High-dose dexamethasone in low pain responders undergoing total knee arthroplasty: a randomised double-blind trial.

BACKGROUND: Postoperative pain after total knee arthroplasty (TKA) is a continuing problem despite optimised multimodal analgesia. Previous studies have shown preoperative glucocorticoids to reduce postoperative pain, but knowledge about specific doses and effects in specific patient groups is lacking. METHODS: A two-centre, double-blind, two-arm study comparing preoperative dexamethasone (1 mg kg-1vs 0.3 mg kg-1 i.v.) on postoperative pain in 160 planned TKA subjects with low preoperative pain catastrophising and no opioid use. Subjects received multimodal analgesia with paracetamol, cyclooxygenase-2 inhibitors, local anaesthetic infiltration analgesia, and rescue opioids. The primary outcome was percentage of subjects experiencing moderate to severe pain (visual analogue scale >30 mm) upon ambulation at 24 h. Secondary outcomes included pain scores, postoperative inflammation (C-reactive protein), opioid and antiemetics use, and 'Quality of Recovery-15' and 'Opioid-Related Symptom Distress Scale', length of stay, readmissions, and complications up to Day 90. RESULTS: A total of 157 subjects (80 vs 77) were included. No difference was found between groups in the incidence of subjects experiencing visual analogue scale >30 on ambulation 24 h after surgery (56% vs 53%, relative risk =1.07, confidence interval: 0.8-1.4, P=0.65). No differences in other pain outcomes or use of rescue opioids and antiemetics, in Quality of Recovery-15 and Opioid-Related Symptom Distress Scale, length of stay, readmissions, or complications. C-reactive protein values were comparable at 24 h (13 [6-25] mg L-1vs 16 [9-38] mg L-1, P = 0.07), but lower at 48 h (26 [9-52] mg L-1vs 50 [30-72] mg L-1, P<0.01) in the high-dose group. CONCLUSION: Use of 1 mg kg-1vs 0.3 mg kg-1 i.v. dexamethasone in low pain responders after TKA did not improve early postoperative pain or other outcomes in contrast to benefits in a high pain responder population. CLINICAL TRIAL REGISTRATION: NCT03758170 (first registration 29-11-2018).

Repeat dose steroid in high pain responders after total knee arthroplasty: A study protocol.

Pain after total knee arthroplasty (TKA) is a well-known clinical problem potentially delaying ambulation and recovery. Perioperative glucocorticoids reduce pain and facilitate early recovery, but the optimal timing and dose are still unknown. High pain catastrophizers have an increased risk of poorly controlled postoperative pain, and moderate to severe pain at 24 h is associated with a risk of pain relapse at 48 h. To evaluate the effect of a repeat moderate dose of glucocorticoids after TKA in high pain catastrophizers presenting with moderate to severe pain 24 h postoperatively, having received preoperative high-dose glucocorticoids. High pain catastrophizers (Pain Catastrophizing Scale > 20) undergoing TKA are screened 24 h postoperatively and are included if they experience moderate to severe pain (VAS > 30) during a 5 m walk test. The included patients will receive either oral 24 mg dexamethasone (n = 55) or placebo (n = 55) on the evening of Day 1 (~30-37 h) after surgery. In addition, patients receive a standard multimodal analgesic regimen, including paracetamol, celecoxib, local infiltration analgesia, and preoperative dexamethasone (1 mg/kg). Patients will fill out a pain diary for 7 days after surgery. The primary outcome is moderate to severe pain (VAS > 30) during a 5 m walk test on the morning of Day 2 after surgery. The secondary outcomes include cumulated pain at rest and during ambulation, cumulated use of rescue analgesics, quality of sleep, lethargy, dizziness, nausea, satisfaction with the analgesic regimen, length of stay, morbidity, mortality, and reasons for readmissions. Follow-up is at 8 and 30 days. The data from this study will provide evidence for the effect of a repeated dose of dexamethasone as an analgesic adjuvant in patients undergoing TKA with a high risk of postoperative pain.

