Self-warming blanket versus forced-air warming blanket during total knee arthroplasty under spinal anaesthesia: A randomised non-inferiority trial.

BACKGROUND: Arthroplasty patients are at high risk of hypothermia. Pre-warming with forced air has been shown to reduce the incidence of intraoperative hypothermia. There is, however, a lack of evidence that pre-warming with a self-warming (SW) blanket can reduce the incidence of perioperative hypothermia. This study aims to evaluate the effectiveness of an SW blanket and a forced-air warming (FAW) blanket peri-operatively. We hypothesised that the SW blanket is inferior to the FAW blanket. METHODS: In total, 150 patients scheduled for primary unilateral total knee arthroplasty under spinal anaesthesia were randomised to this prospective study. Patients were pre-warmed with SW blanket (SW group) or upper-body FAW blanket (FAW group) set to 38°C for 30 min before spinal anaesthesia induction. Active warming was continued with the allocated blanket in the operating room. If core temperature fell below 36°C, all patients were warmed using the FAW blanket set to 43°C. Core and skin temperatures were measured continuously. The primary outcome was core temperature on admission to the recovery room. RESULTS: Both methods increased mean body temperature during pre-warming. However, intraoperative hypothermia occurred in 61% of patients in the SW group and in 49% in the FAW group. The FAW method set to 43°C could rewarm hypothermic patients. Core temperature did not differ between groups on admission to the recovery room, p = .366 (CI: -0.18-0.06). CONCLUSIONS: Statistically, the SW blanket was non-inferior to the FAW method. Yet, hypothermia was more frequent in the SW group, requiring rescue warming as we strictly held to the NICE guideline. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03408197.

Comparison of zero heat flux and double sensor thermometers during spinal anaesthesia: a prospective observational study.

Because of the difficulties involved in the invasive monitoring of conscious patients, core temperature monitoring is frequently neglected during neuraxial anaesthesia. Zero heat flux (ZHF) and double sensor (DS) are non-invasive methods that measure core temperature from the forehead skin. Here, we compare these methods in patients under spinal anaesthesia. Sixty patients scheduled for elective unilateral knee arthroplasty were recruited and divided into two groups. Of these, thirty patients were fitted with bilateral ZHF sensors (ZHF group), and thirty patients were fitted with both a ZHF sensor and a DS sensor (DS group). Temperatures were saved at 5-min intervals from the beginning of prewarming up to one hour postoperatively. Bland-Altman analysis for repeated measurements was performed and a proportion of differences within 0.5 °C was calculated as well as Lin`s concordance correlation coefficient (LCCC). A total of 1261 and 1129 measurement pairs were obtained. The mean difference between ZHF sensors was 0.05 °C with 95% limits of agreement - 0.36 to 0.47 °C, 99% of the readings were within 0.5 °C and LCCC was 0.88. The mean difference between ZHF and DS sensors was 0.33 °C with 95% limits of agreement - 0.55 to 1.21 °C, 66% of readings were within 0.5 °C and LCCC was 0.59. Bilaterally measured ZHF temperatures were almost identical. DS temperatures were mostly lower than ZHF temperatures. The mean difference between ZHF and DS temperatures increased when the core temperature decreased.Trial registration: The study was registered in ClinicalTrials.gov on 13th May 2019, Code NCT03408197.

Risk factors associated with acute kidney injury in a cohort of 20,575 arthroplasty patients.

