances were assessed in 10 child cyclists (VO_2max: 58.5 ± 4.4 mL min^?1 kg^?1) and 13 untrained children (UTC) (VO_2max: 45.9 ± 6.7 mL min^?1 kg^?1). All variables were measured at the end of the resting period, during the final minute of each workload and during the last minute of the progressive maximal aerobic test. At rest and during exercise, stroke index was significantly higher in the child cyclists than in UTC. However, the SV patterns were strictly similar for both groups. Moreover, the patterns of diastolic and systolic left ventricular dimensions, and the pattern of systemic vascular resistance of the child cyclists mimicked those of the UTC. SV patterns, as well as their underlying mechanisms, were not altered by endurance training in children. This result implied that the higher maximal SV obtained in child cyclists depended on factors influencing resting SV, such as cardiac hypertrophy, augmented myocardium relaxation properties or expanded blood volume.     

Non‐invasive and quantitative evaluation of peripheral vascular resistances in rats by combined NMR measurements of perfusion and blood pressure using ASL and dynamic angiography

The in vivo determination of peripheral vascular resistances (VR) is crucial for the assessment of arteriolar function. It requires simultaneous determination of organ perfusion (F) and arterial blood pressure (BP). A fully non‐invasive method was developed to measure systolic and diastolic BP in the caudal artery of rats based on dynamic NMR angiography. A good agreement was found between the NMR approach and the gold standard techniques (linear regression slope = 0.98, R² = 0.96). This method and the ASL‐MRI measurement of skeletal muscle perfusion were combined into one single NMR experiment to quantitatively evaluate the local vascular resistances in the calf muscle of anaesthetized rats, in vivo and non‐invasively 1) at rest: VR = 7.0 ± 1.0 mmHg·min 100 g·ml^?1, F = 13 ± 3 ml min^?1.100 g^?1 and mean BP (MBP) = 88 ± 10 mmHg; 2) under vasodilator challenge (milrinone): VR = 3.7 ± 1.1 mmHg min.100 g ml^?1, F = 21 ± 4 ml min^?1.100 g^?1 and MBP = 75 ± 14 mmHg; 3) under vasopressor challenge (norepinephrine): VR = 9.8 ± 1.2 mmHg min 100 g ml^?1, F = 14 ± 3 ml min^?1.100 g^?1 and MBP = 137 ± 2 mmHg. Copyright © 2009 John Wiley & Sons, Ltd.     

Global cerebral blood flow during infusion of adenosine in humans: assessment by magnetic resonance imaging and positron emission tomography

Adenosine, an endogenous vasodilator, induces a cerebral vasodilation at hypotensive infusion rates in anaesthetized humans. At lower doses (< 100 μg kg^?1 min^?1), adenosine has shown to have an analgesic effect. This study was undertaken to investigate whether a low dose, causing tolerable symptoms of peripheral vasodilation affects the global cerebral blood flow (CBF). In nine healthy volunteers CBF measurements were made using axial magnetic resonance (MR) phase images of the internal carotid and vertebral arteries at the level of C2–3. Quantitative assessment of CBF was also obtained with positron emission tomography (PET) technique, using intravenous bolus []> ¹⁵O]butanol as tracer in four of the subject at another occasion. During normoventilation (5.4 ± 0.2 kPa, mean ± s.e.m.), the cerebral blood flow measured by magnetic resonance imaging technique, as the sum of the flows in both carotid and vertebral arteries, was 863 ± 66 mL min^?1, equivalent to about 64 ± 5 mL 100 g^?1 min^?1. The cerebral blood flow measured by positron emmission tomography technique, was 59 ± 4 mL 100 g^?1 min^?1. All subjects had a normal CO₂ reactivity. When adenosine was infused (84 ± 7 μg kg^?1 min^?1) the cerebral blood flow, measured by magnetic resonance imaging was 60 ± 5 mL 100 g^?1 min^?1. The end tidal CO₂ level was slightly lower (0.2 ± 0.1 kPa) during adenosine infusion than during normoventilation. In the subgroup there was no difference in cerebral blood flow as measured by magnetic resonance imaging or positron emission tomography. In conclusion, adenosine infusion at tolerable doses in healthy volunteers does not affect global cerebral blood flow in unanaesthetized humans.     

