Search

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.

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.

Background Unintentional perioperative hypothermia causes serious adverse effects to surgical patients. Thermal suit (T-Balance®) is an option for passive warming perioperatively. We hypothesized that the thermal suit will not maintain normothermia more efficiently than conventional cotton clothes when also other preventive procedures against unintentional hypothermia are used. Methods One hundred patients were recruited to this prospective, randomized trial. They were allocated to the Thermal Suit group or a Control group wearing conventional hospital cotton clothes. All patients received our institution's standard treatment against unintentional hypothermia including a warming mattress, a forced-air upper body warming blanket and a warming device for intravenous fluids. Eardrum temperature was measured pre-operatively. In the operating room and post-anaesthesia care unit temperatures were measured from four locations: oesophagus, left axilla, dorsal surface of the left middle finger and dorsum of the left foot. The primary outcome measure was temperature change during robotic-assisted laparoscopic radical prostatectomy. Results The temperatures of 96 patients were analysed. There was no difference in mean core temperatures, axillary temperatures or skin temperatures on the finger between the groups. Only foot dorsum temperatures were significantly lower in the Thermal Suit group. Intraoperative temperature changes were similar in both groups. In the post-anaesthesia care unit temperature changes were minimal and they did not differ between the groups. Conclusion Provided that standard preventive procedures in maintaining normothermia are effective the thermal suit does not provide any additional benefit over conventional cotton clothes during robotic-assisted laparoscopic radical prostatectomy.

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 hy...

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.

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 compoared 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 t...

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.

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na + ,K + -ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT 1 -receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na + ,K + -ATPase, but this effect could not be attributed to changes in circulating sodium pump inhibitor concentration.

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 � 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 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)2D2] 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.

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.

This study examined the role of angiotensin II in the increase of blood pressure, activation of cardiac natriuretic peptide gene expression, left ventricular hypertrophy, and vascular changes in nitric oxide-deficient hypertension. N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/d), angiotensin II type 1 receptor (AT ) antagonist losartan (20 mg/kg/d), or their combination were administered orally for 8 weeks in Wistar rats.L-NAME elevated systolic blood pressure, which reached its maximum within 4 weeks (200 +/- 4 mm Hg). Despite hypertension,L-NAME administration for 8 weeks did not induce left ventricular hypertrophy. Losartan treatment significantly decreased the development of hypertension induced byL-NAME and decreased left ventricular hypertrophy in untreated rats. In contrast, losartan did not prevent the hypertrophic remodeling of the mesenteric resistance arteries induced byL-NAME.L-NAME treatment increased ventricular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) mRNA levels and immunoreactive BNP levels significantly. Losartan therapy decreased thel-NAME-induced ventricular ANP gene expression by 69% (p0.05) and also reduced ventricular BNP mRNA levels so that it did not differ from control. Losartan treatment alone decreased ventricular immunoreactive ANP and BNP levels by 30% (p0.05). These results show that ventricular ANP and BNP gene expression are dissociated from the increased ventricular mass in nitric oxide deficiency-induced hypertension. Results suggest thatl-NAME-induced hypertension and the associated activation of ventricular ANP and BNP gene expression are, at least in part, mediated by angiotensin II, whereas the resistance vessel hypertrophy following nitric oxide synthase inhibition is angiotensin II independent.

Disturbances in sphincter of Oddi (SO) function may prevent normal bile flow and thus enhance probability of common bile duct stone (CBDS) formation. We have previously shown increased prevalence of diagnosed hypothyroidism in CBDS patients, which may be explained by thyroxine-induced inhibition of SO contractility, in addition to previously suggested changes in bile composition and hepatocytic excretion. The aim of this study was to investigate biliary dynamics in relation to altered thyroid gland function in rat, a rodent without a gallbladder. Euthyroid, hypothyroid or hyperthyroid Spraque-Dawley rats were anaesthetized with i.p. urethane, and exsanguinated at 15, 45, or 60 min after intravenous 99mTc HIDA injection. At these timepoints, the bile flow to intestine was determined by measuring the relative intestine vs. liver radioactivity. At 45 min this was 44% lower in hypothyroid rats and at 60 min 73% higher in hyperthyroid rats compared to euthyroid rats, while hepatic radioactivity at 15 min and blood pressure at injection were similar in the groups. We conclude that the bile flow to duodenum is reduced in hypothyreosis and enhanced in hyperthyreosis.

Objective To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. Methods Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. Results Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. Conclusions Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.

