l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.     

OBESITY INDUCED RENAL OXIDATIVE STRESS CONTRIBUTES TO RENAL INJURY IN SALT-SENSITIVE HYPERTENSION

• 1 In the present study, we determined the role of hypertension, oxidative stress and inflammation on kidney damage in a rodent model of obesity and diabetes. Hypertension was induced in male obese (db/db) mice and lean (db/m) mice by implantation of deoxycorticosterone acetate (DOCA) pellets and mice were allowed to drink water containing 1% salt. Mice were divided into six groups as follows: obese and lean control, obese and lean 1% salt (salt) and obese and lean DOCA plus 1% salt (DOCA‐salt).
• 2 Blood pressure was significantly increased in lean and obese DOCA‐salt groups relative to their respective controls; however, there was no difference in blood pressure between the lean and obese control and salt groups. Urinary 8‐isoprostane was increased in obese control compared with lean control mice (1464 ± 267 vs 493 ± 53 pg/µmol creatinine, respectively) and this elevation was further increased in the obese DOCA‐salt treated mice (2430 ± 312 pg/µmol creatinine). Urinary monocyte chemoattractant protein‐1 excretion and CD68‐positive cells were also increased in both obese and lean DOCA‐salt groups compared with their respective controls. Furthermore, DOCA‐salt treatment increased collagen IV excretion in both obese and lean mice compared with controls, but there was no difference between obese and lean DOCA‐salt groups. Urinary albumin excretion was significantly increased in the obese compared with the lean DOCA‐salt mice (507 ± 160 vs 202 ± 48 µg/day, respectively).
• 3 These data suggest that obese DOCA‐salt hypertensive mice exhibit greater renal injury than lean DOCA‐salt hypertensive mice in a manner independent of blood pressure and that this renal injury is associated with obesity related pre‐existing renal oxidative stress.

     

Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib

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巴利昔单抗在预防肾移植后排斥反应中的应用

目的:探讨巴利昔单抗诱导治疗预防肾移植后急性排斥反应的有效性和安全性。方法:在使用环孢素、霉酚酸酯及激素三联抗排斥的基础上,将42例肾移植受者随机分2组,每组各21例,试验组术前30min及术后d4各给予巴利昔单抗20mg+氯化钠注射液100mL,静脉滴注,对照组只使用氯化钠注射液静脉滴注。评价急性排斥反应的发生率、严重程度以及巴利昔单抗治疗的安全性。结果:试验组急性排斥反应发生率10%(2/21),发生时间(2.8±s0.8)mo;对照组发生率29%(6/21),发生时间(1.1±0.7)mo,早于试验组(P<0.01)且严重程度高于试验组。血肌酐恢复正常的时间试验组(4.0±0.7)d,对照组(7.8±1.6)d,P<0.01。不良反应发生率2组间差异无显著意义,P<0.05。结论:巴利昔单抗联合环孢素、霉酚酸酯和激素预防肾移植后急性排斥反应安全有效。     

Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid

Mycophenolate mofetil (MMF) is almost completely absorbed from the gut and is rapidly de-esterified into its active drug, mycophenolic acid (MPA). The main metabolite is glucuronidated MPA (MPAG), which is excreted into bile and undergoes enterohepatic recirculation. Studies in healthy volunteers treated with cholestyramine show that interruption of the enterohepatic recirculation decreases MPA exposure by approximately 40%. Published data show a difference in mycophenolic acid plasma concentrations between kidney transplant recipients treated with MMF plus cyclosporine (CsA) and those treated with MMF plus tacrolimus (TRL). However, the interpretation of these data is complicated by interpatient differences in variables that may influence MMF pharmacokinetics (e.g., underlying disease, co-medication, and time since transplantation). To understand the influence of TRL and CsA on MMF pharmacokinetics (PK) more completely, the authors eliminated confounding variables in clinical studies by performing drug interaction studies in inbred rats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) were treated once daily with oral CsA (8 mg/kg), TRL (4 mg/kg), or placebo on days 0-6 before all rats began once-daily oral treatment with MMF (20 mg/kg) on day 7. Combined treatment with either MMF + CsA, MMF + TRL, or MMF + placebo was continued for 1 week (days 8-14). Thereafter, CsA and TRL treatments were stopped but MMF treatment was continued on days 14-21. Blood was sampled during the 24 hours subsequent to dosing on day 7 (after the first MMF dose), on day 14 (after multiple MMF doses) and on day 21 (after CsA/TRL washout). Rats in the MMF + TRL group and in the MMF + placebo group showed a second peak in the MPA-PK profiles consistent with enterohepatic recirculation of MPA. The MPA-PK profiles for the MMF + CsA-treated animals did not show a second MPA peak. On Day 14, the mean plasma MPA-AUC(0-24 hours) for the CsA-treated animals was significantly less than MPA exposures for rats in the MMF + TRL- and the MMF + placebo-treated groups. Furthermore, in contrast to results from other investigators, co-administration of CsA and MMF significantly increased MPAG-AUC(0-24 hours). Serum creatinines did not differ among rats in the three groups. CsA but not TRL decreased MPA plasma levels and increased MPAG-AUC(0-24 hours). These data suggest that CsA inhibits MPAG excretion into bile and offer an explanation for the well-known increased MPA exposure in organ transplant patients caused by conversion from CsA- to TRL-based immunosuppression.     

Th1, Th2, Th17 cell subsets in two different immunosuppressive protocols in renal allograft recipients (Sirolimus vs mycophenolate mofetil): A cohort study

Long-term use of calcineurin inhibitors (CNI) is associated with nephrotoxicity, which is an important cause of renal dysfunction. Therefore, CNI-minimization strategies which decrease the CNI nephrotoxicity under the protection of additional immunosuppressant drugs have been developed. The aim of current cohort study was to compare the effect of two immunosuppressive protocols [tacrolimus (TAC) in combination with mycophenolate mofetil (MMF) and prednisolone (PRED) versus TAC in combination with sirolimus (SRL) and prednisolone] on the frequency of T helper cell subsets (Th1, Th2 and Th17 cells) and their associated cytokine (IFN-γ, IL-4 and IL-17A) levels in renal allograft recipients.In this study, renal transplant recipients who received induction therapy (Antithymocyte globulin) and were also on triple immunosuppressive therapy were included and divided in to two groups: Group A was comprised 14 patients who received TAC, MMF and PERD whereas group B was composed of 10 patients who received TAC, SRL and PERD. The frequency of Th1, Th2 and Th17 cells in the peripheral blood mononuclear cells (PBMCs) of the patients was analyzed by flow cytometry before and 4 months after transplantation. In addition, IFN-γ, IL-4 and IL-17A concentrations in PBMC culture supernatants of patients before and 4 months after transplantation were quantified by ELISA.The results of our study showed that TAC, MMF and PRED protocol did not diminish the frequency of Th17 cells at 4 months post-transplantation (5% ± 2.5) compared with pre-transplantation (2.3% ± 1; P < 0.05). However, Th17 (3.6% ± 1.5 pre-transplantation vs 2.2% ± 0.9 at 4 months post-transplantation; P < 0.05), Th2 (1.4% ± 0.3 pre-transplantation vs 0.8% ± 0.4 at 4 months post-transplantation; P < 0.05) cell subsets and IL-4 concentration (71.5 pg/ml ± 12 pre-transplantation vs 62.5 pg/ml ±4.4 at 4 months post-transplantation; P < 0.05) were significantly decreased after transplantation in patients who had received SRL, TAC and PRED.In conclusion, the data of the current study suggest that using reduced dose of TAC in SRL, TAC and PRED protocol is in favor of allograft survival; however a cohort study with larger sample size is needed for confirming our results.     

The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by N^ω-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080±27 vs 12189±761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628±2395 vs MC=2326±2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08–1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30±3 vs 45±4 and RV/LV+S: 0.46±0.04 vs 0.62±0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61±6 μm vs 81±3 μm for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65±5% and 46±3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.     

