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Paul Smits

Publications and source records attributed to Paul Smits.

At least 37 records · Page 2Linked to original sources
PubMed2005

Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle.

Deconditioning is a risk factor for cardiovascular disease. Exercise reduces this risk, possibly by improving the vascular endothelial nitric oxide (NO) pathway. The effect of deconditioning on the NO pathway is largely unknown. This study was designed to assess baseline NO availability in the leg vascular bed after extreme, long-term deconditioning (spinal cord-injured individuals, SCI) as well as after moderate, short-term deconditioning (4 weeks of unilateral lower limb suspension, ULLS). For this purpose, seven SCI were compared with seven matched controls. Additionally, seven healthy subjects were studied pre- and post-ULLS. Leg blood flow was measured by venous occlusion plethysmography at baseline and during infusion of 5 incremental dosages of N(G)-monomethyl-L-arginine (L-NMMA) into the femoral artery. Sodium nitroprusside (SNP) was infused to test vascular responsiveness to NO. Baseline leg vascular resistance tended to be higher in SCI compared with controls (37+/-4 versus 31+/-2 arbitrary units (AU), P=0.06). Deconditioning altered neither the vasoconstrictor response to L-NMMA (increase in resistance in SCI versus controls: 102+/-33% versus 69+/-9%; pre- versus post-ULLS: 95+/-18% versus 119+/-15%), nor the vascular responsiveness to NO. In conclusion, two human in vivo models of deconditioning show a preserved baseline NO availability in the leg skeletal muscle vascular bed.

Adult↗
PubMed2005

Microvascular permeability during experimental human endotoxemia: an open intervention study.

INTRODUCTION: Septic shock is associated with increased microvascular permeability. As a model for study of the pathophysiology of sepsis, endotoxin administration to humans has facilitated research into inflammation, coagulation and cardiovascular effects. The present study was undertaken to determine whether endotoxin administration to human volunteers can be used as a model to study the sepsis-associated increase in microvascular permeability. METHODS: In an open intervention study conducted in a university medical centre, 16 healthy volunteers were evaluated in the research unit of the intensive care unit. Eight were administered endotoxin intravenously (2 ng/kg Escherichia coli O113) and eight served as control individuals. Microvascular permeability was assessed before and 5 hours after the administration of endotoxin (n = 8) or placebo (n = 8) by three different methods: transcapillary escape rate of I(125)-albumin; venous occlusion strain-gauge plethysmography to determine the filtration capacity; and bioelectrical impedance analysis to determine the extracellular and total body water. RESULTS: Administration of endotoxin resulted in the expected increases in proinflammatory cytokines, temperature, flu-like symptoms and cardiovascular changes. All changes were significantly different from those in the control group. In the endotoxin group all microvascular permeability parameters remained unchanged from baseline: transcapillary escape rate of I(125)-albumin changed from 7.2 +/- 0.6 to 7.7 +/- 0.9%/hour; filtration capacity changed from 5.0 +/- 0.3 to 4.2 +/- 0.4 ml/min per 100 ml mmHg x 10(-3); and extracellular/total body water changed from 0.42 +/- 0.01 to 0.40 +/- 0.01 l/l (all differences not significant). CONCLUSION: Although experimental human endotoxaemia is frequently used as a model to study sepsis-associated pathophysiology, an endotoxin-induced increase in microvascular permeability in vivo could not be detected using three different methods. Endotoxin administration to human volunteers is not suitable as a model in which to study changes in microvascular permeability.

Adult↗
PubMed2005

Impaired KATP channel function in the fetoplacental circulation of patients with type 1 diabetes mellitus.

OBJECTIVE: The increased perinatal morbidity in diabetes may be partly related to vascular dysfunction. Because potassium channels play an important role in the regulation of vascular tone, this study explores the impact of diabetes on potassium channel function in the fetoplacental vascular bed. STUDY DESIGN: Vascular potassium channel function was investigated by ex vivo dual perfusion of isolated placental cotyledons (n = 47). Appropriate control experiments were carried out to exclude nonspecific effects. RESULTS: Glibenclamide (KATP channel blocker) increased perfusion pressure to a maximum fetoplacental arterial pressure of 37 +/- 6 mm Hg in controls versus 15 +/- 6 mm Hg in diabetes (P < .05). 4-Aminopyridine (KV channel blocker) equally increased fetoplacental arterial pressure in controls, and in diabetes (21 +/- 4 mm Hg vs 22 +/- 2 mm Hg). Apamin and charybdotoxin (KCa channel blockers) caused a negligible rise in fetoplacental arterial pressure. CONCLUSION: In the fetoplacental circulation, KATP channels and KV channels significantly contribute to baseline vascular tone. In diabetes, vascular KATP channel function is impaired.