Objective: Since the effects of angiotensin II receptor antagonism on arterial function in nitric oxide (NO)-deficient hypertension are unknown, we investigated the influence of losartan therapy (20 mg kg−1 day−1) on the control of arterial tone in N G-nitro-l-arginine methyl ester (L-NAME; 20 mg kg−1 day−1)-induced hypertension. Methods: Forty Wistar rats were divided into four groups: control, losartan, L-NAME, and losartan+L-NAME. The responses of isolated mesenteric arterial rings were examined in standard organ chambers after 8 treatment weeks. Results: Losartan therapy prevented the development of L-NAME-induced hypertension and the associated impairments of endothelium-independent relaxations to nitroprusside, isoprenaline, and cromakalim, vasodilators acting via the formation of NO, activation of β-adrenoceptors and opening of K+ channels, respectively. In addition, endothelium-dependent relaxations of noradrenaline-precontracted rings to acetylcholine during NO synthase inhibition in vitro were decreased in L-NAME rats, and clearly improved by losartan therapy. The inhibition of cyclooxygenase by diclofenac improved the responses to acetylcholine more effectively in L-NAME than losartan+L-NAME rats, but the relaxations remained decreased in L-NAME rats when compared with losartan+L-NAME rats. When hyperpolarization of smooth muscle was prevented by precontractions induced by high concentration of KCl, the responses to acetylcholine during combined NO synthase and cyclooxygenase inhibition were similar and almost abolished in all groups. Furthermore, superoxide dismutase, a scavenger of superoxide anions, enhanced the acetylcholine-induced relaxations more effectively in L-NAME than losartan+L-NAME rats, although plasma antioxidant capacity was similar in all study groups. Conclusion: Chronic L-NAME-induced hypertension was associated with attenuated arterial relaxation via endothelium-dependent and -independent mechanisms, both of which were improved by the losartan treatment. The mechanisms whereby losartan enhanced arterial relaxation in this model of experimental hypertension may have included enhanced hyperpolarization and increased sensitivity to NO in smooth muscle, and decreased vascular production of superoxide and vasoconstrictor prostanoids.

We studied the effects of 10-week long enalapril and losartan treatments (4 and 15 mg kg−1 day−1, respectively) on mesenteric arterial function in vitro in spontaneously hypertensive rats (SHR) and Wistar–Kyoto rats (WKY). The relaxations of noradrenaline-precontracted rings to acetylcholine, nitroprusside and cromakalim were similar in WKY and enalapril- and losartan-treated SHR, and more pronounced than in untreated SHR. The responses to acetylcholine were attenuated by NG-nitro- l -arginine methyl ester in WKY and drug-treated SHR, but were completely inhibited in untreated SHR. When hyperpolarization of smooth muscle was prevented by KCl-induced precontractions, no differences were found in the relaxations to acetylcholine and nitroprusside between the groups, and the dilatations to cromakalim were abolished. Moreover, in noradrenaline-precontracted rings of drug-treated SHR, the addition of tetraethylammonium attenuated the nitric oxide synthase and cyclooxygenase-resistant relaxations to acetylcholine and abolished the enhanced dilatations to nitroprusside. In conclusion, since the enhancement of vasorelaxation in enalapril- and losartan-treated SHR was abolished by conditions preventing hyperpolarization, the improved vasodilatation following these therapies could be attributed to enhanced vasodilatation via K+ channels in this model of hypertension.

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.A recent series of 1565 primary total knee replacements performed due to osteoarthritis in a specialized, publicly funded hospital for joint replacement was reviewed.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 glucose6.1 mmol/l (110 mg/dl), 6.1-6.9 mmol/l (110-125 mg/dl) andor =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.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.

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 (AT 1 , AT 2 ) 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 AT 1 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.

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 thirdorder 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 þ 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 þ apamin suggested that the K þ 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 þ 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.

This 8-week study investigated the effects of increasing dietary Ca 2+ content from 1.0% to 3.0% and hypercalcemia induced by oral la-OH vitamin D 3 (1OH-D 3 , 1.2 μg/kg), on arterial tone in NaCl-hypertensive rats. The high-Ca 2+ diet completely prevented the increase in blood pressure induced by the 6.0% NaCl chow, while plasma total Ca 2+ and body weight were not different from controls. The 1OH-D 3 treatment moderately elevated plasma total Ca 2+ and attenuated the NaCI-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 N G -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 NaCI-hypertensive rats. All of the impaired relaxations in NaCI hypertension were normalized by concomitant Ca 2+ supplementation. The 1OH-D 3 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-D 3 treatment. In conclusion, a high-Ca 2+ 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-D 3 was associated with moderately lowered blood pressure, possibly because of reduced vasoconstrictor responses in arterial smooth muscle.

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.

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 β-adrenoceptors in experimental renal failure.