PREVENTION OF STRUCTURAL ARTERIOLAR CHANGES IN DOCA HYPERTENSION WITH HYDRALLAZINE

Structural changes in resistance vessels were studied by (a) hindquarter perfusion; and (b) planimetry of cross-sections of renal arterioles in uninephrectomized rats treated for 10 weeks with saline and either DOCA (deoxycorticosterone acetate), DOCA plus hydrallazine, vehicle plus hydrallazine or vehicle only. DOCA-treated rats developed hypertension and structural change. Addition of hydrallazine prevented both hypertension and the development of structural change. Structural arteriolar change in DOCA/salt hypertension is related to the high blood pressure or a closely associated factor rather than some other effect of DOCA.     

Mycophenolate mofetil improves renal haemodynamics,microvascular oxygenation,and inflammation in a rat model of supra‐renal aortic clamping‐mediated renal ischaemia reperfusion injury

Ischaemia/reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), which is characterized by sterile inflammation and oxidative stress. Immune cell activation can provoke overproduction of inflammatory mediators and reactive oxygen species (ROS), leading to perturbation of the microcirculation and tissue oxygenation associated with local and remote tissue injury. This study investigated whether the clinically employed immunosuppressant mycophenolate mofetil (MMF) was able to reduce I/R‐induced renal oxygenation defects and oxidative stress by preventing sterile inflammation. Rats were divided into three groups (n=6/group): (1) a sham‐operated control group; (2) a group subjected to renal I/R alone (I/R); and (3) a group subjected to I/R and MMF treatment (20 mg/kg prior to I/R) (I/R+MMF). Ischaemia was induced by a vascular occluder placed on the abdominal aorta for 30 minutes, followed by 120 minutes of reperfusion. Renal I/R deteriorated renal oxygenation (P<.001) and oxygen delivery (P<.01), reduced creatinine clearance (P<.01) and tubular sodium reabsorption (P<.001), and increased iNOS, renal tissue injury markers (P<.001), and IL‐6 (P<.001). Oral MMF administration prior to insult restored renal cortical oxygenation (P<.05) and iNOS, renal injury markers, and inflammation parameters (P<.001) to near‐baseline levels without affecting renal function. MMF exerted a prophylactic effect on renal microvascular oxygenation and abrogated tissue inflammation and renal injury following lower body I/R‐induced AKI. These findings may have clinical implications during major vascular or renal transplant surgery.     

The effects of acute citalopram dosing on gastric motor function and nutrient tolerance in healthy volunteers

Aliment Pharmacol Ther 2011; 33: 395–402

Summary

Background It is unclear whether endogenous serotonin release is involved in the regulation of gastric motility and food intake. Aim To study the effect of acute administration of the selective serotonin reuptake inhibitor citalopram on gastric motor function in man. Methods Nineteen healthy volunteers underwent a gastric barostat, gastric emptying and/or a drinking test after dosing with either placebo or citalopram (20 mg intravenously). In the barostat protocol, a flaccid bag was introduced in the stomach and inflated at intra‐abdominal pressure +2 mmHg, volume was recorded before and after administration of a liquid meal (300 kcal). Gastric emptying for solids and liquids was simultaneously assessed using the ¹⁴C‐octanoic acid/¹³C‐glycine breath test. During the drink test, volunteers drank at a rate of 15 mL/min until maximal satiation. Citalopram was compared with placebo using t‐tests and mixed model analysis. Results Citalopram induced a significant preprandial gastric relaxation (volume increase of 154 ± 55 mL vs. ?38 ± 33 mL after placebo dosing; P < 0.05), whereas the postprandial volume increase was significantly decreased after citalopram treatment (F_12.80 = 4.78, P < 0.0001; maximum volume increase was 304 ± 40 vs. 201 ± 54 mL after placebo and citalopram treatment respectively). Citalopram enhanced solid (123 ± 17 vs. 77 ± 6 min, P < 0.05) but not liquid emptying (62 ± 6 vs. 57 ± 4 min). Satiation scores during the drink test were lower after citalopram (F_19.153 = 2.02, P = 0.01; volunteers drank 998 ± 129 vs. 765 ± 79 mL after citalopram and placebo treatment respectively). Conclusion The observed effects indicate a role for serotonin in the control of gastric motility and food intake.