An investigation into the physiological relevance of the vagal tachycardia in the anaesthetized dog

Aim: Our aim was primarily to assess whether or not a vagal tachycardia can be elicited in vivo without administration of atropine, and secondly to evaluate whether the dose of atropine, a muscarinic antagonist, determines the magnitude of the tachycardia. Methods: Experiments were carried out in the presence of atenolol (2 mg kg^?1). The vagal tachycardia requires high vagal activity which was induced by noradrenaline infusion (20 μg min^?1). Two techniques were then used to elicit a tachycardia, vagal section and atropine administration. Results: The increase in blood pressure caused heart rate to fall to 60 ± 7 beats min^?1 (mean ± SEM). When the vagi were sectioned (n = 5) heart rate increased by 9 ± 2 beats min^?1 above the intrinsic rate which was 108 beats min^?1, this increase was not significant. In contrast atropine given (9–20 μg kg^?1) (n = 5) during high vagal activity increased heart rate by 81 ± 22 beats min^?1 above the intrinsic rate (P < 0.05). To assess if the dose of atropine affects the magnitude of the vagal tachycardia, the right vagus was stimulated electrically at increasing frequencies (2, 4, 8, 16, 32 Hz) before and after increasing doses of atropine (0.02, 0.05, 1 mg kg^?1). This reduced the magnitude of the bradycardia; however, the magnitude of the vagal tachycardia was unaffected. Conclusion: The vagal tachycardia cannot be elicited without atropine suggesting that it does not play a significant physiological role.     

Systemic effects of angiotensin III in conscious dogs during acute double blockade of the renin-angiotensin-aldosterone-system

Aims: The study was designed to determine (i) whether the effects of angiotensin III (AngIII) are similar to those of angiotensin II (AngII) at identical plasma concentrations and (ii) whether AngIII operates solely through AT₁‐ receptors. Methods: Angiotensin II (3 pmol kg^?1 min^?1–3.1 ng kg^?1 min^?1) or AngIII (15 pmol kg^?1 min^?1–14 ng kg^?1 min^?1) was infused i.v. during acute inhibition of angiotensin converting enzyme (enalaprilate; 2 mg kg^?1) and of aldosterone (canrenoate; 6 mg kg^?1 plus 1 mg kg^?1 h^?1). Arterial plasma concentrations of angiotensins were determined by radioimmunoassay using a cross‐reacting antibody to AngII. During ongoing peptide infusion, candesartan (2 mg kg^?1) was administered to block the AT₁‐receptors. Results: Angiotensin immunoactivity in plasma increased to 60 ± 10 pg mL^?1 during infusion of AngII or infusion of AngIII. AngII significantly increased mean arterial blood pressure (+14 ± 4 mmHg) and plasma aldosterone by 79% (+149 ± 17 pg mL^?1) and reduced plasma renin activity and sodium excretion (?41 ± 16 mIU L^?1 and ?46 ± 6 μmol min^?1 respectively). AngIII mimicked these effects and the magnitude of AngIII responses was statistically indistinguishable from those of AngII. All measured effects of both peptides were blocked by candesartan. Conclusion: At the present arterial plasma concentrations, AngIII is equipotent to AngII with regard to effects on blood pressure, aldosterone secretion and renal functions, and these AngIII effects are mediated through AT₁‐ receptors. The metabolic clearance rate of AngIII is five times that of AngII.     

Pancreatic secretory response to cholecystokinin-pancreozymin and caerulein in the conscious rat

1. The effects of graded intravenous doses of cholecystokinin (CCK) and caerulein on exocrine pancreatic secretion have, been assessed in conscious rats. Bile and pancreatic juice were separately returned to the duodenum between and during tests.
2. Low doses of CCK (from 417 to 3,335 ng kg^?1 h^?1) or caerulein (from 37.5 to 150 ng kg^?1 h^?1) slightly increased flow rate but increased K⁺ and HCO ₃ ^? outputs to a greater extent, without altering Cl^? output. The sum of the anion concentrations (Cl^?+HCO ₃ ^? ) stayed constant, which explains the decrease in Cl^? concentration when the HCO ₃ ^? concentration increased.
3. High doses of CCK (6,670 and 13,335 ng kg^?1 h^?1) and of caerulein (600 ng kg^?1 h^?1 strongly inhibited volume flow and outputs of all the ions, and the sum of the concentrations of anions fell.
4. Protein concentration and output increased with the same time course in response to both CCK and caerulein, i. e. course in response to both CCK and caerulein, i. e. a sustained stimulation during infusion, without any delayed inhibitory effect afterwards. The increase followed a linear dose-response relation to both CCK and caerulein. D50 was approximately 1,000 ng kg^?1 h^?1 for CCK and 95 ng kg^?1 h^?1 for caerulein. The maximal secretory rate of protein in our experiments was obtained with 300 ng kg^?1 h^?1 caerulein (20.27 mg 30 min^?1) and was almost twice that obtained with CCK (10.6 mg 30 min^?1) which suggests that the most potent agonist is a shorter derivative of CCK. Finally, both hormones decreased protein output at supramaximal levels.
5. It is concluded that both CCK and caerulein have similar effects on pancreatic secretion in the conscious rat and in other species. However, the conscious rat differs from other species in that water, HCO ₃ ^? and K⁺ secretions are stimulated by low doses of agonists. In contrast, high doses of agonists inhibited all components of secretion.

