Infusion Of Indomethacin Research Articles

150 Indomethacin infusion through multiple routes and the resulting Prostaglandin F2α metabolite production during late embryonic development in beef cattle

150 Indomethacin infusion through multiple routes and the resulting Prostaglandin F2α metabolite production during late embryonic development in beef cattle

Brainstem inflammation modulates the ventilatory pattern and its variability after acute lung injury in rodents.

Compared with sham rats, rats a week after acute lung injury (ALI) express more pro-inflammatory cytokines in their brainstem respiratory control nuclei, exhibit a higher respiratory frequency (fR) and breathe with a more predictable pattern. These characteristics of the respiratory pattern persist in insitu preparations even after minimizing pulmonary and chemo-afferent inputs. Interleukin (IL)-1β microinjected in the nucleus tractus solitarii increases fR and the predictability of the ventilatory pattern similar to rats with ALI. Intracerebroventricular infusion of indomethacin, an anti-inflammatory drug, mitigates the effect of ALI on fR and ventilatory pattern variability. We conclude that changes in the ventilatory pattern after ALI result not only from sensory input due to pulmonary damage and dysfunction but also from neuro-inflammation. Acute lung injury (ALI) increases respiratory rate (fR) and ventilatory pattern variability (VPV), but also evokes peripheral and central inflammation. We hypothesized that central inflammation has a role in determining the ventilatory pattern after ALI. In rat pups, we intratracheally injected either bleomycin to induce ALI or saline as a sham control. One week later, we recorded the ventilatory pattern of the rat pups using flow-through plethysmography, then formed insitu preparations from these pups and recorded their 'fictive' patterns from respiratory motor nerves. Compared with the ventilatory pattern of the sham rat pups, injured rat pups had increased fR and predictability. Surprisingly, the fictive patterns of the insitu preparations from ALI pups retained these characteristics despite removing their lungs to eliminate pulmonary sensory inputs and perfusing them with hyperoxic artificial cerebral spinal fluid to minimize peripheral chemoreceptor input. Histological processing revealed increased immunoreactivity of the pro-inflammatory cytokine Interleukin-1β (IL-1β) in the nucleus tractus solitarii (nTS) from ALI but not sham rats. In subsequent experiments, we microinjected IL-1β in the nTS bilaterally in anaesthetized naïve adult rats, which increased fR and predictability of ventilatory pattern variability (VPV) after 2h. Finally, we infused indomethacin intracerebroventricularly during the week of survival after ALI. This did not affect sham rats, but mitigated changes in fR and VPV in ALI rats. We conclude that neuro-inflammation has an essential role in determining the ventilatory pattern of ALI rats.

Peripheral-to-central immune communication at the area postrema glial-barrier following bleomycin-induced sterile lung injury in adult rats

The pathways for peripheral-to-central immune communication (P → C I-comm) following sterile lung injury (SLI) are unknown. SLI evokes systemic and central inflammation, which alters central respiratory control and viscerosensory transmission in the nucleus tractus solitarii (nTS). These functional changes coincide with increased interleukin-1 beta (IL-1β) in the area postrema, a sensory circumventricular organ that connects P → C I-comm to brainstem circuits that control homeostasis. We hypothesize that IL-1β and its downstream transcriptional target, cyclooxygenase-2 (COX-2), mediate P → C I-comm in the nTS. In a rodent model of SLI induced by intratracheal bleomycin (Bleo), the sigh frequency and duration of post-sigh apnea increased in Bleo- compared to saline- treated rats one week after injury. This SLI-dependent change in respiratory control occurred concurrently with augmented IL-1β and COX-2 immunoreactivity (IR) in the funiculus separans (FS), a barrier between the AP and the brainstem. At this barrier, increases in IL-1β and COX-2 IR were confined to processes that stained for glial fibrillary acidic protein (GFAP) and that projected basolaterally to the nTS. Further, FS radial-glia did not express TNF-α or IL-6 following SLI. To test our hypothesis, we blocked central COX-1/2 activity by intracerebroventricular (ICV) infusion of Indomethacin (Ind). Continuous ICV Ind treatment prevented Bleo-dependent increases in GFAP + and IL-1β + IR, and restored characteristics of sighs that reset the rhythm. These data indicate that changes in sighs following SLI depend partially on activation of a central COX-dependent P → C I-comm via radial-glia of the FS.