     

Pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, in spontaneously or DOCA-salt-induced hypertensive rats

Hypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20 mg/kg) to 6‐week‐old rats (with blood pressure within the normotensive range) and 16‐week‐old spontaneously hypertensive rats (SHRs) and their age‐matched control normotensive Kyoto–Wistar (KW) rats, and 16‐week‐old deoxycorticosterone acetate–salt‐induced hypertensive rats (DOCA–salt rats) and their age‐matched control Sprague–Dawley (SD) rats were compared. It was found that time‐averaged renal clearance (Cl_r) was of minor importance and that time‐averaged non‐renal clearance (Cl_nr) was dominant. In both 6‐ and 16‐week‐old SHRs, the Cl_nrs and areas under the curve (AUCs) of intravenous mirodenafil were significantly smaller and greater than those of the controls, but in 16‐week‐old DOCA–salt rats, they were comparable to the controls. Although the AUC of oral mirodenafil in 16‐week‐old SHRs was comparable to the controls, the Cl_nrs (or total body clearances, Cls) of intravenous mirodenafil and intestinal intrinsic clearances were significantly smaller than the controls and comparable to the controls for both 6‐ and 16‐week‐old SHRs, unlike in the 16‐week‐old DOCA–salt rats. The above data suggest that the significantly smaller Cl_nr and greater AUC of intravenous mirodenafil and comparable AUC of oral mirodenafil in 16‐week‐old SHR could be due to the hereditary characteristics of SHRs, and not due to the hypertensive state itself. Copyright © 2010 John Wiley & Sons, Ltd.     

Sodium Nitrite Prevents both Reductions in Circulating Nitric Oxide and Hypertension in 7‐Day Lead‐Treated Rats

Hypotensive effects of oral sodium nitrite have been reported as alternative sources of nitric oxide (NO) formation in animals and human beings. Reductions in NO bioavailability were observed in lead‐induced hypertension. However, no previous study has examined whether a single daily dose of sodium nitrite prevents the reductions in the NO bioavailability in lead‐induced hypertension. Then, we expanded previous reports and evaluated the effects of sodium nitrite in 7‐day lead‐treated rats. Wistar rats were divided into four experimental groups: Pb+sodium nitrite group received intraperitoneally (i.p.) 1st dose 8 µg/100 g of lead acetate and a subsequent dose of 0.1 µg/100 g, and daily treatment with sodium nitrite (45 mg/kg/day) or water (Pb group) by gavage for 7 days; Sodium nitrite group received i.p. 1st dose 8 µg/100 g of sodium acetate and a subsequent dose of 0.1 µg/100 g, and daily treatment with sodium nitrite (45 mg/kg/day) or water (saline group) by gavage for 7 days. Similar and higher whole‐blood lead levels (11.5 ± 1.2 and 13.2 ± 0.7 µg/dL) were found in lead‐exposed rats treated with either water or sodium nitrite (Pb or Pb+sodium nitrite, respectively; both p < 0.05 versus control groups). We found lower NO markers such as plasma nitrite and nitrite + nitrate (NOx) levels (both p < 0.05 versus controls) in lead‐exposed rats compared with normotensive (sodium acetate)‐treated controls (Pb group versus saline group; p < 0.05). Lead induced increases in systolic blood pressure (from 130 ± 2 to 164 ± 6 mmHg in Pb group; p < 0.05); however, both lead‐induced decreases in NO markers and hypertension (Pb+sodium nitrite group versus Pb group; both p < 0.05) were prevented by a single daily dose of sodium nitrite. In conclusion, these findings are consistent with the idea that impaired NO bioavailability contributes to the maintenance of elevated blood pressure in lead‐induced hypertension. Additionally, our results show that sodium nitrite exerts antihypertensive effects in lead‐induced hypertension and provide evidence that sodium nitrite prevents the impairment of NO, thus, reaffirming the relevance of nitrite as alternative source of recycling back to NO.     