High dose dexamethasone in high pain responders undergoing total hip arthroplasty: A randomized controlled trial.

BACKGROUND: Postoperative pain after total hip arthroplasty (THA) may delay postoperative mobilization and discharge. Postoperative pain has been shown to be higher in pain catastrophisers and patients receiving opioids. A single dose of glucocorticoid reduces pain after THA, and an increased dose of glucocorticoids has been found to be effective in patients at high risk of postoperative pain after total knee arthroplasty (TKA), however, the ideal dose in THA remains unknown. OBJECTIVE: To evaluate the effect of a high dose (1 mg kg -1 ) vs. intermediate dose (0.3 mg kg -1 ) of dexamethasone on pain after THA. DESIGN: A randomized double-blind controlled study. SETTING: A two-centre study including two large arthroplasty sites in Denmark was conducted from February 2019 to August 2020. PATIENTS: A total of 160 patients undergoing THA by neuraxial block with multimodal analgesia, having a Pain Catastrophising Scale score >20 and/or preoperative opioid use were included. INTERVENTION: Patients were randomly assigned to receive dexamethasone 1 mg kg -1 or 0.3 mg kg -1 before THA. MAIN OUTCOME MEASURES: Primary outcome was percentage of patients experiencing moderate to severe pain (visual analogue scale, VAS > 30 mm on a 0 to 100 mm scale) on ambulating 24 h after surgery. Secondary outcomes included cumulated pain scores, C-reactive protein (CRP), opioid use, postoperative recovery scores, length of stay, complications, and re-admission within 30 and 90 days. RESULTS: No difference was found in percentage of VAS >30 mm 24 h after surgery in the 5-m walk test (VAS > 30/VAS ≤ 30%); 33/42 (44%) vs. 32/43 (43%), relative risk = 1.04 (95% confidence interval 0.72-1.51; P  = 0.814) in 1 mg kg -1vs. 0.3 mg kg -1 respectively. No differences were found in CRP and opioid use between groups. Also, no intergroup differences were found in recovery scores, re-admissions, or complications. CONCLUSION: 1 mg kg -1vs. 0.3 mg kg -1 dexamethasone improved neither postoperative pain nor recovery in THA in a cohort of predicted high pain responders. TRIAL REGISTRATION: ClinicalTrials.gov ID-number NCT03763760 and EudraCT-number 2018-2636-25.

High-dose steroids in high pain responders undergoing total knee arthroplasty: a randomised double-blind trial.

BACKGROUND: Total knee arthroplasty (TKA) is associated with moderate-to-severe postoperative pain despite multimodal opioid-sparing analgesia. Pain catastrophising or preoperative opioid therapy is associated with increased postoperative pain. Preoperative glucocorticoid improves pain after TKA, but dose-finding studies and benefit in high pain responders are lacking. METHODS: A randomised double-blind controlled trial with preoperative high-dose intravenous dexamethasone 1 mg kg-1 or intermediate-dose dexamethasone 0.3 mg kg-1 in 88 patients undergoing TKA with preoperative pain catastrophising score >20 or regular opioid use was designed. The primary outcome was the proportion of patients experiencing moderate-to-severe pain (VAS >30) during a 5 m walk 24 h postoperatively. Secondary outcomes included pain at rest during nights and at passive leg raise, C-reactive protein, opioid use, quality of sleep, Quality of Recovery-15 and Opioid-Related Symptom Distress Scale, readmission, and complications. RESULTS: Moderate-to-severe pain when walking 24 h postoperatively was reduced (high dose vs intermediate dose, 49% vs 79%; P<0.01), along with pain at leg raise at 24 and 48 h (14% vs 29%, P=0.02 and 12% vs 31%, P=0.03, respectively). C-reactive protein was reduced in the high-dose group at both 24 and 48 h (both P<0.01). Quality of Recovery-15 was also improved (P<0.01). CONCLUSIONS: When compared with preoperative dexamethasone 0.3 mg kg-1 i.v., dexamethasone 1 mg kg-1 reduced moderate-to-severe pain 24 h after TKA and improved recovery in high pain responders without apparent side-effects. CLINICAL TRIAL REGISTRATION: NCT03763734.