Background and purpose - Patients developing postoperative acute kidney injury (AKI) are at risk of higher morbidity and mortality. In arthroplasty patients, many pre- and perioperative factors are associated with AKI but some of the risk factors are unclear. We report the incidence of postoperative AKI, the conditions associated with it, and survival rates in AKI patients. Patients and methods - We obtained data from 20,575 consecutive hip or knee arthroplasties. Postoperative AKI, occurring within 7 days after the operation, was defined using the risk, injury, failure, loss, and end-stage (RIFLE) criteria. We analyzed independent risk factors for AKI using binary logistic regression. In addition, we reviewed the records of AKI patients and performed a survival analysis. Results - The AKI incidence was 3.3 per 1,000 operations. We found preoperative estimated glomerular filtration rate, ASA classification, body mass index, and duration of operation to be independent risk factors for AKI. Infections, paralytic ileus, and cardiac causes were the predominant underlying conditions, whereas half of all AKI cases occurred without any clear underlying condition. Survival rates were lower in AKI patients. Interpretation - Supporting earlier results, existing renal insufficiency and patient-related characteristics were found to be associated with an increased risk of postoperative AKI. Furthermore, duration of operation was identified as an independent risk factor. We suggest careful renal monitoring postoperatively for patients with these risk factors.

Risk factors for perioperative hyperglycemia in primary hip and knee replacements.

BACKGROUND AND PURPOSE: Perioperative hyperglycemia has been associated with adverse outcomes in several fields of surgery. In this observational study, we identified factors associated with an increased risk of hyperglycemia following hip and knee replacement. PATIENTS AND METHODS: We prospectively monitored changes in glucose following primary hip and knee replacements in 191 patients with osteoarthritis. Possible associations of patient characteristics and operation-related factors with hyperglycemia (defined as glucose > 7.8 mmol/L in 2 consecutive measurements) and severe hyperglycemia (glucose > 10 mmol/L) were analyzed using binary logistic regression with adjustment for age, sex, operated joint, and anesthesiological risk score. RESULTS: 76 patients (40%) developed hyperglycemia, and 48 of them (25% of the whole cohort) had severe hyperglycemia. Glycemic responses were similar following hip replacement and knee replacement. Previously diagnosed diabetes was associated with an increased risk of hyperglycemia and severe hyperglycemia, compared to patients with normal glucose metabolism, whereas newly diagnosed diabetes and milder glucose metabolism disorders had no effect. In patients without previously diagnosed diabetes, increased values of preoperative glycosylated hemoglobin (HbA1c) and fasting glucose on the day of operation were associated with hyperglycemia. Higher anesthesiological risk score-but none of the operation-related factors analyzed-was associated with an increased risk of hyperglycemia. INTERPRETATION: Perioperative hyperglycemia is common in primary hip and knee replacements. Previously diagnosed diabetes is the strongest risk factor for hyperglycemia. In patients with no history of diabetes, preoperative HbA1c and fasting glucose on the day of operation can be used to stratify the risk of hyperglycemia.

Single periarticular local infiltration analgesia reduces opiate consumption until 48 hours after total knee arthroplasty. A randomized placebo-controlled trial involving 56 patients.

BACKGROUND: Randomized trials evaluating efficacy of local infiltration analgesia (LIA) have been published but many of these lack standardized analgesics. There is a paucity of reports on the effects of LIA on functional capability and quality of life. METHODS: 56 patients undergoing unilateral total knee arthroplasty (TKA) were randomized into 2 groups in this placebo-controlled study with 12-month follow-up. In the LIA group, a mixture of levobupivacaine (150 mg), ketorolac (30 mg), and adrenaline (0.5 mg) was infiltrated periarticularly. In the placebo group, infiltration contained saline. 4 different patient-reported outcome measures (PROMs) were used for evaluation of functional outcome and quality of life. RESULTS: During the first 48 hours postoperatively, patients in the LIA group used less oxycodone than patients in the placebo group in both cumulative and time-interval follow-up. The effect was most significant during the first 6 postoperative hours. The PROMs were similar between the groups during the 1-year follow-up. INTERPRETATION: Single periarticular infiltration reduced the amount of oxycodone used and enabled adequate pain management in conjunction with standardized peroral medication without adverse effects. No clinically marked effects on the functional outcome after TKA were detected.

Predictors of mortality following primary hip and knee replacement in the aged. A single-center analysis of 1,998 primary hip and knee replacements for primary osteoarthritis.