4-Aminopyridine↗
PubMed2005

Oral therapy with dipyridamole limits ischemia-reperfusion injury in humans.

BACKGROUND: Adenosine receptor stimulation induces several effects that could limit ischemia-reperfusion injury. We hypothesize that treatment with the nucleoside uptake inhibitor dipyridamole increases endogenous adenosine and limits ischemia-reperfusion injury in humans. METHODS: Ischemia-reperfusion injury was studied in forearm skeletal muscle by technetium Tc 99m-labeled annexin A5 scintigraphy. Ischemia-reperfusion injury was induced by unilateral forearm ischemic exercise. Immediately on reperfusion, annexin A5 labeled with technetium Tc 99m was administered intravenously, and ischemia-reperfusion injury was expressed as the percentage difference in radioactivity between the experimental arm and the control arm 1 and 4 hours after reperfusion. Targeting was quantified in the region of the thenar muscle and forearm flexor muscles. This approach was used in 9 healthy male volunteers after a 1-week treatment with dipyridamole (200 mg, slow release, twice daily) and in 23 control subjects. RESULTS: Dipyridamole treatment significantly reduced annexin A5 targeting in skeletal muscle compared with the control group (thenar region, 13% +/- 7% versus 22% +/- 15% at 1 hour after reperfusion and 9% +/- 6% versus 27% +/- 13% at 4 hours for dipyridamole and control groups, respectively [P = .01]; flexor region, 4% +/- 8% versus 7% +/- 6% at 1 hour after reperfusion and 1% +/- 4% versus 10% +/- 9% at 4 hours for dipyridamole and control groups, respectively [P = .01]). CONCLUSIONS: One week of oral treatment with the nucleoside uptake inhibitor dipyridamole (200 mg, slow release, twice daily) significantly limits ischemia-reperfusion injury in humans in vivo, as assessed by technetium Tc 99m-labeled annexin A5 scintigraphy of forearm skeletal muscle.

Administration, Oral↗
PubMed2005

Glibenclamide depletes ATP in renal proximal tubular cells by interfering with mitochondrial metabolism.

Sulfonylurea drugs, like glibenclamide, stimulate insulin secretion by blocking ATP-sensitive potassium channels on pancreatic beta cells. Renal tubular epithelial cells possess a different class of K(ATP) channels with much lower affinities for sulfonylurea drugs, necessitating the use of micromolar glibenclamide concentrations to study these channels. Here, we describe the toxic effects of these concentrations on mitochondrial energy metabolism in freshly isolated renal proximal tubular cells. Glibenclamide, at concentrations of 50 and 100 microM, reduced intracellular ATP levels by 28+/-4 and 53+/-5%, respectively (P<0.01). This decline in ATP could be attributed to a dose-dependent inhibition of mitochondrial respiration. Glibenclamide (10-500 microM) inhibited ADP-stimulated mitochondrial oxygen consumption. In addition to this toxic effect, specific association of radiolabeled and fluorescent glibenclamide to renal mitochondria was found. Association of [(3)H]glibenclamide with renal mitochondria revealed a low-affinity site with a K(D) of 16+/-6 microM and a B(max) of 167+/-29 pmol mg(-1). We conclude that micromolar concentrations of glibenclamide interfere with mitochondrial bioenergetics and, therefore, should be used with care for inhibition of epithelial K(ATP) channels.

Adenosine Triphosphate↗
PubMed2005

Reproducibility of blood flow and post-occlusive reactive hyperaemia as measured by venous occlusion plethysmography.