香荚兰乙酮对DOCA盐高血压大鼠血压及大动脉结构的影响

目的观察香荚兰乙酮对醋酸脱氧皮质酮(DOCA)盐高血压大鼠血压及大动脉结构的影响。方法 34只SD大鼠分为假手术组(n=10),DOCA盐高血压模型组(模型组,n=13)和香荚兰乙酮治疗组(治疗组,n=11),模型组和治疗组大鼠于左肾切除术1 wk后开始给药(DOCA 12.5 mg.wk-1皮下注射,1%NaCl饮水;治疗组饮水中加入1.5 mmol.L-1香荚兰乙酮),共5 wk。所有动物在术后wk 2,4,6测定尾动脉血压;6 wk后通过超声活体观察颈总动脉内膜-中膜厚度(IMT),并取胸主动脉测定血管中层厚度。结果模型组大鼠血压呈逐步升高趋势,wk 6治疗组大鼠血压明显下降[(140.6±10.5)mmHg vs.(166.6±13.5)mmHg,P<0.01],胸主动脉中层厚度[(165.52±33.65)μm vs.(194.25±17.91)μm,P<0.05]及颈动脉IMT[(53.33±10.22)μm vs.(78.00±12.96)μm,P<0.05]均显著降低。结论香荚兰乙酮干预可明显降低DOCA盐高血压大鼠尾动脉血压,抑制颈动脉内IMT的增厚,降低胸主动脉中层厚度。     

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischaemia–reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR‐induced kidney injury. In euvolemic anaesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121 ± 2 to 144 ± 3 mmHg; P<.05), decreased glomerular filtration rate (GFR; 1.6 ± 0.3 to 0.5 ± 0.2 mL/min; P<.05) and increased urinary sodium excretion (UNaV; 14 ± 1 to 109 ± 25 mmol/L per hour; P<.05). In rats subjected to IR, autophagy induction, p‐mTOR expression and serum creatinine increased (1.9 ± 0.2 to 3 ± 0.3 mg/dL; P<.05); treatment with rapamycin blunted p‐mTOR expression but further increased autophagy induction and serum creatinine (3 ± 0.3 to 5 ± 0.6 mg/dL; P<.05). In contrast, clenbuterol, an mTOR activator, blunted the effect of rapamycin on serum creatinine (4 ± 0.6 vs 2.3 ± 0.3 mg/dL; P<.05), autophagy induction and p‐mTOR expression. IR also increased 24 hour protein excretion (9 ± 3 to 17 ± 2 mg/day; P<.05) and kidney injury molecule‐1 (KIM‐1) expression, and rapamycin treatment further increased KIM‐1 expression. Clenbuterol exacerbated protein excretion (13 ± 2 to 26 ± 4 mg/day; P<.05) and antagonized the effect of rapamycin on KIM‐1 expression. Histopathological data demonstrated kidney injury in IR rats that was worsened by rapamycin treatment but attenuated by clenbuterol treatment. Thus, mTOR signalling is crucial for normal kidney function and protecting the kidney against IR injury through autophagy suppression.     

Plasma catecholamines,noradrenaline metabolism and vascular response in desoxycorticosterone acetate hypertension of rats