Cyclooxygenase inhibitors in preterm infants with patent ductus arteriosus: effects on cardiac and vascular indices.

Existing data suggest subendocardial ischemia in preterm infants with patent ductus arteriosus (PDA) and alterations in cardiac function after indomethacin administration. This study aimed to explore the evolution of left ventricular function by conventional echocardiography and speckle-tracking echocardiography (STE) and to ascertain the interrelationship with coronary flow indices in response to indomethacin. A prospective observational study was performed with preterm infants receiving indomethacin for medical closure of PDA. Serial echocardiography was performed, and the results were analyzed using analysis of variance. Intra- and interobserver variability was assessed using the intraclass correlation coefficient. Indomethacin was administered to 18 infants born at a median gestational age of 25.8 weeks (interquartile range [IQR], 24.2-28.1 weeks) with a birth weight of 773 g (IQR, 704-1,002 g). The median age of the infants was 7.5 days (IQR, 4-17). Global longitudinal strain (GLS) values significantly decreased immediately after indomethacin infusion (preindomethacin GLS, -19.1 ± 2.4 % vs. -15.9 ± 1.7 %; p < 0.0001) but had improved at reassessment after 1 h (-17.4 ± 1.8 %). Conventional echocardiographic indices did not show significant alterations. A significant increase in arterial resistance in the coronary vasculature from 1.7 to 2.4 mmHg/cm/s was demonstrated. A significant correlation was noted between peak systolic GLS and flow resistance in the coronary vasculature. Significant changes in myocardial indices were observed immediately after indomethacin infusion. Compared with conventional methods, STE is a more sensitive tool to facilitate understanding of hemodynamics in preterm infants.

Mammary blood flow and metabolic activity are linked by a feedback mechanism involving nitric oxide synthesis

To test which, if any, of the major milk precursors can elicit a rapid change in the rate of mammary blood flow (MBF) and to define the time course and magnitude of such changes, 4 lactating cows were infused with glucose, amino acids, or triacylglycerol into the external iliac artery feeding one udder half while iliac plasma flow (IPF) was monitored continuously by dye dilution. Adenosine and saline were infused as positive and negative controls, respectively, and insulin was infused to characterize the response to a centrally produced anabolic hormone. To test the roles of cyclooxygenase, NO synthase and ATP-sensitive K (KATP) channels in nutrient-mediated changes in blood flow, their respective inhibitors—indomethacin, Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and glibenclamide—were infused simultaneously with glucose. Each day, 1 infusate was given twice to each cow, over a 20-min period each time, separated by a 20-min washout period. In addition, each treatment protocol was administered on 2 separate days. A 73% increase in IPF during adenosine infusion showed that the mammary vasodilatory response was quadratic in time, with most changes occurring in the first 5min. Glucose infusion decreased IPF by 9% in a quadratic manner, most rapidly in the first 5min, indicating that a feedback mechanism of local blood flow control, likely through adenosine release, was operative in the mammary vasculature. Amino acid infusion increased IPF 9% in a linear manner, suggesting that mammary ATP utilization was stimulated more than ATP production. This could reflect a stimulation of protein synthesis. Triacylglycerol only tended to decrease IPF and insulin did not affect IPF. A lack of IPF response to glibenclamide indicates that KATP channels are not involved in MBF regulation. Indomethacin and L-NAME both depressed IPF. In the presence of indomethacin, glucose infusion caused a quadratic 9% increase in IPF. Indomethacin is an inhibitor of mitochondrial function, so the glucose-induced increase in IPF was interpreted as feedback on mammary adenosine release from an anabolic response to glucose. Because NO synthase was not inhibited during indomethacin infusion, the feedback system is postulated to act through endothelial NO synthase. In the presence of L-NAME, glucose infusion had no effect on IPF, indicating that endothelial cyclooxygenase is not involved in glucose-induced changes in MBF.