Disturbances in the function of sphincter of Oddi (SO) may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. Previously, we have shown increased prevalence of hypothyroidism in CBDS patients.In animal (pig) experiments, thyroxine (T4) and triiodothyronine have a specific inhibitory effect on SO contractility, which raises the possibility that the lack of this prorelaxing effect in hypothyroidism could, at least in part, explain the increased prevalence of CBDS. The aims of the present study were to investigate, whether human SO reacts similarly to T4, and to study the mechanisms of the T4 prorelaxing effect.We found that T4 had similar inhibitory effects on both human and pig SO contractions. The T4 effect was dose-dependent, and maximum was observed in 30 min. The maximal prorelaxing effect was achieved with 0.1 nM T4 concentration, the effect of the physiological T4 concentration (0.01 nM) being about half of the maximal effect. Addition of alpha-adrenoceptor antagonist phentolamine, beta-adrenoceptor antagonist propranolol, nitric oxide (NO)-synthesis inhibitor L-NAME, nerve conductance blocker tetrodotoxin, or cyclooxygenase inhibitor diclofenac did not affect the T4-induced inhibition of contraction. Addition of transcription inhibitor actinomycin D or translation inhibitor cyclophosphamide partially reversed the T4-induced inhibition of contraction. Addition of K+ channel blocker glibenclamide totally reversed the T4-induced inhibition of contraction. In Western blotting, the thyroid hormone receptor (TR) antibody recognized 53 kDa and 58 kDa proteins, corresponding to beta1 and beta2 isoforms of TR, in the human SO tissue.We conclude that T4 has a direct prorelaxing effect on human SO that expresses TR beta1 and beta2. This effect is mediated through a transcriptional mechanism that requires new mRNA and protein synthesis and subsequently leads to the activation of K+ channels.

Chronic renal failure is associated with increased cardiovascular morbidity and abnormal arterial tone, but the underlying pathophysiological mechanisms are poorly understood. Therefore, we studied the responses of isolated mesenteric arterial rings from Wistar-Kyoto rats in standard organ chambers 6 wk after subtotal (5/6) nephrectomy or sham operation. Subtotal nephrectomy resulted in a 1.7-fold elevation of plasma urea nitrogen, whereas blood pressure was not significantly affected. Endothelium-mediated relaxations of norepinephrine-precontracted rings to ACh were impaired in renal failure rats. The nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester inhibited relaxations to ACh more effectively in the renal failure group, whereas the cyclooxygenase inhibitor diclofenac did not significantly affect the response in either group. Inhibition of Ca2+-activated K+channels by charybdotoxin and apamin attenuated NO synthase- and cyclooxygenase-resistant relaxations to ACh in control but not renal failure rats and abolished the difference between these groups. Endothelium-independent relaxations to isoproterenol and cromakalim, vasodilators acting via β-adrenoceptors and ATP-sensitive K+channels, respectively, were impaired in the renal failure group, whereas relaxations to the NO donor nitroprusside were similar in both groups. In conclusion, endothelium-mediated relaxation in renal failure rats was impaired in the absence and presence of NO synthase and cyclooxygenase inhibition but not with prevented smooth muscle hyperpolarization. Endothelium-independent relaxations to isoproterenol and cromakalim were also attenuated after 5/6 nephrectomy. These results suggest that impaired vasodilatation in experimental renal failure could be attributed to reduced relaxation via arterial K+channels.

Because the effects of calcium supplementation on arterial tone in nitric oxide-deficient hypertension are unknown, we investigated the influence of elevating dietary calcium from 1.1 to 3.0% in Wistar rats treated with N G-nitro-l-arginine methyl ester (l-NAME; 20 mg · kg−1 · day−1) for 8 wk. A high-calcium diet attenuated the development of hypertension induced by l-NAME and abrogated the associated impairments of endothelium-independent mesenteric arterial relaxations to nitroprusside, isoproterenol, and cromakalim. Endothelium-dependent relaxations to acetylcholine during nitric oxide synthase inhibition in vitro were decreased in l-NAME rats and improved by calcium supplementation. The inhibition of cyclooxygenase by diclofenac augmented the responses to acetylcholine in l-NAME rats but not in calcium + l-NAME rats. When hyperpolarization of smooth muscle was prevented by KCl precontraction, the responses to acetylcholine during combined nitric oxide synthase and cyclooxygenase inhibition were similar in all groups. Furthermore, superoxide dismutase enhanced the acetylcholine-induced relaxations in l-NAME rats but not in calcium + l-NAME rats. In conclusion, calcium supplementation reduced blood pressure during chronic nitric oxide synthase inhibition and abrogated the associated impairments in endothelium-dependent and -independent arterial relaxation. The augmented vasorelaxation after increased calcium intake inl-NAME hypertension may be explained by enhanced hyperpolarization and increased sensitivity to nitric oxide in arterial smooth muscle and decreased vascular production of superoxide and vasoconstrictor prostanoids.

Clodronate, etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca2+ antagonists. Human internal mammary artery rings were incubated with 14C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 mumol/l of clodronate were, respectively, 3.0 +/- 0.5 (mean +/- S.E.M.) and 1.3 +/- 0.2, with 4 and 40 mumol/l of etidronate 7.4 +/- 0.9, and 3.2 +/- 0.4, and with 0.4 and 4 mumol/l of pamidronate 4.7 +/- 0.7 and 3.9 +/- 0.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by alpha-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCl. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCl as the agonist, and had an additive inhibitory effect on this response with the L-type Ca2(+)-channel blocker nifedipine. The results demonstrate that 1) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to alpha-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca2(+)-channel blocker.