Effects of sildenafil on nanostructural and nanomechanical changes in mitochondria in an ischaemia‐reperfusion rat model

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP‐sensitive potassium channels to attenuate ischaemia–reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil‐mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague‐Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham‐operated rats (control; n = 5); (ii) IR‐injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR‐injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil‐treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil‐treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm², respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm²; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.     

Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg(-1)) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140+/-52 vs 437+/-127% and episodes of ventricular tachycardia 4.0+/-3.2 vs 19.3+/-7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.     

Role of endothelium in ischaemia‐induced myocardial dysfunction of isolated working hearts: cardioprotection by activation of adenosine A2A receptors

1 This study aimed to determine the role of the vascular endothelium on recovery of contractile function following global low‐flow ischaemia of guinea‐pig isolated working hearts and the effects of adenosine analogues on this recovery. 2 Guinea‐pig isolated spontaneously beating or paced working hearts were set up and coronary flow (CF), aortic output (AO) (as an index of cardiac function), heart rate (HR), left ventricular pressure (LVP) and dP/dt max recorded. The endothelium was either intact or removed by a blast of oxygen. 3 In spontaneously beating hearts, low‐flow ischaemia for 30 min reduced CF and cardiac contractility (LVP, dP/dt max) but not AO. On reperfusion, CF, LVP and dP/dt max recovered, while AO fell precipitously followed by a gradual recovery, indicative of myocardial stunning. The effects of ischaemia did not differ between endothelium‐intact and ‐denuded hearts, indicating no role of the endothelium in the changes observed. 4 The adenosine analogues, N⁶‐cyclopentyladenosine (CPA, A₁ selective), 5'‐N‐ethylcarboxamidoadenosine (NECA, two‐fold A₂ selective over A₁) and 2‐p‐((carboxyethyl)‐phenethylamino)‐5'carboxamidoadenosine (CGS21680, A_2A selective) were infused (3 × 10^?7 M ) from 10 min into the 30‐min low‐flow ischaemia of denuded hearts and during reperfusion. 5 CGS21680 increased CF and improved the postischaemic functional recovery, as measured by the AO. NECA and CPA were not cardioprotective. The A_2A selective antagonist, ZM241385, attenuated the coronary vasodilatation by CGS21680 and abolished the improved recovery of AO on reperfusion. 6 Reperfusion of paced working hearts caused a dramatic fall in AO which failed to recover. Infusion of CGS21680 from 15 min into the ischaemic period produced vasodilatation but failed to restore AO, presumably because the ischaemic damage was irreversible. 7 Thus, the endothelium plays no role in myocardial dysfunction following low‐flow global ischaemia and reperfusion of guinea‐pig working hearts. The A_2A adenosine receptor‐selective agonist but not the non‐selective A₂ receptor agonist, NECA, attenuated ischaemia‐ and reperfusion‐induced stunning. This was attributed to increased CF and was independent of the endothelium.     

Reperfusion Therapy with Low‐Dose Insulin or Insulin‐Like Growth Factor 2; Myocardial Function and Infarct Size in a Porcine Model of Ischaemia and Reperfusion

In an open‐chest porcine model, we examined whether myocardial pharmacological conditioning at the time of reperfusion with low‐dose insulin or insulin‐like growth factor 2 (IGF2), not affecting serum glucose levels, could reduce infarct size and improve functional recovery. Two groups of anaesthetized pigs with either 60 or 40 min. of left anterior descending artery occlusion (total n = 42) were randomized to receive either 0.9% saline, insulin or IGF2 infusion for 15 min., starting 5 min. before a 180‐min. reperfusion period. Repeated fluorescent microsphere injections were used to confirm ischaemia and reperfusion. Area at risk and infarct size was determined with Evans blue and triphenyltetrazolium chloride staining. Local myocardial function was evaluated with multi‐layer radial tissue Doppler strain and speckle‐tracking strain from epicardial echocardiography. Western blotting and TUNEL staining were performed to explore apoptosis. Infarct size did not differ between treatment groups and was 56.7 ± 6.8%, 49.7 ± 9.6%, 56.2 ± 8.0% of area at risk for control, insulin and IGF2 group, respectively, in the 60‐min. occlusion series. Corresponding values were 45.6 ± 6.0%, 48.4 ± 7.2% and 34.1 ± 5.8% after 40‐min. occlusion. Global and local cardiac function did not differ between treatment groups. No differences related to treatment could be found in myocardial tissue cleaved caspase‐3 content or the degree of TUNEL staining. Reperfusion therapy with low‐dose insulin or with IGF2 neither reduced infarct size nor improved function in reperfused myocardium in this in vivo porcine model.     