BACKGROUND AND PURPOSE: High age is associated with increased postoperative mortality, but the factors that predict mortality in older hip and knee replacement recipients are not known. METHODS: Preoperative clinical and operative data on 1,998 primary total hip and knee replacements performed for osteoarthritis in patients aged ≥ 75 years in a single institution were collected from a joint replacement database and compared with mortality data. Average follow-up was 4.2 (2.2-7.6) years for the patients who survived. Factors associated with mortality were analyzed using Cox regression analysis, with adjustment for age, sex, operated joint, laterality, and anesthesiological risk score. RESULTS: Mortality was 0.15% at 30 days, 0.35% at 90 days, 1.60% at 1 year, 7.6% at 3 years, and 16% at 5 years, and was similar following hip and knee replacement. Higher age, male sex, American Society of Anesthesiologists risk score of > 2, use of walking aids, preoperative walking restriction (inability to walk or ability to walk indoors only, compared to ability to walk > 1 km), poor clinical condition preoperatively (based on clinical hip and knee scores or clinical severity of osteoarthritis), preoperative anemia, severe renal insufficiency, and use of blood transfusions were associated with higher mortality. High body mass index had a protective effect in patients after hip replacement. INTERPRETATION: Postoperative mortality is low in healthy old joint replacement recipients. Comorbidities and functional limitations preoperatively are associated with higher mortality and warrant careful consideration before proceeding with joint replacement surgery.

Obesity, diabetes, and preoperative hyperglycemia as predictors of periprosthetic joint infection: a single-center analysis of 7181 primary hip and knee replacements for osteoarthritis.

BACKGROUND: Diabetes and obesity are common in patients undergoing joint replacement. Studies analyzing the effects of diabetes and obesity on the occurrence of periprosthetic joint infection have yielded contradictory results, and the combined effects of these conditions are not known. METHODS: The one-year incidence of periprosthetic joint infections was analyzed in a single-center series of 7181 primary hip and knee replacements (unilateral and simultaneous bilateral) performed between 2002 and 2008 to treat osteoarthritis. The data regarding periprosthetic joint infection (defined according to Centers for Disease Control and Prevention criteria) were collected from the hospital infection register and were based on prospective, active surveillance. Patients diagnosed with diabetes were identified from the registers of the Social Insurance Institution of Finland. The odds ratios (ORs) for infection and the accompanying 95% confidence intervals (CIs) were calculated with use of binary logistic regression with adjustment for age, sex, American Society of Anesthesiologists risk score, arthroplasty site, body mass index, and diabetic status. RESULTS: Fifty-two periprosthetic joint infections occurred during the first postoperative year (0.72%; 95% CI, 0.55% to 0.95%). The infection rate increased from 0.37% (95% CI, 0.15% to 0.96%) in patients with a normal body mass index to 4.66% (95% CI, 2.47% to 8.62%) in the morbidly obese group (adjusted OR, 6.4; 95% CI, 1.7 to 24.6). Diabetes more than doubled the periprosthetic joint infection risk independent of obesity (adjusted OR, 2.3; 95% CI, 1.1 to 4.7). The infection rate was highest in morbidly obese patients with diabetes; this group contained fifty-one patients and periprosthetic infection developed in five (9.8%; 95% CI, 4.26% to 20.98%). In patients without a diagnosis of diabetes at the time of the surgery, there was a trend toward a higher infection rate in association with a preoperative glucose level of ≥6.9 mmol/L (124 mg/dL) compared with <6.9 mmol/L. The infection rate was 1.15% (95% CI, 0.56% to 2.35%) in the former group compared with 0.28% (95% CI, 0.15% to 0.53%) in the latter, and the adjusted OR was 3.3 (95% CI, 0.96 to 11.0). The type of diabetes medication was not associated with the infection rate. CONCLUSIONS: Diabetes and morbid obesity increased the risk of periprosthetic joint infection following primary hip and knee replacement. The benefits of joint replacement should be carefully weighed against the incidence of postoperative infection, especially in morbidly obese patients. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Preoperative hyperglycemia predicts infected total knee replacement.