The Rosenberg view and coronal stress radiographs give similar measurements of articular cartilage height in knees with osteoarthritis.

PURPOSE: Choosing the optimal radiographic methods to diagnose the cartilage height and degree of knee osteoarthritis is crucial to determine suitability for unicompartmental knee replacement. This study aims to evaluate and compare articular cartilage thickness measured using the Rosenberg view and coronal stress radiography. Intra- and interrater agreement and test-retest reliability of each method were determined. The hypothesis of the study was that the Rosenberg view and coronal stress radiographs provide similar assessments of articular cartilage height in the medial and lateral knee compartments of osteoarthritic knees. METHODS: A prospective diagnostic study, including 73 patients was performed. Inclusion criteria were enrollment for either a medial unicompartmental or a total knee replacement. Radiographs were taken as the Rosenberg view, and coronal stress radiography using the Telos stress device. Repeated measurements were performed. Experienced knee surgeons performed measurements of cartilage height at a standardized location of joint space width (JSW), and a rater-perceived location of minimal joint space width (mJSW), thus allowing for reliability and agreement analysesusing weighted kappa. Coronal stress measurements were ultimately compared to the Rosenberg view using Spearman's rank correlation. RESULTS: A total of 12,264 measurements were performed. The radiographic methods proved substantial reliability. Intra- and interrater agreement showed substantial to almost perfect agreement. A very strong correlation was observed in the medial knee compartment (r = 0.91; CI = 0.84-0.95; p < 0.001), with a mean difference of 0.1 mm and limits of agreement of - 1.5 to 1.7 mm, when comparing JSW between the Rosenberg view and varus stress. Only a strong correlation was observed medially when using mJSW, and when using this measurementmore incidences of bone-on-bone were observed than when measuring with JSW. A Strong correlation was observed in the lateral knee compartment (r = 0.83; CI = 0.71-0.89; p < 0.001), with a mean difference of 0.62 mm and limits of agreement of - 1.5 to 2.7 mm, when comparing JSW between the Rosenberg view and valgus stress. CONCLUSION: The Rosenberg view is similar to 20° coronal valgus-varus stress radiography for determining articular cartilage thickness. Both techniques can be used in a clinical setting. Therefore, extra radiographs, equipment and expertise could be saved, when solely utilizing the Rosenberg view which is simple to perform. LEVEL OF EVIDENCE: III.

Preoperative high-dose Steroids in Total Knee and Hip Arthroplasty - Protocols for three randomized controlled trials.

BACKGROUND: Patients undergoing total knee arthroplasty (TKA)/ total hip arthroplasty (THA) still experience moderate-severe postoperative pain despite optimized pain management regimes. The patients already on opioid treatment and pain catastrophizers (PCs) have a higher risk of postoperative pain. The use of preoperative intravenous high-dose glucocorticoids decreases postoperative pain after TKA and THA, but optimal dose is yet to be found, and the effect on subpopulations at high pain risk is unknown. AIM: To investigate the effect of a higher than previously used dose of glucocorticoids (dexamethasone (DXM)), administered intravenously before surgery, as part of standardized fast-track regimen, on postoperative pain in TKA/THA subgroups. METHOD: Three separate randomized, double-blinded, controlled trials were planned to compare a new higher dose DXM (1 mg/kg) to the earlier used high-dose DXM (0.3 mg/kg). Study 1: predicted Low Pain TKA; study 2: predicted High Pain Responder (HPR) TKA; study 3: predicted HPR THA. Predicted HPR groups consist of either PCs with PCS-score of ≥ 21 and/or history of ongoing opioid-treatment of 30 mg/day of morphine or equivalents > 30 days. In total, 408 patients were planned for inclusion (160 Low Pain TKA, 88 HPR TKA, 160 HPR THA). PRIMARY OUTCOME: Pain upon ambulation in a 5-meter walk test 24 hours after surgery. Secondary outcomes include use of analgesics, rescue-opioids, antiemetics, cumulated pain, CRP, OR-SDS, QoR-15, quality of sleep, length of stay (LOS), reasons for hospitalization, readmission, morbidity, and mortality. Patients completed follow-up on day 90. Recruiting commenced February 2019 and is expected to finish in September 2020.