Remote ischaemic preconditioning modifies serum apolipoprotein D,met‐enkephalin,adenosine, and nitric oxide in healthy young adults

Remote ischaemic preconditioning (RIPC) has been employed as a non‐invasive protective intervention against myocardial ischaemia–reperfusion injury in animal studies. However, the underlying mechanisms are incompletely defined in humans and its clinical efficacy has been inconclusive. As advanced age, disease, and drugs may confound RIPC mechanisms in patients, our aim is to measure whether RIPC evokes release of adenosine, bradykinin, met‐enkephalin, nitric oxide, and apolipoproteins in healthy young adults. Healthy subjects (n = 18, 9 males, 23 ± 1.5 years old; 9 females, 23 ± 1.8 years old) participated after informed consent. RIPC was applied using a blood pressure cuff to the dominant arms for four cycles of 5‐minute cuff inflation (ischaemia) and 5‐minute cuff deflation (reperfusion). Blood was sampled at baseline and immediately after the final cuff deflation (Post‐RIPC). Baseline and Post‐RIPC plasma levels of adenosine, bradykinin, met‐enkephalin, apolipoprotein A‐1 (ApoA‐1), apolipoprotein D (ApoD), and nitric oxide (as nitrite) were measured via ELISA and high‐performance liquid chromatography. Mean (±SD) baseline levels of adenosine, bradykinin, met‐enkephalin, ApoA‐1, ApoD, and nitrite in healthy young adults were 13.8 ± 6.5 ng/mL, 2.6 ± 1.9 μg/mL, 594.1 ± 197.4 pg/mL, 3.0 ± 0.7 mg/mL, 22.2 ± 4.0 μg/mL, and 49.8 ± 13.4 nmol/L, respectively. Post‐RIPC adenosine and nitrite levels increased (59.5 ± 37.9%, P < .0001; 32.2 ± 19.5%, P < .0001), whereas met‐enkephalin and ApoD levels marginally decreased (5.3 ± 14.0%, P = .04; 10.8 ± 20.5%, P = .04). Post‐RIPC levels were not influenced by sex, age, blood pressure, waist circumference, or BMI. RIPC produces increased levels of adenosine and nitrites, and decreased met‐enkephalin and ApoD in the plasma of young healthy adults.     

Safety,Tolerability, Pharmacokinetics and Pharmacodynamics of Recombinant Human Parathyroid Hormone after Single‐ and Multiple‐Dose Subcutaneous Administration in Healthy Chinese Volunteers