The Physiologic Effects of Indomethacin Test on CPP and ICP in Severe Traumatic Brain Injury (sTBI)

Refractory intracranial hypertension (RICH) is associated with high mortality in severe traumatic brain injury (sTBI). Indomethacin (INDO) can decrease intracranial cerebral pressure (ICP) improving cerebral pressure perfusion (CPP). Our aim was to determine modifications in ICP and CPP following INDO in RICH secondary to sTBI. INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by continuous 2-h infusion period (0.5 mg/kg/h). Clinical outcome was assessed at 30 days according to Glasgow Outcome Scale (GOS). Differences in ICP and CPP values were assessed using repeated-measures ANOVA. Receiver operating characteristic curve (AUC) was used for discrimination in predicting 30-day survival and good functional outcome (GOS 4 or 5). Analysis of INDO safety profile was also conducted. Thirty-two patients were included. Median GCS score was 6 (interquartile range: 4-7). The most frequent CT finding was the evacuated mass lesion (EML) according to Marshall classification (28.1 %). Mortality rate was 34.4 %. Within 15 min of INDO infusion, ICP decreased (Δ%: -54.6 %; P < 0.0001), CPP increased (Δ%: +44.0 %; P < 0.0001), and the remaining was stable during the entire infusion period. Patients with good outcome (n = 12) showed a greater increase of CPP during INDO test (P = 0.028). CPP response to INDO test discriminated moderately well surviving patients (AUC = 0.751; P = 0.0098) and those with good functional recovery (AUC = 0.763; P = 0.0035) from those who died and from those with worse functional outcome, respectively. No adverse events were observed. INDO appears effective in reducing ICP and improving CPP in RICH. INDO test could be a useful tool in identifying RICH patients with favorable outcome. Future studies are needed.

The heat shock protein response following eccentric exercise in human skeletal muscle is unaffected by local NSAID infusion

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely consumed in relation to pain and injuries in skeletal muscle, but may adversely affect muscle adaptation probably via inhibition of prostaglandin synthesis. Induction of heat shock proteins (HSP) represents an important adaptive response in muscle subjected to stress, and in several cell types including cardiac myocytes prostaglandins are important in induction of the HSP response. This study aimed to determine the influence of NSAIDs on the HSP response to eccentric exercise in human skeletal muscle. Healthy males performed 200 maximal eccentric contractions with each leg with intramuscular infusion of the NSAID indomethacin or placebo. Biopsies were obtained from m. vastus lateralis before and after (5, 28 hrs and 8 days) the exercise bout from both legs (NSAID vs unblocked leg) and analysed for expression of the HSPs HSP70, HSP27 and αB-crystallin (mRNA and protein). NSAID did not affect the mRNA expression of any of the HSPs. Compared to pre values, the mRNA expression of all HSPs was increased; αB-crystallin, 3.6- and 5.4-fold; HSP70, 26- and 3.4-fold; and HSP27: 4.8- and 6.5-fold at 5 and 28 hrs post-exercise, respectively (all p < 0.008). Immunohistochemical stainings for αB-crystallin and HSP70 revealed increased staining in some samples but with no differences between legs. Changes in force-generating capacity correlated with both αB-crystallin and HSP70 mRNA and immunohistochemisty data. Increased expression of HSPs was observed on mRNA and protein level following eccentric exercise; however, this response was unaffected by local intramuscular infusion of NSAIDs.

Effects of Indomethacin Test on Intracranial Pressure and Cerebral Hemodynamics in Patients With Refractory Intracranial Hypertension

Intracranial hypertension is the final pathway of many neurocritical entities, such as spontaneous intracerebral hemorrhage (sICH) and severe traumatic brain injury (sTBI). This study aimed to (1) determine alterations in intracranial pressure (ICP) and cerebral hemodynamics after an indomethacin (INDO) infusion test and the related association with survival in patients with refractory intracranial hypertension (RICH) secondary to sICH or sTBI and (2) assess the safety profile after INDO. INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by a 2-hour continuous infusion (0.5 mg/kg/h) in RICH patients with ICP greater than 20 mm Hg who did not respond to first-line therapies. Changes in ICP, cerebral perfusion pressure (CPP), and cerebrovascular variables (assessed by transcranial Doppler and jugular bulb saturation) were observed. Clinical outcome was assessed at 1 and 6 months according to the Glasgow Outcome Scale and correlated with INDO infusion test response. Analysis of INDO safety profile was conducted. Thirteen sICH and 10 sTBI patients were studied. The median GCS score at admission was 6. Within 30 minutes of INDO infusion, ICP decreased (42.0 ± 13.5 vs 27.70 ± 12.7 mm Hg; Δ%: -48.4%; P < .001), and both CPP (57.7 ± 4.8 vs 71.9 ± 7.0 mm Hg; Δ%: +26.0%; P < .001) and middle cerebral artery velocity (35.2 ± 5.6 vs 42.0 ± 5.1 cm·s(-1); Δ%: +26.1%; P < .001) increased. The CPP response to a 2-hour INDO infusion test was correlated (R2 = 0.72, P < .001) with survival. No adverse events were observed after INDO. Our findings support the effectiveness and feasibility of an INDO test in decreasing ICP and improving cerebral hemodynamics in surviving RICH patients. Future studies to evaluate different doses, lengths of infusion, and longer term effects are needed.