BACKGROUND: Diabetes increases the risk of surgical site infections. In many patients undergoing total knee replacement, however, diabetes has not been diagnosed. The purpose of this study was to analyze the applicability of preoperative screening for hyperglycemia in identifying patients predisposed to infected knee replacement. METHODS: A recent series of 1565 primary total knee replacements performed due to osteoarthritis in a specialized, publicly funded hospital for joint replacement was reviewed. RESULTS: Preoperative hyperglycemia was significantly associated with infected knee replacement: during the 1-year follow-up infection occurred in 0.44%, 0.93% and 2.42% of patients with preoperative plasma glucose <6.1 mmol/l (<110 mg/dl), 6.1-6.9 mmol/l (110-125 mg/dl) and > or =7.0 mmol/l (> or =126 mg/dl). In age- and gender-adjusted analysis the patients with the highest glucose levels had a 4-fold risk for infected knee replacement compared to the patients with the lowest glucose. Obesity increased the risk of infected knee replacement, but the effect of hyperglycemia on the infection rates remained significant also after adjustment for body mass index. None of the patients with normal but 2.8% of patients with increased glycosylated hemoglobin (>6.5%) experienced infected knee replacement. CONCLUSION: Obesity and hyperglycemia associate with a higher risk of infected knee replacement. Preoperative screening of plasma glucose is an efficient way to identify patients in increased risk of infection following primary total knee replacement.

Hyperuricemia, oxidative stress, and carotid artery tone in experimental renal insufficiency.

BACKGROUND: Hyperuricemia may play a role in the pathogenesis of cardiovascular disease, but uric acid is also a significant antioxidant. We investigated the effects of oxonic acid-induced hyperuricemia on carotid artery tone in experimental renal insufficiency. METHODS: Three weeks after 5/6 nephrectomy (NX) or Sham operation, male Sprague-Dawley rats were allocated to 2.0% oxonic acid or control diet for 9 weeks. Blood pressure was monitored using tail cuff, isolated arterial rings were examined using myographs, and blood and urine samples were taken, as appropriate. Oxidative stress and antioxidant status were evaluated by measuring urinary 8-isoprostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) excretion and plasma total peroxyl radical-trapping capacity (TRAP), respectively. RESULTS: Plasma creatinine was elevated twofold in NX rats, but neither NX nor oxonic acid diet influenced blood pressure. Urinary 8-iso-PGF(2 alpha) excretion was increased over 2.5-fold in NX rats on control diet. Oxonic acid diet increased plasma uric acid 2-3-fold, TRAP 1.5-fold, and reduced urinary 8-iso-PGF(2 alpha) excretion by 60-90%. Carotid vasorelaxation to acetylcholine in vitro, which could be abolished by nitric oxide (NO) synthase inhibition, was reduced following NX, whereas maximal response to acetylcholine was augmented in hyperuricemic NX rats. Vasorelaxation to nitroprusside was impaired in NX rats, whereas oxonic acid diet increased sensitivity also to nitroprusside in NX rats. CONCLUSIONS: Oxonic acid-induced hyperuricemia reduced oxidative stress in vivo, as evaluated using urinary 8-iso-PGF(2 alpha) excretion, increased plasma TRAP, and improved NO-mediated vasorelaxation in the carotid artery in experimental renal insufficiency.

High-calcium vs high-phosphate intake and small artery tone in advanced experimental renal insufficiency.