Medial unicompartmental knee arthroplasty: increasingly uniform patient demographics despite differences in surgical volume and usage-a descriptive study of 8,501 cases from the Danish Knee Arthroplasty Registry.

Background and purpose - Using contemporary indications, up to 50% of patients undergoing knee arthroplasty are eligible for unicompartmental knee arthroplasty (UKA), and lower UKA use likely reflects a restrictive approach to patient selection. Since broader indications have been successfully introduced, and low surgical volume and UKA percentage (usage) are associated with higher revision rates, it is of interest whether the actual use of UKA has changed accordingly. We explored this by assessing time trends in patient demographics and whether these are associated with center UKA volume and usage. Patients and methods - From the Danish Knee Arthroplasty Registry, we included 8,501 medial UKAs performed for primary osteoarthritis during 2002-2016. Using locally weighted regression, we examined changes-both overall and by center volume and usage (low vs high)-in sex distribution, age, weight, and preoperative American Knee Society Score (AKSS-O). Results - Over the last 20 years, UKA use in Denmark has been increasing steadily. Age, weight, and proportion of men all increased regardless of volume and usage. AKSS-O showed an initial increase followed by a decrease. In low-usage and low-volume centers, the proportion of women was higher, patients were younger, weighed less, and had higher AKSS-O scores; however, for age and AKSS-O, the groups were converging during the last part of the period. Interpretation - Characteristics of UKA patients have changed in the last 15 years irrespective of center volume and usage. We found between-group differences for both volume and usage, though with convergence for age and AKSS-O, which suggests an increasingly uniform approach to patient selection.

Microdialysis as a tool to determine the local tissue concentration of dicloxacillin in man.

AIMS: The most common pathogen to cause postoperative infections in Denmark is Staphylococcus aureus. Despite using prophylactic antibiotics, infections are still seen. Whether the tissue concentration is above the minimal inhibitory concentration (MIC) for the pathogen is unknown. Thus, the concentration of dicloxacillin in muscle and adipose tissue was measured after intravenous administration, in healthy men. METHODS: MIC for dicloxacillin against S. aureus was determined using the broth macrodilution method. A microdialysis (MD) catheter was placed in the subcutaneous tissue of the abdomen and in the lateral vastus muscle of the thigh of six healthy male volunteers. They were given 2 g dicloxacillin intravenously. Samples from blood and MD fluid were collected. The unbound dicloxacillin was isolated from plasma. Samples were analysed with high performance liquid chromatography (HPLC). RESULTS: The maximum concentration was reached in muscle tissue after 0.5 h and in adipose tissue after 0.8 h. AUC0-6h for the dicloxacillin concentration in adipose tissue was significantly lower when compared to the unbound dicloxacillin concentration in plasma. The dicloxacillin concentration was above the MIC for sensitive S. aureus for a minimum of 2.3 h and a median of 4.1 h in muscle tissue and a minimum of 1.8 h and a median of 3.2 h in adipose tissue. CONCLUSIONS: The unbound dicloxacillin concentration in adipose and muscle tissue remained above the MIC for sensitive S. aureus, for a period sufficient for many orthopaedic procedures. Whether this is true in patients with compromised circulation remains to be investigated.

Does changes in unicompartmental knee arthroplasty practice pattern influence reasons for revision?