Abstract: Recombinant human parathyroid hormone [rhPTH(1–84)] represents a new class of anabolic agents for the treatment of osteoporosis. The present study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of rhPTH(1–84) after single‐ and multiple‐dose subcutaneous administration in healthy Chinese volunteers. Six cohorts of 32 volunteers received a single dose of rhPTH(1–84) at 0.5–5.0 μg/kg, and two cohorts of 12 volunteers received 2.0 and 3.0 μg/kg of rhPTH(1–84) once daily for 7 consecutive days to assess its safety and tolerability. The results indicated that rhPTH(1–84) appeared to be safe and well tolerated. Additionally, pharmacokinetics of rhPTH(1–84) and its active N‐terminal fragment rhPTH(1–34) were investigated after administration of single 1.0, 2.0 and 4.0 μg/kg doses of rhPTH(1–84) in 30 other volunteers and after multiple doses of 2.0 μg/kg once daily for 7 consecutive days. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after subcutaneous administration of a single dose of 1.0, 2.0 and 4.0 μg/kg were as follows: C_max = (110.54 ± 59.18), (149.70 ± 50.61) and (372.52 ± 94.96) pg/mL; (53.93 ± 6.27), (61.12 ± 11.28) and (89.04 ± 7.08) pg/mL, respectively. AUC_0–10 = (268.87 ± 47.72), (538.93 ± 146.89) and (1364.11 ± 176.82) pg hr/mL; (197.20 ± 50.78), (207.15 ± 72.08) and (344.05 ± 77.06) pg hr/mL, respectively. t_1/2 = (2.34 ± 1.93), (2.58 ± 1.18) and (2.74 ± 1.31) hr; (3.37 ± 1.82), (4.39 ± 3.79), and (3.99 ± 1.85) hr, respectively. Plasma C_max and AUC values of rhPTH(1–84) and rhPTH(1–34) were found to be dose proportional. The pharmacokinetic parameters for rhPTH(1–84) and rhPTH(1–34) after administration of multiple doses of 2.0 μg/kg were as follows: C_{ss_max} = (164.96 ± 52.61) and (75.05 ± 7.31) pg/mL; C_{ss_min} = (6.99 ± 7.73) and (2.05 ± 2.82) pg/mL; AUC_ss = (567.26 ± 118.41) and (306.02 ± 77.55) pg hr/mL; t_1/2 = (1.81 ± 0.89) and (2.27 ± 1.11) hr; DF = (6.93 ± 2.64) and (6.00 ± 1.37), respectively. After multiple doses, the pharmacokinetic parameters for rhPTH(1–84) were consistent with those after single dose. However, the mean C_max and AUC_0–10 of rhPTH(1–34) after multiple dosing were significantly higher than the corresponding values obtained after single‐dose administration. Serum total calcium and phosphate concentrations increased and decreased significantly at 4 hr post‐dosing, respectively.     

Unravelling the cardiovascular effects induced by α‐terpineol: A role for the nitric oxide–cGMP pathway

1. α‐Terpineol is a monoterpene found in the essential oils of several aromatic plant species. In the present study, we investigated the mechanisms underlying the cardiovascular changes induced by α‐terpineol in rats. 2. In normotensive rats, administration of α‐terpineol (1, 5, 10, 20 and 30 mg/kg, i.v.) produced a dose‐dependent hypotension (?10 ± 3, ?20 ± 8, ?39 ± 16, ?52 ± 21 and ?57 ± 23 mmHg, respectively; n = 5) followed by tachycardia. The hypotensive responses to 1, 5, 10, 20 and 30 mg/kg, i.v., α‐terpineol were significantly attenuated following the administration of N^G‐nitro‐l‐ arginine methyl ester (l ‐NAME; 20 mg/kg, i.v.; ?2 ± 1, ?5 ± 2, ?7 ± 3, ?22 ± 9 and ?22 ± 10 mmHg, respectively; P < 0.05; n = 5). 3. In 10 μmol/L phenylephrine (PE)‐precontracted mesenteric artery rings, α‐terpineol (10^?12 to 10^?5 mol/L) caused a concentration‐dependent relaxation (maximum relaxation 61 ± 6%; n = 7). After removal of the endothelium, the vasorelaxation elicited by α‐terpineol was attenuated (maximum relaxation 20 ± 1%; P < 0.05; n = 7). In addition, vasorelaxation induced by α‐terpineol in rings pretreated with 100 or 300 μmol/L l ‐NAME, 30 μmol/L hydroxocobalamin or 10 μmol/L 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one was attenuated (maximum relaxation 18 ± 3, 23 ± 3, 24 ± 7 and 21 ± 1%, respectively; n = 6; P < 0.05). 4. Furthermore, in a rabbit aortic endothelial cell line, 10^?6, 10^?5 and 10^?4 mol/L α‐terpineol induced concentration‐dependent increases in nitric oxide (NO) levels (12 ± 6, 18 ± 9 and 34 ± 12%Δ fluorescence, respectively; n = 3). 5. In conclusion, using combined functional and biochemical approaches in the present study, we were able to demonstrate that α‐terpineol‐induced hypotension and vasorelaxation are mediated, at least in part, by the endothelium, most likely via NO release and activation of the NO–cGMP pathway.     

Effects of fatty acids on cardioprotection by pre‐ischaemic inhibition of the malate–aspartate shuttle

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Endothelial cationic amino acid transporter‐1 overexpression blunts the effects of oxidative stress on pressor responses to behavioural stress in mice

Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of l ‐arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild‐type (WT; n = 6) and endothelial cationic amino acid transporter‐1 (CAT‐1)‐overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non‐aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg/kg per day; 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11–12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively; P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg; P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT‐1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.     