BACKGROUND: Disturbed calcium-phosphorus balance significantly contributes to uraemic changes in large arteries. We examined the influences of high-calcium and high-phosphate intake on small artery tone in experimental renal insufficiency. METHODS: Sixty-five rats were assigned to 5/6 nephrectomy (NTX) or sham operation. After 15 week disease progression, NTX rats were given high-calcium (3%), high-phosphate (1.5%) or control diet (0.3% calcium, 0.5% phosphate) for 12 weeks. Then isolated segments of small mesenteric arteries were studied using wire and pressure myographs. RESULTS: Subtotal nephrectomy reduced creatinine clearance by 60% and increased parathyroid hormone (PTH) and phosphate 12-fold and 2.7-fold, respectively. High-phosphate intake further elevated PTH and phosphate (33-fold and 5.5-fold, respectively), while the calcium diet suppressed them (to 3.5 and 62% vs sham, respectively). Ventricular B-type natriuretic peptide synthesis was increased, and blood pressure was 27 and 18 mmHg higher in NTX rats on control and phosphate diet, respectively, than in calcium-fed rats. Vasorelaxation to acetylcholine was impaired by approximately 50% in uraemic rats, and was further deteriorated by high-phosphate intake, whereas the calcium diet improved endothelium-mediated relaxation via nitric oxide and potassium channels. Small arteries of all NTX groups featured eutrophic inward remodelling: wall-to-lumen ratio was increased 1.3-fold without change in cross-sectional area. CONCLUSION: High-phosphate intake had a detrimental influence on secondary hyperparathyroidism and vasodilatation, whereas high-calcium intake reduced blood pressure and PTH, alleviated volume overload and improved vasorelaxation in experimental renal insufficiency. Therefore, alterations in the calcium-phosphorus balance can significantly modulate small artery tone during impaired kidney function.

Paricalcitol [19-nor-1,25-(OH)2D2] in the treatment of experimental renal bone disease.

UNLABELLED: Paricalcitol is a less hypercalcemic vitamin D analog that has been shown to suppress secondary hyperparathyroidism and to prevent the associated histomorphometric changes in bone. In this study, we show that paricalcitol also ameliorates the renal insufficiency-induced loss of bone mineral and the mechanical competence of bone. INTRODUCTION: Renal bone disease is a common consequence of chronic renal insufficiency and the associated secondary hyperparathyroidism (SH). Paricalcitol [19-nor-1,25(OH)(2)D(2)] has been shown to ameliorate SH and prevent renal failure-induced histomorphometric changes in bone with minimal calcemic and phosphatemic activity. However, information about its efficacy on restoration of bone structural strength is lacking. In this study, we explored the effects of paricalcitol treatment on bone structure and strength in a model of advanced renal disease. MATERIALS AND METHODS: Forty-five 8-week-old rats were randomly assigned to either surgical 5/6 nephrectomy (NTX) or Sham-operation. After a 15-week postoperative disease progression period, the NTX rats were further allocated to uremic control (NTX) and treatment (NTX + paricalcitol) groups, the latter of which received paricalcitol for the subsequent 12 weeks. After 27 weeks, the animals were killed, plasma samples were collected, and both femora were excised for comprehensive analysis of the femoral neck and midshaft (pQCT and biomechanical testing). RESULTS: High mortality that exceeded 30% was observed in both NTX groups. NTX induced over a 13-fold increase in plasma PTH, whereas this increase was only 5-fold after paricalcitol treatment. At the femoral neck, NTX was associated with an 8.1% decrease (p < 0.05) in vBMD and a 16% decrease in breaking load (p < 0.05) compared with the Sham group, whereas paricalcitol treatment completely prevented these changes. At the femoral midshaft, the NTX resulted in a 6.6% decrease in cortical BMD (p < 0.01 versus Sham), and this change was also prevented by paricalcitol. CONCLUSIONS: Paricalcitol administration prevented renal insufficiency-associated decreases in BMD in the femoral neck and the femoral midshaft and restored bone strength in the femoral neck. Therefore, paricalcitol can efficiently ameliorate renal insufficiency-induced loss of bone mineral and mechanical competence of bone.

Renal insufficiency-induced bone loss is associated with an increase in bone size and preservation of strength in rat proximal femur.