Prophylactic indomethacin infusion increases fractional cerebral oxygen extraction in ELBW neonates

Intraventricular hemorrhage (IVH) occurs in up to 25% of very low birth weight (VLBW) preterm neonates. Previous studies found that indomethacin administered in the first 6 h of life reduces the incidence of severe IVH in VLBW neonates and decreases cerebral blood flow, suggesting a decrease in cerebral oxygen delivery. Using near-infrared spectroscopy (NIRS), we monitored cerebral oxygenation before, during and after slow indomethacin infusion in extremely low birth weight (ELBW) neonates to determine whether indomethacin decreases cerebral oxygen saturation and increases cerebral oxygen extraction. Twenty-seven ELBW neonates less than 30 weeks gestational age treated with indomethacin for IVH prophylaxis were monitored for arterial oxygen saturation (SaO(2)) and NIRS-determined regional cerebral oxygen saturation (rSO(2)). At 30 to 60 s intervals, SaO(2), rSO(2) and mean arterial pressure (MAP) were recorded using a VitalSync. Average fractional cerebral oxygen extraction was calculated for the hour before indomethacin infusion, during the infusion and 2 h after infusion. Fractional cerebral oxygen extraction increased from baseline after indomethacin administration from 0.23±0.11 to 0.25±0.10 (P=0.034). Fractional cerebral oxygen extraction increased 9% with indomethacin 0.1 mg kg(-1) given over 1 to 2 h. However, the clinical implications of this small increase in extraction, likely representative of decreased cerebral perfusion, are unknown but may be harmful to the developing brain.

Relationship Between Contractions of the Uterus and Concentration of PGF2α in Uterine Venous Blood after Luteolysis in Gilts

The origin and physiological significance of high pulses of prostaglandin F2α (PGF2α) in uterine venous blood that occur 2-3 days after luteolysis are not well understood. We studied the relationship between contractions of the uterus evoked by exogenous oxytocin (OT) and PGF2α concentration in uterine venous blood on day 17 of the porcine oestrous cycle. The infusion of OT into the uterine artery produced an immediate increase in the uterine intraluminal pressure (UIP) (p < 0.001) and a simultaneous elevation in PGF2α concentration in uterine venous blood (p < 0.0001). The infusion of indomethacin (IND) into the uterine artery slightly decreased PGF2α concentration in uterine venous blood, but it did not suppress uterine contraction or the rapid increase in PGF2α concentration in uterine venous blood just after OT infusion (p < 0.0001), which was lower that in gilts not treated with IND. We conclude that the spikes of PGF2α concentration in uterine venous blood occurring after OT infusion on day 17 of the porcine oestrous cycle are mainly caused by the excretion with venous blood from the remodelled uterus and that PGF2α synthesis may contribute to this. These results suggest that the high spikes in PGF2α concentration that occur 2-3 days after luteolysis in pigs, sheep, cows and mares all have a similar origin.

Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition

The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H(2)O(15) and (15)O(2) during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of L-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced (P < 0.05) muscle blood flow. NOS inhibition increased (P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ∼20% increase (P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased (P < 0.05). NOS and COX inhibition reduced (P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake.

Progesterone turnover to its 5α-reduced metabolites in the ventral tegmental area of the midbrain is essential for initiating social and affective behavior and progesterone metabolism in female rats.