Aims: The aim of this study was to describe the pattern of revision indications for unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) and any change to this pattern for UKA patients over the last 20 years, and to investigate potential associations to changes in surgical practice over time. Methods: All primary knee arthroplasty surgeries performed due to primary osteoarthritis and their revisions reported to the Danish Knee Arthroplasty Register from 1997 to 2017 were included. Complex surgeries were excluded. The data was linked to the National Patient Register and the Civil Registration System for comorbidity, mortality, and emigration status. TKAs were propensity score matched 4:1 to UKAs. Revision risks were compared using competing risk Cox proportional hazard regression with a shared γ frailty component. Results: Aseptic loosening (loosening) was the most common revision indication for both UKA (26.7%) and TKA (29.5%). Pain and disease progression accounted for 54.6% of the remaining UKA revisions. Infections and instability accounted for 56.1% of the remaining TKA revision. The incidence of revision due to loosening or pain decreased over the last decade, being the second and third least common indications in 2017. There was a decrease associated with fixation method for pain (hazard ratio (HR) 0.40; 95% confidence interval (CI) 0.17 to 0.94) and loosening (HR 0.29; 95% CI 0.10 to 0.81) for cementless compared to cemented, and units UKA usage for pain (HR 0.67, 95% CI 0.50 to 0.91), and loosening (HR 0.51; 95% CI 0.37 to 0.70) for high usage. Conclusion: The overall revision patterns for UKA and TKA for the last 20 years are comparable to previous published patterns. We found large changes to UKA revision patterns in the last decade, and with the current surgical practice, revision due to pain or loosening are significantly less likely.

An Investigation of Medial Tibial Component Overhang in Unicompartmental and Total Knee Replacements Using Ultrasound in the Outpatient Department.

Tibial component overhang is known to be a contributor to worse outcomes in knee arthroplasty. The aim of this study is to investigate the presence of tibial component overhang, and whether overhang correlates to a higher local tenderness in both medial unicompartmental and total knee replacements. Also, to determine if a rotational projection phenomenon is presented with radiographs when investigating tibial component overhang. A prospective study, including 64 participants, was performed, where ultrasound measurements were compared with postoperative radiographs. Local tenderness was measured as a pressure pain threshold, determined at 3 months postoperatively using algometry. Sixty-two of sixty-four patients had an underdiagnosed medial overhang on radiographs, with a mean difference of 2.4 mm between radiographs and ultrasound (p < 0.001), presenting a rotational projection phenomenon. When comparing sites with ultrasound measured overhang to sites without overhang measured by ultrasound, a higher local tenderness was observed (p < 0.001). A positive linear correlation was found between patients' overhang and local tenderness (r = 0.2; p = 0.045). Subgroup analysis of medial overhang showed significantly higher tenderness than all other locations. No significant differences were seen for lateral overhang. An apparent rotational projection phenomenon of overhang on radiographs was seen, and a linear association between overhang and local tenderness was demonstrated. This study warrants the use of ultrasound when a surgeon is presented with a patient with postoperative medial tenderness, but no overhang can be seen on radiographs. It should also raise awareness of implant selection and positioning during surgery, especially avoiding the overhang to be localized directly medially.

Readmissions and mortality after outpatient vs inpatient unicompartmental knee arthroplasty in Denmark - A propensity score matched study of 5,384 procedures.

BACKGROUND: Limited nationwide data on the development of outpatient unicompartmental knee arthroplasty (UKA) practice and patient safety exist. The primary objective of this study on patients receiving a medial or lateral UKA was to investigate 7-, 30- and 90-day readmission risk and 90-day mortality in outpatient vs inpatient surgeries. Secondary to investigate the nationwide development of outpatient UKA surgery in 2014-2018. METHODS: Included patients received a medial or lateral UKA in the period January 1, 2014 to December 31, 2018 in any Danish hospital. Data were collected from the Danish National Patient Register. The cohort consisted of 1,059 outpatient and 4,325 inpatient surgeries, hereof 5,182 medial and 202 lateral UKA. After propensity score matching (1:1) 1,057 patients were included in each group. RESULTS: We found a 7-day readmission risk of 1.5 % vs 1.4 % (p = 0.8), 30-day readmission risk of 2.6 % vs 3.2 % (p = 0.3), and 90-day readmission risk of 4.2 % vs 4.8 % (p = 0.4) after outpatient vs inpatient UKA. Similar results were found after matching. We found no significant differences in 90-day mortality for the unmatched or matched cohorts. The amount of outpatient UKA surgeries in Denmark increased from 86 in 2014 to 214 in 2018. CONCLUSION: Outpatient medial or lateral UKA seem to be as safe as inpatient UKA on a nationwide basis.