Chronic renal insufficiency (CRI) results in phosphate retention and secondary hyperparathyroidism, the treatment of which is largely based on the use of calcium salts as phosphate binders. Advanced CRI causes bone fragility, but information about bone geometry and strength in moderate CRI is scarce. We assigned 39 8-week-old male Sprague-Dawley rats to sham-operation (Sham) or 5/6 nephrectomy (NTX). Four weeks later, the rats were randomized to 0.3% calcium (Sham, NTX) or 3.0% calcium diet (Sham + Calcium, NTX + Calcium). After 8 weeks, the animals were sacrificed, plasma samples collected, and femora excised for neck and midshaft analyses: dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and biomechanical testing. The NTX increased plasma urea and PTH 1.6-fold and 3.6-fold, respectively, whereas high calcium intake suppressed PTH to 30% of controls. Total femoral bone mineral content decreased (-6.3%) in the NTX group, while this deleterious effect was reversed by high calcium diet. In the site-specific analysis of the femoral neck, the volumetric bone density (-6.5%) was decreased in the NTX group but not NTX + Calcium group. However, in the nephrectomized rats, there was also a concomitant increase in the cross-sectional area (+15%), and, despite the decrease in bone density, the mechanical strength of the femoral neck was maintained. In the midshaft, NTX decreased cortical volumetric bone density (-1.2%), but similar to the femoral neck, no differences were found in the mechanical strength. In conclusion, a decrease in bone mass in moderate experimental CRI was associated with a concomitant increase in bone size, and maintenance of mechanical competence. Although high calcium diet suppressed plasma PTH to under normal physiological levels, it prevented the CRI-induced loss of bone mass without an adverse influence on bone strength.

High calcium diet down-regulates kidney angiotensin-converting enzyme in experimental renal failure.

BACKGROUND: Calcium salts are used as phosphate binders in renal failure, while high calcium diet also improves vasorelaxation and enhances natriuresis. The influences of calcium intake on renal renin-angiotensin system (RAS) are largely unknown. METHODS: Four weeks after NTX, rats were put on 3.0% or 0.3% calcium diet for 8 weeks (12-week study). In additional experiments, 15 weeks after NTX, rats were put on similar diets for 12 weeks (27-week study). Appropriate blood, urine, and kidney samples were taken. Renal angiotensin-converting enzyme (ACE) and angiotensin II receptors (AT1, AT2) were examined using autoradiography, ACE also using Western blotting, and connective tissue growth factor (CTGF) using immunohistochemistry. RESULTS: In the 12-week study, albuminuria increased 5-fold in NTX rats, but only 2-fold in calcium NTX rats on 3.0% calcium. In the 27-week study, high calcium intake decreased blood pressure, retarded progression of renal failure, reduced glomerulosclerosis, interstitial damage, and aortic calcifications, and improved survival from 50% to 92% in NTX rats. In both experiments plasma parathyroid hormone and phosphate were elevated after NTX, and suppressed by high calcium diet, while kidney ACE was down-regulated by 40% or more after increased calcium intake. In the 27-week study renal CTGF was decreased and cortical AT1 receptor density reduced after high calcium diet. CONCLUSION: High calcium diet down-regulated kidney ACE, reduced albuminuria and blood pressure, and favorably influenced kidney morphology in experimental renal failure. These findings suggest a link between calcium metabolism and kidney ACE expression, which may play a role in the progression of renal damage.

Effect of angiotensin II type 1 receptor blockade on conduit artery tone in subtotally nephrectomized rats.

BACKGROUND: Angiotensin II type 1 (AT1) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT1 blockade on conduit artery function in renal failure is unknown. METHODS: The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT1 receptors quantified using autoradiography. RESULTS: NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [125I]-Sar1,Ile8-angiotensin II binding to renal AT1 receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca2+-activated K+ channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K+ channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K+ channel agonist, was impaired in untreated but not in losartan-treated NX rats. CONCLUSION: Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K+ channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT1 blockade confers functional benefits to large arteries in renal failure.

Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure.