     

Effect of intense interval workouts on running economy using three recovery durations

The purposes of this study were to determine whether running economy (RE) is adversely affected following intense interval bouts of 10?×?400-m running, and whether there is an interaction effect between RE and recovery duration during the workouts. Twelve highly trained male endurance athletes [maximal oxygen consumption; V˙O_{2 max} =72.5 (4.3) ml·kg^?1·min^?1; mean (SD)] performed three interval running workouts of 10?×?400 m with a minimum of 4 days between runs. Recovery duration between the repetitions was randomly assigned at 60, 120 or 180 s. The velocity for each 400-m run was determined from a treadmill V˙O_{2 max} test. The average running velocity was 357.9 (9.0) m?·?min^?1. Following the workout, the rating of perceived exertion (RPE) increased significantly (P??1. Changes in RE from pre- to post-workout, as well as heart rate (HR) and respiratory exchange ratio (R) were similar for the three recovery conditions. When averaged across conditions, oxygen consumption (V˙O₂) increased significantly (P??1?·?min^?1 at 200?m?·?min^?1, and from 53.1 to 54.5?ml?·?kg^?1?·?min^?1 at 268 m?·?min^?1, respectively). HR increased (from 124 to 138, and from 151 to 157 beats?·?min^?1 respectively) and R decreased (from 0.90 to 0.78, and from 0.93 to 0.89, respectively) at 200 and 268 m?·?min^?1, respectively (P?V˙O₂, HR and R were independent of the recovery duration between the repetitions.     

Heme oxygenase-1/biliverdin/carbon monoxide pathway downregulates hypernociception in rats by a mechanism dependent on cGMP/ATP-sensitive K<Superscript>+</Superscript> channels

Objective and design

To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats.

Materials and Methods

Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1β mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg^?1), DMDC (0.025, 0.25, or 2.5 µmol kg^?1), biliverdin (1, 3, or 10 mg kg^?1), or ZnPP-IX (1, 3 or 9 mg kg^?1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg^?1; s.c.) or glibenclamide (10 mg kg^?1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg^?1; s.c), respectively.

Results

Hemin (1 mg kg^?1), DMDC (2.5 µmol kg^?1), and BVD (10 mg kg^?1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg^?1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1β mRNA expression and immunolabelling increased.

Conclusions

HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.

     

Gender comparison of peak oxygen uptake: repetitive box lifting versus treadmill running

The gender differences in peak oxygen uptake (V˙O_2peak) for various modes of exercise have been examined previously; however, no direct gender comparisons have been made during repetitive lifting (RL). In the present study the V˙O_2peak between RL and treadmill running (TR) was compared between 20 men [mean (SD) age, height, body mass and body fat: 21 (3) years, 1.79 (0.06)?m, 81 (9)?kg, 19 (6)%, respectively] and 20 women [mean (SD) age, height, body mass and body fat: 21 (3) years, 1.63 (0.05)?m, 60 (7)?kg, 27 (6)%, respectively]. V˙O_2peak (l?·?min^?1), defined as the highest value obtained during exercise to volitional fatigue, was determined using discontinuous protocols with treadmill grade or box mass incremented to increase exercise intensity. For RL V˙O_2peak, a pneumatically driven shelf was used to lower a loaded box to the floor, and subjects then lifted the box, at a rate of 15 lifts?·?min^?1. V˙O_2peak (l?·?min^?1 and ml?·?kg^?1?·?min^?1) and minute ventilation (V˙ _E, l?·?min^?1) were determined using an on-line gas analysis system. A two-way repeated measures analysis of variance revealed significant gender effects, with men having higher values for V˙O_2peak (l?·?min^?1 and ml?·?kg^?1?·?min^?1) and V˙ _E, but women having higher values of the ventilatory equivalent for oxygen (V˙ _E/V˙O₂). There were also mode of exercise effects, with TR values being higher for V˙O_2peak (l?·?min^?1 and ml?·?kg^?1?·?min^?1) and V˙ _E and an interaction effect for V˙O_2peak {1?·?min^?1 and ml?·?kg^?1?·?min^?1) and V˙ _E/V˙O₂. The women obtained a greater percentage (≈84%) of their TR V˙O_2peak during RL than did the men (≈79%). There was a marginal tendency for women to decrease and men to increase their V˙ _E/V˙O₂ when comparing TR with RL. The magnitude of the gender differences between the two exercise modalities appeared to be similar for heart rate, V˙ _E and R, but differed for V˙O_2peak (1?·?min^?1 and ml?·?kg^?1?·?min^?1). Lifting to an absolute height (1.32?m for the RL protocol) may present a different physical challenge to men and women with respect to the degree of involvement of the muscle groups used during lifting and ventilation.     