Venous occlusion plethysmography is commonly used as a tool to assess BF (blood flow) and VR (vascular resistance) at baseline and during PORH (post-occlusive reactive hyperaemia). However, little is known about the reproducibility of this method. The purpose of the present study was to investigate short- (hours) and medium (week)-term reproducibility of forearm, calf and thigh BF and VR at baseline and during PORH. Reproducibility was assessed by the CV (coefficient of variation). In eight subjects, baseline BF and VR of the forearm, calf and thigh were measured using venous occlusion plethysmography (50 mmHg). PORH and minimal VR were measured after 13 min of arterial occlusion (220 mmHg). Reproducibility of baseline forearm and calf BF was acceptable and in agreement with previous studies (CV, 12.9-21.2%). Short- and medium-term reproducibility of thigh BF was good (CV, 5.9% and 8.7% respectively). Baseline VR showed acceptable-to-good reproducibility for forearm, calf and thigh (8.3-22.5%). Forearm PORH showed a CV of 6.1% (short term) and 8.6% (medium term); this was 6.1% (short term) and 6.4% (medium term) for the calf and 6.4% (short term) and 8.0% (medium term) for the thigh. Minimal VR showed good-to-acceptable reproducibility (CV, 6.1-11.7%). In conclusion, forearm, calf and thigh BF and PORH measured by plethysmography have an acceptable-to-good short- and medium-term reproducibility. Short- and medium-term reproducibility of forearm and calf baseline BF are acceptable and thigh baseline BF has a good short- and medium-term reproducibility. Therefore plethysmography is a suitable low-cost tool to assess thigh baseline BF and PORH.

Adult↗
PubMed2005

Mechanisms of adenosine-induced renal vasodilatation in hypertensive patients.

BACKGROUND: Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive. OBJECTIVE: To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the possible involvement of nitric oxide in this mechanism. In addition, the production of renin and catecholamines was studied during infusion of adenosine, caffeine, or both. METHODS: Thirty-three hypertensive patients who underwent diagnostic renal angiography received intrarenal infusions of adenosine either alone or in combination with caffeine or the nitric oxide synthase inhibitor, N-monomethyl-L-arginine (L-NMMA). The effects on renal blood flow (RBF) were assessed by the xenon-133 washout technique and both arterial and renal venous blood samples were taken for measurement of renin and catecholamine concentrations. Intra-arterial blood pressure and heart rate were monitored continuously. RESULTS: Adenosine induced a dose-dependent vasodilatation. Caffeine alone did not change RBF, but shifted the dose-response curve of adenosine to the right during concomitant infusion of caffeine. RBF during combined infusion of L-NMMA and adenosine was not different from that during adenosine alone, but the decrease in renal vascular resistance was less pronounced during this combination. Renin secretion did not change during the infusion of either adenosine alone or adenosine in combination with caffeine. Catecholamine concentrations also did not change during any of the experiments. CONCLUSIONS: Adenosine induces vasodilatation in the human hypertensive kidney and this effect is mediated by the adenosine receptor. Nitric oxide plays, at most, a minor part in the adenosine-induced vasodilatation. Furthermore, renin secretion is not affected by adenosine and caffeine.

Adenosine↗
PubMed2005

Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability.

Meningococcal septic shock is an important cause of morbidity and mortality in children and young adults worldwide and is the prototypical gram-negative septic shock. One of the key factors in the development of shock is increased microvascular permeability. Vascular endothelial growth factor (VEGF) is a central factor in angiogenesis and is an important mediator of vascular permeability. Thirteen patients with meningococcal infection (eight presenting with shock) were investigated in the early phase of invasive meningococcal disease. Cytokines, complement activation, and VEGF plasma concentrations were measured during the first 48 h on the pediatric intensive care unit. Increased cytokine concentrations and activation of the complement system were observed. VEGF plasma concentrations were increased (median 193 pg/mL, range 71-1082) and were highest in the presence of shock (208 pg/mL, 169-1082) compared with patients presenting without shock (92 pg/mL range 71-299). VEGF concentration at admission correlated with the severity of disease (pediatric risk of mortality score, R=0.90 [Spearman], P=0.0001) and the amount of fluids administered within the first 24 h (R=0.90, P<0.0001). In all patients, a decrease in VEGF was associated with a decrease in fluid intake during t=24 to 48 h. The results suggest that apart from correlation with IL-1 beta, -10, -12, and complement activation, microvascular permeability in sepsis is also closely linked to the plasma concentration of VEGF. The role of VEGF in sepsis-associated increased microvascular permeability needs further exploration and may represent a new therapeutic target.

Capillary Permeability↗
PubMed2005

Long-term effect of inhibition of the angiotensin-converting enzyme (ACE) on cavernosal perfusion in men with atherosclerotic erectile dysfunction: a pilot study.