BACKGROUND: Vasorelaxation is impaired in renal failure (RF) and hypertension. A high calcium diet enhances vasodilatation and reduces blood pressure in experimental hypertension. Oral calcium salts are used as phosphate binders in RF. However, the effect of increased calcium intake on arterial tone in RF is unknown. METHODS: We investigated the influence of an 8-week high calcium diet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized (NTX) rats. Calcium was supplemented as carbonate salt, blood pressure measured by tail-cuff, urine collected in metabolic cages, and samples taken for blood chemistry and parathyroid hormone (PTH). Functional studies of isolated third-order branches of the mesenteric artery in vitro were performed using the Mulvany multimyograph. RESULTS: Plasma urea was elevated 1.6-fold and systolic blood pressure by 10 mmHg after NTX, while increased calcium intake was without effect on these variables. Plasma PTH and phosphate were raised following NTX, and suppressed by high calcium diet. Vasorelaxations induced by K(+) channel agonists 11,12-epoxyeicosatrienoic acid and levcromakalim were impaired after NTX. Vasorelaxation induced by acetylcholine was also reduced following NTX, and experiments with N(G)-nitro-L-arginine methyl ester, diclofenac and charybdotoxin + apamin suggested that the K(+) channel-mediated component of endothelium-dependent relaxation was deficient after NTX. Increased calcium intake corrected all impairments of vasodilatation in NTX rats. CONCLUSIONS: Deficient vasorelaxation via K(+) channels was normalized by high calcium diet in experimental RF. This effect was independent of the degree of renal impairment and blood pressure, but was associated with improved calcium metabolism: plasma levels of PTH and phosphate were decreased and ionized calcium was increased.

Increased calcium intake reduces plasma cholesterol and improves vasorelaxation in experimental renal failure.

Chronic renal failure (CRF) is associated with abnormal lipid metabolism and high prevalence of vascular complications. Calcium salts are commonly used in CRF as phosphate binders. Increased calcium intake may also lower plasma cholesterol and beneficially influence vascular tone. Therefore, we investigated the influence of increasing dietary calcium from 0.3% to 3.0% for 8 wk after 5/6 nephrectomy (NTX) on plasma cholesterol and mesenteric resistance vessel tone in male Sprague-Dawley rats. The groups were Sham, Sham-Calcium, NTX, and NTX-Calcium (n = 10-11). Blood pressure was modestly elevated after NTX, whereas the plasma creatinine, urea nitrogen, phosphate, and parathyroid hormone levels were clearly increased. The high-calcium diet suppressed plasma phosphate and parathyroid hormone but was without effect on blood pressure. The NTX resulted in 1.6-fold elevation in plasma total cholesterol and 40% reduction in high density-to-low density lipoprotein ratio (HDL/LDL). However, the lipid profile in NTX rats on the high-calcium diet did not differ from sham-operated controls. The endothelium-mediated relaxations induced by acetylcholine were impaired in NTX rats, whereas the response was normalized by a high-calcium diet. No differences in vasorelaxations by the endothelium-independent vasodilator nitroprusside were detected. In conclusion, improved vasorelaxation after a high-calcium diet could be due to reduced plasma total cholesterol and ameliorated HDL/LDL ratio, although decreased plasma phosphate and parathyroid hormone may also play a significant role in the vascular effects of increased calcium intake.

Prostacyclin and thromboxane A2 production in nitric oxide-deficient hypertension in vivo. Effects of high calcium diet and angiotensin receptor blockade.