Effects of angiotensin-converting enzyme inhibition on arterial,venous and capillary functions in cat skeletal muscle in vivo

The aim of the present study was to analyse quantitatively, on a cat gastrocnemius muscle preparation in vivo, the effects of local angiotensin-converting enzyme (ACE) inhibition by enalaprilat on total regional vascular resistance (tone) and its distribution to the large-bore arterial resistance vessels (>25 μm), the small arterioles (<25 μm) and the veins. Associated effects on capillary pressure and fluid exchange were also studied. Close-arterial infusion of enalaprilat (0.05–0.20 mg kg muscle tissue min^-1) elicited a moderate dilator response in all three consecutive sections of the muscle vascular bed, an increase in capillary pressure and transcapillary fluid filtration. This dilation could be abolished by the selective bradykinin B₂-receptor antagonist Hoe 140 (2 mg kg^-1 min^-1, i.a.), indicating that the dilator mechanism of ACE inhibition was an increased local concentration of bradykinin, and hardly at all a decreased concentration of angiotensin (AT) II. The generalized dilator response to ACE inhibition along the vascular bed suggested a relatively uniform distribution of ACE from artery to vein and this was further supported by the finding that a close-arterial infusion of AT I (0.04–0.32 μg kg^-1 min^-1), which was vasoactive only after conversion to AT II by local ACE, elicited a generalized constrictor response in all three vascular sections. In contrast, infused AT II (0.01–0.16 μg kg^-1 min^-1) constricted almost selectively the large-bore arterial vessels. The specific angiotensin AT₁-receptor antagonist losartan (2 mg kg^-1 min^-1, i.a.) abolished the constrictor response to AT II but did not affect vascular tone under control conditions, indicating that AT II is not involved in the initiation of basal vascular tone in muscle. These results, taken together, indicate that under basal conditions vascular ACE contributes to the local control of vascular tone in skeletal muscle by degrading the endogenous dilator bradykinin, and not by converting AT I into vasoconstrictor AT II.     

Inhibition of Gastric and Intestinal Motor Activity in Dogs by (Gln4) Neurotensin

The action of (Gln⁴)-neurotensin was studied on the spontaneous motor activity in isolated canine fundic, antral and intestinal pouches. All pouches had been prepared more than 6 months prior to the experiments. Spontaneous motor activity was recorded for at least 1 h before the (Gln⁴)-neurotensin was infused i.v. for 30 min in doses ranging between 6.3 and 100 ng × kg^-1× min^-1. In the vagally denervated fundic pouches (Gln⁴)-neurotensin inhibted motor activity in doses above 25 ng × kg^-1× min^-1. The vagally innervated antral pouches were more sentitive than the vagally denervated fundic pouches to the action of (Gln₄)-neurotensin. Thus motor inhibition was induced by doses as low as 6.3 ng × kg^-1× min^-1. The effect of (Gln⁴)-neurotensin on motor activity in intestinal pouches was inconsistent. Inhibition was seen in 1 out of 7 expts. The present results show that the gastric motor activity is the most sensitive function to (Gln⁴)-neurotensin so far studied.     