Mineralocorticoid hypertension was induced in male Wistar rats by the injection of desoxycorticosterone acetate (DOCA) in oily solution (2×5 mg/kg daily for 7 days) and of desoxycorticosterone trimethylacetate in a microcrystalline suspension (15 mg/kg every third day for 4 weeks). A 1% NaCl solution or demineralized water was given as drinking fluid. Four weeks after the beginning of treatment, mean arterial blood pressure was 161±3.8 mmHg in DOCA-saline-treated and 140±5.9 mmHg in DOCA-water-treated rats. Basal plasma levels of noradrenaline and adrenaline did not differ in conscious, unrestrained DOCA-treated rats and in control rats, 3, 7 and 28 days after the beginning of hormone administration. Furosemide (50 mg/kg) caused within 30 min the same degree of diuresis and natriuresis in DOCA-treated and in control rats, but the plasma noradrenaline concentration in DOCA-treated rats rose to a higher level than in the controls. The isolated perfused hearts of rats which received DOCA for 7 and 28 days, respectively, had a reduced uptake of [³H]noradrenaline as compared to the controls. In isolated perfused hindlimb preparations from rats which had received DOCA for 7 days, the dose-response curve to noradrenaline but not that to KCl was shifted to the left. However, when DOCA and saline were given for 28 days, besides a higher sensitivity to noradrenaline an increased maximum response was observed with both noradrenaline and KCl. It is concluded that adrenergic tone is enhanced during the development of DOCA hypertension. Since the changes in the sympathetic nervous system in DOCA-water-treated rats, which had a less pronounced hypertension, were similar to those in DOCA-NaCl-treated rats, alterations in adrenergic vascular tone were not directly related to the level of the blood pressure.     

Alpha adrenergic activity and renal function in two-kidney deoxycorticosterone-acetate hypertensive swine

To evaluate the role of alpha-adrenergic activity in deoxycorticosterone-acetate (DOCA) hypertensive swine, eight two-kidney Yucatan miniature swine were implanted with DOCA silicone strips (100 mg/kg) for 12–16 weeks. Mean arterial pressure (MAP) in these animals increased progressively from control values of approximately 1 15 mm Hg to 173 ± 5 mm Hg. Treatment of four conscious animals with phenoxybenzamine (POB) (1 mg/kg) resulted in a significant decrease in MAP from 190 ± 3 to 157 ± 5 mm Hg (P < 0.05). This decline was due to a 21% decrease in total peripheral resistance (TPR) (P < 0.05), while cardiac output (CO) and heart rate (HR) remained unchanged. Pentobarbital anesthesia caused a small insignificant decrease in MAP to 165 ± 5 mm Hg. While under anesthesia, infusion of POB into the left renal artery (0.04 μg/kg/min) caused a slight increase in left renal blood flow (P > 0.05), without affecting MAP, HR, TPR, or CO. Left kidney urine flow and sodium excretion also increased during intra-renal POB infusion. Potassium excretion was unchanged and GFR decreased slightly. When POB (1 mg/kg) was infused systemically during anesthesia, MAP decreased to 82 ± 6 mmHg (P < 0.05). This was due to a 34% and 14% decrease in TPR and CO, respectively (P < 0.05). Whole animal urine flow, sodium excretion, and GFR all decreased significantly with systemic POB. These findings suggest that alpha-adrenergic activity plays a role in the maintenance MAP and the determination of renal function in DOCA hypertensive swine.     

ONSET AND OFFSET OF STRUCTURAL ARTERIOLAR CHANGES IN DOCA/SALT HYPERTENSION IN THE RAT

1.Structural changes in resistance vessels were studied sequentially (a) by hind-quarter perfusion and (b) by planimetry of renal arterioles ≤ 20 μm radius, for 10 weeks during development of DOCA (deoxycorticosterone acetate)/salt hypertension in uninephrectomized rats and 5 weeks after cessation of DOCA treatment. 2. Blood pressure and haemodynamically significant structural change increased progressively during DOCA treatment and both had partially reversed 5 weeks after cessation of DOCA. 3. Arteriolar structural changes contribute progressively to the hypertension during 10 weeks DOCA treatment. Partial reversal of structural changes contributes to the fall in blood pressure after cessation of DOCA. The persisting postDOCA hypertension can be attributed to relatively irreversible structural changes.     