The effects of chronic nitric oxide deficiency on prostacyclin and thromboxane A(2) production in vivo are unknown. Therefore, we treated rats with N(G)-nitro-L-arginine methyl ester (L-NAME), and used losartan and high calcium diet as antihypertensive treatments. Forty eight Wistar rats were divided into six groups: control; losartan (20mgkg(-1)day(-1)); high calcium diet (dietary calcium elevated from 1.1% to 3%); L-NAME (20mgkg(-1)day(-1)); losartan+L-NAME and high calcium diet+L-NAME. Prostacyclin and thromboxane A(2) production were measured after eight weeks as urinary 2,3-dinor-6-keto-PGF(1alpha) and 11-dehydro-TXB(2), respectively. Both the high calcium diet and losartan reduced blood pressure in L-NAME hypertension. Chronic nitric oxide deficiency did not modulate prostacyclin production but it nearly doubled thromboxane A(2) production in vivo. This effect was not influenced by lowering of blood pressure by blockade of angiotensin II type 1 receptors. Independent of the level of blood pressure and blockade of nitric oxide synthesis the high calcium diet decreased prostacyclin production by one third and increased thromboxane A(2) production almost two-fold in vivo.

Vascular influences of calcium supplementation and vitamin D-induced hypercalcemia in NaCl-hypertensive rats.

This 8-week study investigated the effects of increasing dietary Ca2+ content from 1.0% to 3.0% and hypercalcemia induced by oral 1alpha-OH vitamin D3 (1OH-D3, 1.2 microg/kg), on arterial tone in NaCl-hypertensive rats. The high-Ca2+ diet completely prevented the increase in blood pressure induced by the 6.0% NaCl chow, while plasma total Ca2+ and body weight were not different from controls. The 1OH-D3 treatment moderately elevated plasma total Ca2+ and attenuated the NaCl-induced rise in blood pressure, but also impaired weight gain. The tone of isolated mesenteric arterial rings was examined at the end of study. The endothelium-independent relaxations to nitroprusside, isoproterenol, and cromakalim were impaired in NaCl-hypertension. Experiments with NG-nitro-l-arginine methyl ester and tetraethylammonium in vitro suggested that both the nitric oxide- and hyperpolarization-mediated components of endothelium-dependent relaxation to acetylcholine were reduced in NaCl-hypertensive rats. All of the impaired relaxations in NaCl hypertension were normalized by concomitant Ca2+ supplementation. The 1OH-D3 treatment did not affect vascular relaxation, but it attenuated maximal contractile responses induced by norepinephrine and KCl by more than 50%. The reduced vasoconstrictor responses could not be explained by increased apoptosis in the vessel wall, but calcification may have played a role, since moderate signs of medial or adventitial calcification were observed in the aortic preparations after the 1OH-D3 treatment. In conclusion, a high-Ca2+ diet, which did not cause hypercalcemia, normalized blood pressure and endothelium-dependent and endothelium-independent vasorelaxation in NaCl-hypertensive rats. In contrast, chronic hypercalcemia induced by 1OH-D3 was associated with moderately lowered blood pressure, possibly because of reduced vasoconstrictor responses in arterial smooth muscle.

AT1 receptor blockade improves vasorelaxation in experimental renal failure.

It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8-week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6-fold after nephrectomy, and ventricular synthesis of atrial and B-type natriuretic peptides was increased 2.2-fold and 1.7-fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium-mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium-activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham-operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate-sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodeling: Wall-to-lumen ratio was increased without change in wall cross-sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin-angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.

Preserved endothelium-dependent but impaired beta-adrenergic relaxation of the resistance vessels in experimental renal failure.

Chronic renal failure is associated with increased cardiovascular morbidity and reduced arterial elasticity. Only little information is available on the functional effects of uraemia on resistance arteries. Therefore, we studied the influence of renal failure on rat small mesenteric vessels. The responses of arterial rings were investigated in a Mulvany myograph 6 weeks after 5/6 nephrectomy or sham operation. The subtotal nephrectomy resulted in a 1.9-fold elevation of plasma urea nitrogen but was without significant effect on blood pressure. Endothelium-dependent relaxations, largely mediated via arterial K(+) channels, were preserved in the resistance vessels of uraemic rats. Endothelium-independent vasorelaxations, mediated via exogenous nitric oxide and the opening of ATP-sensitive K(+) channels, were also unchanged. However, the responses induced by isoprenaline were slightly reduced, indicating impaired relaxation via beta-adrenoceptors in experimental renal failure.