Long-lasting coronary vasoconstrictor effects and myocardial uptake of endothelin-1 in humans

The effect of intravenous administration of the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1 0.2, 1 and 8 pmol kg^?1 min^?1) on coronary blood flow in relation to plasma ET-1 as well as blood lactate and glucose levels were investigated in six healthy volunteers. Coronary sinus blood flow was measured by thermodilution. Administration of ET-1 elevated arterial plasma ET 35-fold, dose-dependently increased mean arterial blood pressure from 95±5 mmHg to 110±6 mmHg (P<0.01) and reduced heart rate from 64±4 beats min^?1 to 58±4 beats min^?1 (P<0.05) at 8 pmol kg^?1 min^?1. Coronary sinus blood flow was reduced maximally by 23±4% (P<0.01) and coronary vascular resistance increased by 48±11% (P<0.01). Coronary sinus oxygen saturation decreased from 35±1% to 22±2% at 2 min after the infusion (P<0.01). A coronary constrictor response was observed at a 4-fold elevation in plasma ET. The reduction in coronary sinus blood flow lasted 20 min and coronary sinus oxygen saturation was still reduced 60 min after the infusion. Myocardial oxygen uptake or arterial oxygen saturation were not affected by ET-1. Myocardial lactate net uptake decreased by 40% whereas glucose uptake was unaffected. At the highest infusion rate there was a net removal of plasma ET by 24±3% over the myocardium (P<0.05). The results show that ET-1 induces long-lasting reduction in coronary sinus blood flow via a direct coronary vasoconstrictor effect in healthy humans observable at a 4-fold elevation in plasma ET-1. Furthermore, there is a net removal of circulating ET-1 by the myocardium.     

Preface to the third Acta Physiologica Scandinavica international symposium on signalling mechanisms in vascular smooth muscle

To investigate the contribution of nitric oxide in the regulation of regional blood flow and metabolism in vivo, we administered incremental doses of N ^ω-L -arginine-methyl ester (L -NAME 1, 3, 10, 30 and 100 mg kg^?1, intravenously) in isoflurane anaesthetized pigs. The pulmonary vascular bed exhibited a greater sensitivity to the L -NAME-induced pressor effects compared with the systemic arterial bed as the slope of the dose–response curve was steeper (42.9 ± 4.3 vs. 24.3 ± 3.6, P < 0.05) and the dose of L -NAME required to induce a 25% pressure increase was lower (PD₂₅ of 6.2 ± 2.5 vs. 22.8 ± 5.2 mg kg^?1, P < 0.05). L -NAME infusion produced a dose-dependent reduction in cardiac output that was evenly distributed among the mesenteric, femoral, hepatic and carotid arterial circulation as demonstrated by unchanged regional blood flows-to-cardiac output ratios, except in the kidney where the L -NAME-induced vasoconstriction was most pronounced (renal blood flow/cardiac output decreased from 6.2 ± 0.6 to 3.7 ± 0.7% after 100 mg kg^–1 of L -NAME, P < 0.05). After the administration of L -NAME 30 mg kg^?1, intestinal O₂ uptake (Vo₂) increased (+39 ± 3%, P < 0.05) whereas renal Vo₂ tended to decrease (?19 ± 4%, P = 0.07) and whole body Vo₂ remained unchanged. Plasma noradrenaline and adrenaline concentrations did not change significantly with L -NAME infusion. These data demonstrate that in anaesthetized pigs, endogenous nitric oxide is most important for the regulation of pulmonary and renal blood flows and in spite of unchanged global metabolic demand, nitric oxide inhibition leads to an increase in intestinal Vo₂ associated with enhanced gut motility without rise in circulating lactate levels.     

Development and Validation of Enzyme‐Linked Immunosorbent Assays for Quantification of Anti‐Methotrexate IgG and Fab in Mouse and Rat Plasma