Metformin prevents vascular prostanoid release alterations induced by a high‐fat diet in rats

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METABOLIC STUDIES OF URIDINE IN RATS WITH DOCA-SALT HYPERTENSION AND ON HIGH SODIUM DIET

1. The steady-state metabolic clearance and calculated secretion rate of the pyrimidine nucleoside uridine were studied by equilibrium infusion in normal rats, rats on a high sodium diet, rats made hypertensive by subcutaneous injection of deoxycorticosterone acetate (DOCA), unilateral nephrectomy and high sodium drinking fluid, and two control groups of rats for the hypertensive group. 2. Basal plasma uridine concentration in DOCA-salt hypertension rats was found to be significantly reduced to 3.99 ± 0.31 pmol/L (mean ± s.e.m.) compared with control rats (11.98 ±1.64 μmol/L). Metabolic clearance (MCR) in DOCA-salt hypertensive rats was significantly raised (200.54±10.77 mL/kg per min) compared with control rats (65.17 ± 1.99 mL/kg per min). No difference was found in plasma uridine concentration and MCR among the other two control groups and high sodium diet rats. Calculated secretion rate was unchanged in all animals. No significant differences were found between different groups of rats in blood pressure responses to uridine. 3. The raised metabolic clearance and reduced plasma uridine concentration in DOCA-salt hypertension may be consistent with increased intracellular transport and phosphorylation of uridine to the physiologically active compound uridine monophosphate (UMP) which would lead to arteriolar constriction, hypertension and natriuresis. The results contrast with those in humans with extracellular fluid (ECF) expansion from endstage renal failure and rats with one-kidney, one-clip (1K1C) hypertension but are not due to the pharmacological effects of deoxycorticosterone. The difference may be due to the haemodynamic consequences of reduced renal perfusion pressure or reduced renal mass compared with DOCA-salt model.     

The pharmacodynamics and pharmacokinetics of S‐tenatoprazole‐Na 30 mg, 60 mg and 90 mg vs. esomeprazole 40 mg in healthy male subjects

Aliment Pharmacol Ther 31 , 648–657

Summary

Background Racemic tenatoprazole 40 mg/day provides more prolonged acid suppression than esomeprazole 40 mg/day. Aim To compare pharmacodynamic and pharmacokinetic profiles of tenatoprazole and esomeprazole. Methods A single‐centre, double‐blind, double‐dummy, randomized, 4‐way, cross‐over study was conducted in 32 healthy male subjects. S‐tenatoprazole‐Na 30, 60 or 90 mg, or esomeprazole 40 mg was administered once daily for 5 days with 10‐day washout intervals. The 24‐h intragastric pH was recorded at baseline and on day 5 of each period. Results On day 5, median pH (5.34 ± 0.45 and 5.19 ± 0.52 vs. 4.76 ± 0.82, respectively, P < 0.002) and percentage time with pH > 4 (80 ± 11 and 77 ± 12, vs. 63 ± 11 respectively, P < 0.0001) for 24‐h were higher with S‐tenatoprazole‐Na 90 mg and 60 mg than esomeprazole. In nocturnal periods, S‐tenatoprazole‐Na 90 mg, 60 mg and 30 mg were superior to esomeprazole with regard to median pH (5.14 ± 0.64, 4.94 ± 0.65, 4.65 ± 0.86 and 3.69 ± 1.18 respectively, P < 0.0001) and percentage time with pH > 4 (77 ± 12, 73 ± 17, 64 ± 17 and 46 ± 17 respectively, P < 0.0001). Proportion of subjects with nocturnal acid breakthrough with S‐tenatoprazole‐Na 90 mg, 60 mg and 30 mg was significantly less than with esomeprazole (54.8, 43.3, 56.7 and 90.3 respectively, P < 0.04). The proportion of subjects with >16 hrs with pH >4 was significantly higher with S‐tenatoprazole‐Na 90 mg and 60 mg than with esomeprazole (87.1%, 83.3% and 41.9% respectively, P < 0.02). Conclusions S‐tenatoprazole‐Na produced significantly greater and more prolonged dose‐dependent 24‐h and nocturnal acid suppression than esomeprazole. S‐tenatoprazole‐Na may provide greater clinical efficacy compared with current PPIs for patients with ineffective once‐daily therapy.