INTRODUCTION: Impaired perfusion of the corpora cavernosa is considered an important causal factor of erectile dysfunction (ED) in the aging male with atherosclerosis. Aim. On the basis of this notion, we hypothesized that inhibition of angiotensin-converting enzyme (ACE) may have a structural beneficial effect on cavernosal perfusion and subsequently on erectile function in men with impaired cavernosal perfusion. METHODS: A total of 59 men with atherosclerotic ED (mean age, 60.0 +/- 6.8 years) and impaired cavernosal perfusion, as demonstrated with penile-pharmaco duplex ultrasonography, were randomized between an ACE inhibitor and placebo treatment arm. The minimum period of intervention was 26 weeks (26-46 weeks). The goal of the study was to demonstrate an improvement of (i) cavernosal arterial perfusion demonstrated by a decrease of blood flow velocity waveform; and (ii) erectile function in the erection domain of the International Index of Erectile Function. RESULTS: Cavernosal perfusion improved significantly (paired samples t-test, P < 0.05) in both study arms, but the improvement did not differ significantly (anova, P > 0.05) between both arms. The number of sexually active men increased, and the severity of ED decreased in both groups. CONCLUSION: Although a persisting improvement of cavernosal perfusion by at least a 6 month-administration of an ACE inhibitor in men with advanced atherosclerotic ED could not be demonstrated in this pilot study, the beneficial effect on cavernosal perfusion, sexual activity, and erectile function in all participants of this study is remarkable. This pilot study warrants a follow-up study in sexually more active men with ED and less advanced atherosclerosis to show that ACE inhibition may result in persisting improvement of cavernosal perfusion.

Analysis of Variance↗
PubMed2005

Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia.

Clinical experience suggests that the administration of fluids in human endotoxemia reduces symptoms. In the present study, the effects of a standardised fluid protocol on symptoms, inflammatory and hemodynamic parameters in human endotoxemia are determined. With approval of the local ethics committee, 16 healthy volunteers received 2 ng/kg of Escherichia coli endotoxin (O:113). After an overnight fast, nine subjects received 1.5 l of 2.5% glucose/0.45% NaCl the hour prior to the endotoxin administration and 150 ml/h during the course of the experiment ('prehydrated group'). Seven subjects only received a continuous infusion of 75 ml/h during the experiment ('non-prehydrated group'). The course of inflammatory parameters and symptoms were determined and mean arterial pressure, heart rate and forearm blood flow were measured. In the prehydrated group, TNF-alpha increased to 522 +/- 63 pg/ml (mean +/- SEM) while the maximum in the non-prehydrated group was 927 +/- 187 pg/ml (P < 0.04). IL-10 increased similarly in both groups (non-prehydrated 117 +/- 18 pg/ml and prehydrated 99 +/- 18 pg/ml; P = NS). The prehydrated group had a significantly lower (P < 0.004) symptom score and recovered sooner (P = 0.004). Endotoxin-induced changes in hemodynamics revealed no significant differences between groups. We demonstrate that prehydration in experimental human endotoxemia significantly shifts the cytokine balance towards a more anti-inflammatory pattern. This effect is associated with a reduction in symptoms, whereas the changes in hemodynamic parameters are not influenced by prehydration.

Adult↗
PubMed2005

Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia.

In this review we discuss the hypothesis, and current evidence, that a decreased concentration of the endogenous purine-nucleoside adenosine contributes to the increased cardiovascular risk of patients with hyperhomocysteinemia. In hyperhomocysteinemia, the reaction equilibrium of the reaction catalysed by S-adenosylhomocysteine hydrolase will shift towards synthesis of S-adenosylhomocysteine, at the expense of free adenosine. Adenosine receptor stimulation induces several cardiovascular protective effects, such as vasodilation, inhibition of thrombocyte aggregation, of inflammation and of vascular smooth muscle cell proliferation. A decreased adenosine concentration could, therefore, well contribute to the cardiovascular complications of hyperhomocysteinemia. Previous animal studies have shown that administration of homocysteine decreases extracellular adenosine, associated with increased synthesis of S-adenosylhomocysteine. Recently, we showed that in patients with classical homocystinuria, cellular adenosine uptake is enhanced, thus limiting adenosine-induced vasodilation. These observations provide us with additional pharmacological targets, such as adenosine uptake inhibition, to reduce cardiovascular risk in patients with hyperhomocysteinemia.