Abstract

This laboratory is investigating the use of anti‐methotrexate IgG (AMI) and anti‐methotrexate Fab fragments (AMF) within an inverse targeting strategy that is designed to enhance the pharmacokinetic selectivity of intraperitoneal (i.p.) chemotherapy. The goal of this study was to develop enzyme‐linked immunosorbent assays (ELISAs) to determine concentrations of AMI and AMF in mouse and rat plasma. An antigen‐specific ELISA was developed for AMI and AMF in mouse and rat plasma. The assay was validated with respect to precision and accuracy by evaluating the recovery of AMI and AMF from mouse and rat plasma samples. Preliminary pharmacokinetic studies of AMI and AMF were performed in Sprague‐Dawley rats and Swiss Webster mice. The animals were instrumented with a jugular vein cannula and administered AMI or AMF, 15?mg?kg^?1 via the cannula. Plasma samples were taken at various time points and analyzed using the ELISA, and the observed concentration vs. time profiles were subjected to non‐compartmental pharmacokinetic analyses. Standard curves for the ELISAs were found to be linear over concentration ranges of 0–250 and 0–350?ng?mL^?1 for AMI and AMF, respectively. Intra‐assay and inter‐assay recovery of AMI and AMF from plasma samples were found to be within 15% of theoretical values. Preliminary pharmacokinetic investigations of AMI allowed estimation of AMI clearance to be 0.017?mL?kg^?1?min^?1 in the rat and 0.043?mL?kg^?1?min^?1 in the mouse. AMF clearance was estimated to be 0.038 and 1.93?mL?kg^?1?min^?1 in the mouse and rat, respectively. In conclusion, ELISAs have been developed and validated for quantitation of AMI and AMF in rat and mouse plasma. The assays will allow further investigations of AMI and AMF pharmacokinetics.     

Stroke volume response to cycle ergometry in trained and untrained older men

The aims of this study were threefold: (1) to investigate the stroke volume (SV) response of trained older male cyclists [Cyclists: 65 (2.1) years; n?=?10] during incremental cycle ergometry (20 W?·?min^?1); (2) to determine the SV dynamics and total peripheral resistance response of untrained, but healthy and active older male controls [Controls: 66 (1.1) years; n?=?10]; (3) to compare the maximum oxygen consumption (˙VO_2max) and SV response of trained older male runners [Runners: 65 (3.4) years; n?=?11] with that of age-matched Cyclists. Impedance cardiography was used to assess the response of cardiac output (CO), SV and total peripheral resistance to exercise involving cycle ergometry. The mean ˙VO_2max of the trained Cyclists [54 (1.6) ml?·?kg^?1?·?min^?1] was significantly higher (P??1?·?min^?1], whereas both groups possessed a significantly higher ˙VO_2max than the Controls [28 (1.3) ml?·?kg^?1?·?min^?1]. During exercise, at a heart rate of 90 beats?·?min^?1, the SV of the Cyclists increased by 41%, that of the Runners increased by 47%, and that of the Controls increased by 31%. However, the Cyclists' and Runners' SV response was significantly greater than that of the Controls. The SV for cyclists and controls peaked at 30% of ˙VO_2max. This early increase in SV was a major factor underlying the increase in CO during exercise in both the trained and the untrained subjects. In addition, all three groups showed a significant decrease in total peripheral resistance throughout exercise. The finding that older male runners possessed a large exercise SV and high ˙VO_2max suggests that run training results in enhanced cardiovascular performance during cycle ergometry.     

Cardiovascular and renal effects of intracerebroventricular angiotensin II in conscious sheep

Effects on systemic and pulmonary haemodynamics, renal electrolyte excretion, and plasma concentration of vasopressin, catecholamines, electrolytes and proteins in response to intracerebroventricular infusions of [Val⁵]-angiotensin II (ANG II) at 1, 2 and 4 pmol kg^-1min^-1in isotonic saline for 30 min were studied in conscious sheep (n = 6). Vehicle control infusions were performed in four of the animals. All three doses of ANG II were expected to increase CFS concentration of the peptide above physiological levels. All ANG II infusions were noticed to be dipsogenic, but the animals were not allowed to drink freely until at the end of the experiments (at 120 min post-infusion). The systemic arterial blood pressure increased significantly only in response to 2 and 4 pmol kg^-1min^-1, concomitant with an increase of the systemic vascular resistance, whereas the cardiac output and heart rate remained unchanged. The central venous pressure increased only after administration of the highest ANG II dose, while pulmonary artery, and capillary wedge pressures were unaffected during all experiments. The plasma protein and K concentration fell in response to ANG II administration. Also here, the effects were significant only at 2 and 4 pmol kg^-1min^-1. The plasma levels of vasopressin, noradrenaline, adrenaline and dopamine did not change significantly in response to any of the infusions. The renal Na excretion increased by 100–400%, but not in a strictly dose-dependent manner. Much smaller and more variable effects were seen on the renal K excretion. We conclude that: (1) supraphysiological CSF ANG II levels are needed to cause a pressor effect when the peptide is administered via the intracerebroventricular route in conscious sheep; (2) the blood pressure is increased exclusively via peripheral vasoconstriction and; (3) increased vasopressin release does not contribute to the cardiovascular changes. The results also demonstrate that ANG II may cause haemodilution via a central site of action.