Among women and female rodents, progesterone (P) influences social affiliation and affect. These effects may be partly due to formation of its 5α-reduced, 3α- hydroxylated metabolite, 5α-pregnan-3α-ol-20-one (3α,5α- THP). To elucidate whether actions of 3α,5α-THP in the midbrain ventral tegmental area (VTA) are both necessary and sufficient to enhance non-sexual and sexual social behaviors, affect, and central 3α,5α-THP metabolism. P and 3α,5α-THP formation were unperturbed or blocked in VTA via infusions of vehicle, PK11195 (400 ng), and/or indomethacin (10 μg). Rats then received subsequent infusions of vehicle or 3α,5α-THP (100 ng) and were assessed in a battery of tasks that included open field (exploration), elevated plus maze (anxiety behavior), social interaction (social affiliation), and paced mating (sexual behavior) or were not tested. Metabolic turnover of P to its 5α-reduced metabolites was assessed in plasma, midbrain, hippocampus, frontal cortex, diencephalon, and remaining subcortical tissues (control interbrain). Infusions of any combination of inhibitors significantly reduced social and affective behavior in all tasks compared to vehicle, concomitant with reduced turnover of P to its 5α-reduced metabolites, in midbrain only. Subsequent infusions of 3α,5α-THP significantly reinstated/enhanced anti- anxiety behavior, lordosis, and P turnover to its 5α-reduced metabolites in midbrain, as well as hippocampus, cortex, and diencephalon (but not plasma or interbrain). These data are the first to provide direct evidence that actions of 3α,5α-THP in the VTA are both necessary and sufficient for social and affective behavior, as well as initiation of central 5α-reduction.

Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus: Is the Difference in the Mode of Administration?

Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects.

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

The progesterone (P 4) metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP) acts in the midbrain ventral tegmental area (VTA) to modulate lordosis of female rats. 3α,5α-THP also mediates exploratory, affective, and social behaviors; whether actions of 3α,5α-THP in the VTA mediate these behaviors is of interest. To elucidate the role of the VTA in mediating exploratory, affective, and social behaviors, the present study examined effects of inhibiting 3α,5α-THP formation in the VTA. Rats received intra-VTA infusions of either PK11195 (400 ng/μl, which inhibits de novo 3α,5α-THP production), indomethacin (10 μg/μl, which blocks metabolism of P 4 to 3α,5α-THP), PK11195 and indomethacin together, or β-cyclodextrin vehicle and tested on a battery of anxiety (open field and elevated plus maze), social (partner preference and social interaction), and sexual (paced mating) tasks. Compared to rats infused with vehicle to the VTA, rats infused with inhibitor(s) demonstrated significant reductions in central entries in the open field, time on open arms of an elevated plus maze, time spent interacting with a conspecific, initiation and intensity of lordosis, sexual solicitations, and midbrain 3α,5α-THP levels. These findings suggest that actions of 3α,5α-THP in the VTA are important for mediating aspects of exploration, anxiety, and social behavior related to mating.

The effect of indomethacin on systemic and renal hemodynamics in neonatal piglets during experimental endotoxemia

Systemic and renal hemodynamics are affected by prostaglandin production during endotoxemia. To study indomethacin effects on endotoxinemia in a neonatal piglet model, sixteen 7-10 day old piglets were anesthetized, ventilated, and catheterized. Mean arterial pressure (MAP), heart rate (HR), and urine output were continuously monitored. Endotoxin (0.06 mcg/kg) was injected after baseline measurements. We studied two groups with either endotoxinemia alone (n = 7) or an additional indomethacin infusion (0.2 mg/kg per h, n = 9). HR, MAP, renal blood flow (RBF), systemic and renal vascular resistance (SVR, RVR), cardiac index (CI), and glomerular filtration rate (GFR), were obtained at baseline, at 1, 2 and 3 h. We observed a drop in CI and an increase in SVR and HR within 3 h of endotoxinemia, while MAP remained unchanged. These effects were prevented by indomethacin. RVR was not altered significantly. Endotoxinemia triggered a drop of RBF in both control (P < 0.01) and intervention group (P < 0.05). In the intervention group, drop of GFR, urine volume, and paraaminohippuric acid clearance were apparent signs of nephrotoxicity (P < 0.01, <0.05, and <0.01). In conclusion, indomethacin maintains hemodynamic parameters during endotoxinemia at the expense of nephrotoxicity. We speculate that indomethacin counteracts the renoprotective effect of prostaglandins.