Adenosine↗
PubMed2005

Clinical relevance of drug-drug interactions : a structured assessment procedure.

INTRODUCTION: Computerised drug interaction surveillance systems (CIS) may be helpful in detecting clinically significant drug interactions. Experience with CIS reveals that they often yield alerts with questionable clinical significance, fail to provide relevant information on risk factors for the adverse reaction of the interaction and fail to detect all significant drug interactions. These problems highlight the importance of transparency and selectivity in choosing the drug interactions to be included in CIS. In The Netherlands, the Working Group on Pharmacotherapy and Drug Information is responsible for maintenance of the CIS of the Royal Dutch Association for the Advancement of Pharmacy (KNMP). METHODS: The Working Group developed an evidence-based procedure for structured assessment of drug-drug interactions and revised all drug interactions in the CIS accordingly. RESULTS: For every drug interaction four core parameters were assessed: (i) evidence on the interaction; (ii) clinical relevance of the potential adverse reaction resulting from the interaction; (iii) risk factors identifying patient, medication or disease characteristics for which the interaction is of special importance; and (iv) the incidence of the adverse reaction. On the basis of this assessment the drug-drug interactions for inclusion in the CIS were selected. After revision of the drug combinations in the KNMP-CIS, the Working Group judged 22% of the combinations to be not interacting and another 12% to be interacting but not requiring action. On the basis of this assessment the subset of drug combinations for which interaction alerts are generated and the information on management of a drug interaction alert for users of the CIS were adapted. When an alert is generated by the CIS, the user of the system is supplied with comprehensive information on the four core parameters, the mechanism of the interaction and critical information for management of the interaction for the individual patient. DISCUSSION: This structured procedure offers the possibility for transparent and reproducible assessment of the clinical relevance of drug interactions. CONCLUSION: A CIS selectively generating interaction alerts based on this assessment may help in realising the goal of good clinical practice and may offer a methodology to further increase drug safety.

Adverse Drug Reaction Reporting Systems↗
PubMed2004

Annexin A5 scintigraphy of forearm as a novel in vivo model of skeletal muscle preconditioning in humans.

BACKGROUND: Nonlethal ischemia and reperfusion reduce ischemia-reperfusion-induced cell death, a phenomenon called ischemic preconditioning. In animal models, this potent endogenous protection is mimicked in vivo by administration of adenosine. In humans, exploitation of ischemic preconditioning is hindered by the lack of an appropriate in vivo model to study this phenomenon. To solve this problem, we aimed to set up an easy-to-use human in vivo model to study ischemic or pharmacological preconditioning. METHODS AND RESULTS: Healthy male volunteers performed unilateral ischemic handgrip. At reperfusion, we intravenously injected technetium-99m-labeled Annexin A5, a presumed marker of ischemic injury, and we imaged both forearms and hands simultaneously with a gamma camera. Region of interest analysis (counts per pixel) and subsequent calculation of the percentage difference in radioactivity between experimental and control hands (thenar muscle; mean+/-SE) revealed significant uptake to the ischemically exercised tissue (26+/-3% at 4 hours after reperfusion; P<0.05). This selective localization of Annexin A5 was reduced by ischemic preconditioning (10 minutes of ischemia plus reperfusion before ischemic exercise) or by infusion of adenosine into the brachial artery to 6+/-1% and 10+/-3%, respectively (P<0.05 versus ischemic exercise alone), resembling observations in animal models with infarct size as an end point. Appropriate control experiments supported our conclusion. CONCLUSIONS: Annexin A5 scintigraphy can be applied to test pharmacological or physiological interventions for their ability to prevent ischemia-reperfusion injury.

Adenosine↗
PubMed2004

Vascular adaptation to 4 wk of deconditioning by unilateral lower limb suspension.