Tourniquet time in total knee arthroplasty.

BACKGROUND: Whether the arterial tourniquet in total knee arthroplasty (TKA) is a friend or a foe is still debated. Longer ischemia causes hypoxic damage; yet short duration of a tourniquet may influence outcome. Understanding the time-dependent influence of the tourniquet in TKA patients could improve the overall outcome and safety. The purpose of the study was to measure the tourniquet-induced time-dependent alterations in skeletal muscle metabolism in TKA to establish a 'safe tourniquet time.' METHODS: In the femoral quadriceps muscle of 12 patients undergoing a total knee arthroplasty with a tourniquet (TKA) we measured the ischemic response using microdialysis. Lactate, pyruvate, glucose and glycerol were measured in the muscle underneath the tourniquet, in the ischemic muscle distally to the tourniquet and in the opposite muscle as a reference. RESULTS: Lactate pyruvate ratio (L/P ratio) increased time-dependently after 15min of ischemia. L/P ratio increased faster underneath the tourniquet compared to ischemic tissue distal to the tourniquet. Glycerol was elevated underneath the tourniquet compared to ischemic tissue distal to the tourniquet and correlated to the individual ischemic response. Only minor increases in creatine-kinase, asparagine-aminotransferase, and lactate-dehydrogenase were observed. Thirty minutes of reperfusion normalized lactate levels. CONCLUSIONS: The muscle underneath the tourniquet suffered more from ischemia than the ischemic tissue distal to the tourniquet. Less than 15min of ischemia did not increase ischemic markers. If any muscle damage occurs from longer tourniquet time, it is likely reversible and occurs mainly underneath the tourniquet. Fifteen minutes of ischemia appears safe.

Rapid actions of aldosterone in vascular health and disease--friend or foe?

The mineralocorticoid receptor (MR) and the enzyme 11betahydroxysteroid dehydrogenase type 2, which confers aldosterone specificity to the MR, are present in endothelium and vascular smooth muscle. In several pathological conditions aldosterone promotes vascular damage by formation of reactive oxygen species. The effect of aldosterone on vascular function, however, is far from clear. By rapid non-genomic mechanisms aldosterone may cause calcium mobilization and vasoconstriction, or may stimulate nitric oxide formation through the PI-3 kinase/Akt pathway and thereby counteract vasoconstriction. Vasoconstrictor, vasodilator or no effects of aldosterone have been reported from studies on human forearm blood flow. Inhibition of MR with spironolactone improves endothelial function in patients with heart failure but worsens endothelial function in type 2 diabetic patients. The aim of the present review is to reconcile some of the apparently conflicting data. A key observation is that reactive oxygen and nitrogen species serve as physiological signaling molecules at low concentrations, while they initiate pathological processes at higher concentrations. The net effect of aldosterone, which stimulates ROS production, therefore depends on the ambient level of oxidative stress. Thus, in situations with low levels of oxidative stress aldosterone may promote vasodilatation, while at higher oxidative stress (high NaCl intake, pre-existing vascular pathological conditions, high oxygen tension in vitro) aldosterone is likely to be associated with vasoconstriction and oxidative damage, and in this setting inhibition of the MR is likely to be beneficial.

Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase.

The present experiments were designed to test the hypothesis that prostaglandin (PG) E(2) causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE(2) were measured in conscious mice. Single doses of PGE(2) caused concentration-dependent relaxations during contractions to phenylephrine (EC(50)=5*10(-8) mol/L). Relaxation after PGE(2) was absent in rings without endothelium and in rings from eNOS(-/-) mice and was abolished by N(G)-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H(1,2,4)-oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE(2)-relaxed aortic rings, the cGMP content increased significantly. PGE(2)-induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10(-8) mol/L) and mimicked by an EP4 agonist (AE1-329, 10(-7) mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4(-/-) mice but normal in EP2(-/-). Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10(-8) mol/L), abolished the PGE(2)-mediated relaxation. In aortic rings, PGE(2) dephosphorylated eNOS at Thr(495). Chronically catheterized eNOS(-/-) mice were hypertensive (137+/-3.6 mm Hg, n=13, versus 101+/-3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE(2) compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE(2) elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr(495) resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings.