Effect of Unspecific Inhibition of Cyclooxygenase by Indomethacin on Retinal and Choroidal Blood Flow

Animal studies suggest that retinal and choroidal blood flow decrease after administration of indomethacin, a nonspecific cyclooxygenase inhibitor. Cyclooxygenase is the key enzyme involved in the arachidonic pathway and regulates the production of vasoactive substances such as prostaglandins and thromboxans. The aim of the present study was to investigate the short-term effects of indomethacin on ocular blood flow in healthy humans. A randomized, double-masked, placebo-controlled, two-way crossover study in 12 healthy, male, nonsmoking subjects was performed. Indomethacin was administered as a bolus injection of 0.4 mg/kg followed by continuous infusion of 0.4 mg/kg/h over 120 minutes. Ocular hemodynamic parameters were measured at baseline and up to 3 hours after start of the infusion. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser Doppler flowmetry and laser interferometry, respectively. Retinal vessel diameters were assessed using a retinal vessel analyzer. Retinal blood flow was calculated based on retinal vessel diameters, and red blood cell velocity was measured with laser Doppler velocimetry. Administration of indomethacin decreased retinal arterial diameters up to -4.3% +/- 3.4% and reduced retinal blood velocity by a maximum of -29% +/- 20% (P < 0.05). Calculated retinal blood flow decreased by -27% +/- 21% (P < 0.05), reaching the maximal decrease 60 minutes after administration. Choroidal blood flow and fundus pulsation amplitude (FPA) also decreased during the infusion of indomethacin with maximum effects of -17% +/- 13% (P < 0.05, vs. placebo) and -7% +/- 4% (P < 0.05, vs. placebo), respectively. Results showed a marked decrease in retinal and choroidal blood flow after short-term administration of indomethacin. Whether this decrease can be attributed to a reduced production of prostaglandins or an unknown mechanism has yet to be clarified. Further studies appear to be indicated to investigate whether the long-term intake of indomethacin is associated with an increased risk for vascular eye disease.

Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure

Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation [muscle sympathetic nerve activity (MSNA)] during exercise in heart failure (HF) patients is heightened compared with that of healthy humans and that muscle mechanoreceptors are sensitized by metabolic by-products. We sought to determine whether cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip (RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control were infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control were infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise, consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 min of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 min of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of the very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which also appears to be mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.

Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants.

Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Although a 3-dose schedule has been commonly used, there is no consensus on optimal dosage and duration of indomethacin therapy for PDA closure. There are potential adverse effects of indomethacin use in premature infants such as a reduction in cerebral, mesenteric and renal blood flow and platelet dysfunction. Administering indomethacin continuously over 36-hours has been suggested as a safer and more effective option to prevent such adverse effects. To compare the efficacy and safety of continuous infusion versus bolus administration of indomethacin in closing a symptomatic PDA in preterm infants. The standard search strategy of Cochrane Neonatal Review was used: MEDLINE and EMBASE (1966 - March 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), bibliographies of reviews and trials were examined for references to other trials, previous symposia proceedings published in Pediatric Research (Pediatric Academic Societies Annual Meeting Abstract Book, 1972 - 2006). No language restrictions were applied. Randomized and quasi-randomized controlled trials comparing continuous indomethacin infusion to bolus doses for closure of a symptomatic PDA in preterm infants with a symptomatic PDA diagnosed clinically and/or by echocardiography. The methodological quality of each study was assessed. Authors were contacted regarding missing data as well as to inquire about the outcomes that were not reported. Meta-analysis was performed to calculate relative risk (RR), risk difference (RD) and 95% confidence intervals (CI). Only two small trials comparing continuous versus bolus indomethacin were eligible. Analysis of these studies showed that, although the primary outcome of PDA closure on days two and five slightly favored bolus administration, there was no statistical difference between the two groups. The estimates for PDA closure were RR 1.57 (95% CI 0.54, 4.60), RD 0.10 (95% CI -0.13, 0.33) for day 2 and RR 2.77 (95% CI 0.33, 23.14), RD 0.15 (95% CI -0.13, 0.42) for day five. There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These analyses were based on a very small number of events reported by these trials. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hour. In one study (Christmann 2002), the decrease in blood flow was maximum at 10 minutes [MD -46.40 (95% CI -75.41, -17.39)], while the other study (Hammerman 1995) reported a maximum drop at 30 minutes [MD -55.60 (95% CI -62.92, -48.28)]. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). In both of these circulations, the decrease was maximum 30 minutes after the bolus injection [typical estimates for renal and mesenteric circulations, respectively: MD -42.00 (95% CI -76.59, -7.41) and MD -26.50 (95% CI -45.34, -7.66)] and lasted about two hours. None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. Due to a paucity of events and lack of precision, the available data was found to be insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion versus bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be made based on the current findings of this review.

Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle

Prostaglandins are known to be involved in the regulation of local blood flow within human skeletal muscles during exercise, and the concentration of prostaglandins increases locally and systemically in response to exercise. The systemic release of prostaglandins can be inhibited by oral intake of nonsteroidal anti-inflammatory drugs (NSAIDs). However, to study the local role of prostaglandins, the formation of prostaglandins within the tissue must be controlled. Microdialysis enables determination of local concentrations of water-soluble substances within the tissue. In the present study, the microdialysis method was used to infuse NSAIDs locally into human skeletal muscles producing a local block of prostaglandin formation. In addition, the graded blockade at various distances from the infusion site within the muscle during rest, exercise and recovery was determined. Microdialysis was performed in thigh muscles (vastus lateralis muscle) in six healthy men. One of the microdialysis catheters was used to block prostaglandin synthesis by infusion of the NSAID indomethacin. Additional catheters were placed 1 and 4 cm away from the infusion and in the contralateral leg (working control). Following 2 h of rest, the subjects performed 200 maximal eccentric contractions with each leg followed by 3 h of rest. The study revealed that infusion of NSAID reduced local prostaglandin E(2) concentration by approximately 30-50% (4 cm away from the infusion) and 85% (1 cm away from the infusion) compared with the contralateral (unblocked) thigh muscle. In conclusion, the present study shows that infusion of NSAIDs into human muscle via microdialysis catheters results in a graded blockade of prostaglandin synthesis.

Inhibition of nitric oxide and prostaglandins, but not endothelial‐derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg

Prostaglandins, nitric oxide (NO) and endothelial-derived hyperpolarizing factors (EDHFs) are substances that have been proposed to be involved in the regulation of skeletal muscle blood flow during physical activity. We measured haemodynamics, plasma ATP at rest and during one-legged knee-extensor exercise (19 +/- 1 W) in nine healthy subjects with and without intra-arterial infusion of indomethacin (Indo; 621 +/- 17 microg min(-1)), Indo + N(G)-monomethyl-L-arginine (L-NMMA; 12.4 +/- 0.3 mg min(-1)) (double blockade) and Indo + L-NMMA + tetraethylammonium chloride (TEA; 12.4 +/- 0.3 mg min(-1)) (triple blockade). Double and triple blockade lowered leg blood flow (LBF) at rest (P<0.05), while it remained unchanged with Indo. During exercise, LBF and vascular conductance were 2.54 +/- 0.10 l min(-1) and 25 +/- 1 mmHg, respectively, in control and they were lower with double (33 +/- 3 and 36 +/- 4%, respectively) and triple (26 +/- 4 and 28 +/- 3%, respectively) blockade (P<0.05), while there was no difference with Indo. The lower LBF and vascular conductance with double and triple blockade occurred in parallel with a lower O(2) delivery, cardiac output, heart rate and plasma [noradrenaline] (P<0.05), while blood pressure remained unchanged and O(2) extraction and femoral venous plasma [ATP] increased. Despite the increased O(2) extraction, leg was 13 and 17% (triple and double blockade, respectively) lower than control in parallel to a lower femoral venous temperature and lactate release (P<0.05). These results suggest that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise and that EDHFs do not compensate for the impaired formation of NO and prostaglandins. Moreover, inhibition of NO and prostaglandin formation is associated with a lower aerobic energy turnover and increased concentration of vasoactive ATP in plasma.