Effect of continuous infusion of asialoerythropoietin on short‐term changes in infarct volume,penumbra apoptosis and behaviour following middle cerebral artery occlusion in rats

1. Asialoerythropoietin (aEPO), a derivative of cytokine erythropoietin, has been shown to have neuroprotective effects without haematological complications when administered in single or repeated doses. The present study examines our hypothesis that aEPO may provide neuroprotection against programmed apoptotic cell death when administered in a continuous low dose. 2. Focal cerebral ischaemia was introduced by occlusion of the middle cerebral artery using a surgically placed intraluminal filament in young male Sprague Dawley rats (9 weeks old). After 90 min ischaemia, reperfusion was established by filament removal. Both study and control groups had implanted osmotic minipumps through which they received either aEPO (1 μL/h; 20 μg/kg per 24 h) or normal saline (1 μL/h) for 4 days. On Day 4, infarct volume, the number of apoptotic cells and concentrations of activated caspase 3 and 9 were evaluated in the penumbra region. 3. Asialoerythropoietin was detected in the cerebrospinal fluid of the study group, whereas none was detected in the control group. Although there were no significant changes in haematocrit levels or behaviour scores (on Days 1 and 4) between the study and control groups, aEPO administration significantly reduced infarct volume in the study group compared with the control group (168 ± 19 vs 249 ± 28 mm³, respectively; P < 0.05). 4. The number of terminal deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling (TUNEL)‐positive cells and the concentration of activated caspase 3 and 9 in the penumbra region were significantly lower in the study group compared with the control group. 5. In conclusion, our data suggest that aEPO provides a short‐term, possibly histological, protection in young adult male rats when administered immediately after reperfusion.     

THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

ISCHAEMIC POST-CONDITIONING PROTECTS BOTH ADULT AND AGED SPRAGUE-DAWLEY RAT HEART FROM ISCHAEMIA–REPERFUSION INJURY THROUGH THE PHOSPHATIDYLINOSITOL 3-KINASE–AKT AND GLYCOGEN SYNTHASE KINASE-3β PATHWAYS

• 1 Numerous studies have demonstrated that ischaemic post‐conditioning (IPoC) protects adult rats from myocardial ischaemia‐reperfusion (I/R) injury. Recent evidence suggests compromised cardioprotection by IPoC in aged mice. The present study was designed to test the hypothesis that IPoC protects against I/R injury in aged hearts, potentially through a phosphatidylinositol 3‐kinase (PI3‐K)–Akt‐ and glycogen synthase kinase (GSK)‐3β‐dependent mechanism.
• 2 Hearts from adult (3–4 months) or aged (16–18 months) Sprague‐Dawley rats were subjected in vivo to 30 min ischaemia followed by 3 h reperfusion. Ischaemic post‐conditioning (four cycles of 10 s reperfusion–10 s ischaemia) was applied at the beginning of reperfusion, either alone or in combination with the PI3‐K inhibitor LY294002 (0.3 mg/kg). Infarct size and the phosphorylation of Akt and GSK‐3β were determined.
• 3 Ischaemic post‐conditioning reduced infarct size in both adult and aged rat hearts. This protection was accompanied by a significant increase in phosphorylation of Akt and GSK‐3β. LY294002 abolished the IPoC‐induced phosphorylation of Akt and GSK‐3β, as well as the infarct‐limiting effect of IPoC in adult and aged rats. In addition, IPoC significantly attenuated plasma concentrations of creatine kinase and lactate dehydrogenase after reperfusion in both adult and aged rats.
• 4 In conclusion, IPoC, at the onset of reperfusion, reduces myocardial infarct size in both adult and aged rat hearts, potentially through a PI3‐K‐, Akt‐ and GSK‐3β‐dependent mechanism.