Continuous flow augments reactivity of rabbit carotid artery by reducing bioavailability of NO despite an increase in release of EDHF.

Experiments were designed to investigate the influence of steady flow and pressure on endothelial function in the rabbit carotid artery. Increases and decreases in isometric force were compared in static rings and perfused (5 or 50 ml/min) segments of the same arteries in the presence and absence of endothelium. The alpha(1)-adrenoceptor agonist phenylephrine and the muscarinic agonist acetylcholine were applied as vasoconstrictor and vasodilator stimuli, respectively. Continuous flow (5 and 50 ml/min) reduced the cGMP content and shifted the concentration-response curve to phenylephrine to the left compared with nonperfused static rings. Removal of the endothelium abolished the differences in cGMP content and the sensitivity to phenylephrine between static rings and perfused segments. No difference in sensitivity to phenylephrine was observed in tissues treated with N(omega)-nitro-l-arginine methyl ester (l-NAME). Acetylcholine-evoked relaxations were increased in perfused segments. l-NAME nearly abolished the acetylcholine-evoked relaxation in static rings, whereas about one-half of the relaxation remained in segments exposed to flow. This remnant relaxation was blocked by inhibition of endothelial small- and intermediate-conductance calcium-activated potassium channels by apamin plus 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34). These experiments demonstrate that continuous flow increases the constriction evoked by alpha(1)-adrenergic activation in the rabbit carotid artery through a reduced influence of basally released endothelial NO and, furthermore, that luminal flow unmasks an ability of the endothelium to release a non-NO, noncyclooxygenase vasodilator, presumably endothelium-derived hyperpolarizing factor.

Effects of reboxetine on sympathetic neuroeffector transmission in rabbit carotid artery.

The effect of reboxetine on sympathetic neuroeffector transmission in rabbit isolated carotid artery was examined. Reboxetine (10-8-3 x 10-6 M) and cocaine (10-6-3 x 10-5 M), but not desipramine (10-8-3 x 10-7 M), increased contractions evoked by electrical field stimulation. At higher concentrations, reboxetine (10-4 M), cocaine (3 x 10-4 M), and desipramine (3 x 10-7-10-5 M) inhibited the neurogenic contractions. The enhancement seen with reboxetine and cocaine was partially reversible, whereas the inhibition was readily reversible. Reboxetine (10-7 M) and cocaine (10-5 M) prevented the inhibitory action of bretylium (10-6 M). Reboxetine (10-8-10-5 M), desipramine (10-7-10-4 M), and cocaine (10-6-10-5 M) increased the stimulation-evoked [3H]norepinephrine release. Pargyline (5 x 10-4 M) augmented the facilitatory effect of reboxetine (3 x 10-9-10-6 M) and cocaine (10-7-3 x 10-5 M). Reboxetine (10-8-10-6 M), desipramine (10-8-10-6 M), and cocaine (3 x 10-8-10-5 M) reduced the [3H]norepinephrine (10-8 M) uptake. Reboxetine (10-7 M) and cocaine (10-5-2 x 10-4 M) enhanced the contractions evoked by phenylephrine and norepinephrine. Higher concentrations of reboxetine antagonized the contractions. Reboxetine (10-5-6 x 10-5 M) antagonized the contractions evoked by potassium. The contractions evoked by tyramine (3 x 10-6-10-3 M) was reduced by reboxetine (3 x 10-8-10-6 M) and by cocaine (10-7-10-5 M). We conclude that reboxetine inhibits the membrane amine pump (uptake-1) in the terminals of postganglionic adrenergic neurons in a cocaine-like manner.