Physical inactivity or deconditioning is an independent risk factor for atherosclerosis and cardiovascular disease. In contrast to exercise, the vascular changes that occur as a result of deconditioning have not been characterized. We used 4 wk of unilateral lower limb suspension (ULLS) to study arterial and venous adaptations to deconditioning. In contrast to previous studies, this model is not confounded by denervation or microgravity. Seven healthy subjects participated in the study. Arterial and venous characteristics of the legs were assessed by echo Doppler ultrasound and venous occlusion plethysmography. The diameter of the common and superficial femoral artery decreased by 12% after 4 wk of ULLS. Baseline calf blood flow, as measured by plethysmography, decreased from 2.1 +/- 0.2 to 1.6 +/- 0.2 ml.min(-1).dl tissue(-1). Both arterial diameter and calf blood flow returned to baseline values after 4 wk of recovery. There was no indication of a decrease in flow-mediated dilation of the superficial femoral artery after ULLS deconditioning. This means that functional adaptations to inactivity are not simply the inverse of adaptations to exercise. The venous pressure-volume curve is shifted downward after ULLS, without any effect on compliance. In conclusion, deconditioning by 4 wk of ULLS causes significant changes in both the arterial and the venous system.

Adaptation, Physiological↗
PubMed2004

Enhanced cellular adenosine uptake limits adenosine receptor stimulation in patients with hyperhomocysteinemia.

OBJECTIVE: Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (n=9, plasma homocysteine 93.1+/-24.7 micromol/L) and matched controls (n=8, homocysteine 9.1+/-1.0). METHODS AND RESULTS: Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 microg/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9+/-0.4, 4.3+/-0.5, 5.6+/-1.1, and 9.6+/-2.1 in the patients and to 2.8+/-0.6, 4.4+/-1.0, 9.0+/-1.7, and 17.0+/-3.1 mL/min/dL in controls (P<0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 microg/min/dL) was similar in both groups (P=0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4+/-0.3 versus 8.1+/-0.5 minutes, P<0.001) associated with increased intracellular formation of S-adenosylhomocysteine (P<0.0001). CONCLUSIONS: In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole. Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia.

Adenosine↗
PubMed2004

Severe vagal response after endotoxin administration in humans.

OBJECTIVE: Endotoxin administration to humans is a common means to study systemic inflammation. Worldwide, thousands of volunteers have received endotoxin, and adverse events are rarely reported. The aim of this report was to increase awareness of specific risks of the intravenous administration of endotoxin to human volunteers. DESIGN: Report of four cases who developed severe bradycardia or protracted asystole after administration of endotoxin. Interviews with investigators at three large centers that conduct normal volunteer endotoxin studies. SETTING: Clinical research unit. CASES: Four subjects developed severe bradycardia or protracted asystole, approximately 1 h after administration of endotoxin. Further analyses revealed that the subjects had a history of vasovagal syncope or a positive head-tilt test, indicating increased vagal sensitivity. Relative volume depletion associated with fasting overnight may have predisposed these subjects to this condition. CONCLUSIONS: These responses are very rare and are likely due to the cardioinhibitory Bezold-Jarisch reflex. A thorough screening regarding a history of vagal sensitivity and liberal oral or intravenous fluid administration prior to and during the endotoxin challenge may decrease the risk of these events.

Adult↗
PubMed2004

N-acetylcysteine restores nitric oxide-mediated effects in the fetoplacental circulation of preeclamptic patients.

OBJECTIVE: Preeclampsia is associated with an imbalance between oxidants and antioxidants, resulting in reduced effects of the endothelium-derived, relaxing-factor nitric oxide (NO). Antioxidants, like N-acetylcysteine (NAC), remove reactive oxygen species, resulting in an improvement of endothelial function. We aimed to investigate the effect of NAC on the NO-pathway in the human fetoplacental circulation in preeclampsia and control pregnancies. STUDY DESIGN: The NO-pathway was investigated by use of the NO-synthase inhibitor L-NAME in an ex vivo cotyledon perfusion model. RESULTS: At baseline, fetoplacental arterial pressure was comparable in preeclamptic pregnancies (n=8) and control pregnancies (n=8), and increased dose-dependently after L-NAME. The maximal L-NAME-induced rise in fetoplacental arterial pressure was attenuated in preeclamptic versus control pregnancies (20.8 +/- 2.0 mm Hg vs 36.7 +/- 3.5 mm Hg, P<.05). Addition of NAC increased the L-NAME-induced rise in fetoplacental arterial pressure to 36.4 +/- 3.4 mm Hg in preeclampsia pregnancies (P<.05) and to 49.2 +/- 2.6 mm Hg in control pregnancies (P<.05). CONCLUSION: Preeclampsia is associated with a dysfunction of the NO-pathway. N-acetylcysteine increases NO-mediated effects in the fetoplacental circulation in preeclamptic placentas as well as in healthy control placentas.

Acetylcysteine↗