     

Human muscle sympathetic nerve responses to urocortin‐2 in health and stable heart failure

Sympatholytic and vasodilator drugs have been of major therapeutic benefit in patients with heart failure (HF). Urocortin‐2 (Ucn2) is a small corticotrophin‐related peptide distributed throughout the cardiovascular system which inhibits cardiac sympathetic nerve activity (CSNA) and is also a powerful vasodilator. This study analysed the effects of a 60‐min infusion of Ucn2 (25 μg) on muscle sympathetic nerve activity (MSNA) recorded from the lower limb in eight healthy men and four men with stable HF. During Ucn2 infusion, mean arterial pressure fell to a nadir of 84 ± 2 compared to 95 ± 2 mmHg during placebo (P = 0.001) and heart rate increased to a maximum of 74 ± 1 compared to 64 ± 1 b.p.m. (P < 0.001). Total peripheral resistance fell by 23 ± 4% compared with an increase of 23 ± 4% (P < 0.001) and cardiac output increased by 22 ± 4 compared to 4 ± 4% (P = 0.001). The MSNA burst frequency increased by 9 ± 2 compared to 1 ± 2 burst/min (P = 0.005) and burst area/min by 133 ± 7 vs 107 ± 7% (P = 0.01). Burst incidence and baroreflex sensitivity were not significantly altered. Qualitatively similar changes were observed in stable HF patients. Ucn2‐induced vasodilatation increased MSNA in humans, as opposed to the decrease in CSNA we observed in sheep. Therefore, if Ucn2 has a central inhibitory effect on MSNA, it was over‐run by off‐loading the cardiovagal baroreflex. Alternatively, CSNA may be less responsive to baroreflex off‐loading than MSNA.     

Efficacy of perioperative dexmedetomidine in postoperative neurocognitive function: a meta‐analysis

Neuroprotective effects of dexmedetomidine are reported in preclinical and clinical studies but evidence regarding the postoperative neurocognitive function is not as clear. This study performed a meta‐analysis on outcomes of studies which examined neurocognitive performance by using valid assessment tools before and after perioperative dexmedetomidine treatment. Literature was searched in several electronic databases and studies were selected by following précised inclusion criteria. Meta‐analyses of mean differences in percent changes from baseline in neurocognitive assessment scores were carried out and subgroup analyses were performed. Eighteen studies were included. Initial dose of dexmedetomidine (mean ± SD) was 1.28 ± 0.97 μg/kg and maintenance dose was 0.41 ± 0.11 μg/kg per hour. In healthy volunteers, there was no significant difference in the neurocognitive performance between dexmedetomidine and controls/comparators (mean difference (95% confidence interval (CI)): ?12.72 (?50.25, 24.80) %; P = 0.51). Perioperative dexmedetomidine treatment was associated with significantly better neurocognitive performance in comparison with saline (mean difference (95% CI): 9.10 (3.03, 15.16) %; P = 0.003) as well as with comparator anaesthetics (mean difference: 5.50 (0.15, 10.86) %; P = 0.04) treated patients. In the submeta‐analyses of studies which utilized neurocognitive assessment tools other than Mini‐Mental State Examination (mean difference: 6.66 (–3.42, 16.74); P = 0.20) or studies with patients under 60 years of age (mean difference: 7.48 (?3.00, 17.96); P = 0.16), the differences were not significant between dexmedetomidine‐ and saline‐/comparator‐treated patients. Perioperative dexmedetomidine treatment is associated with significantly better neurocognitive function postoperatively in comparison with both saline controls and comparator anaesthetics (predominantly midazolam).     

Wall tension and contraction of the aorta in 6‐month‐old spontaneously hypertensive rats

1 The present study aimed at comparing the influence of passive tension on the effect exerted by noradrenaline on the thoracic aorta of 6‐month‐old Wistar and spontaneously hypertensive rats (SHR). 2 Concentration–response curves to noradrenaline were obtained in aorta rings, at two levels of passive tension: 3 and 0.5 g. 3 The maximal responses (in percentage of the maximal response to noradrenaline obtained in the beginning of the experiment at a tension of 2 g) were significantly larger (P < 0.05) at 3 g than at 0.5 g in both kinds of rats: 171 versus 69%, respectively, for SHR; 139 versus 76%, respectively, for Wistar rats. 4 When expressed as mg of active tension per mg of tissue, the maximal contraction at both 3 and 0.5 g was smaller in SHR than in Wistar rats (at 3 g: 64.6 ± 6.7, n=6 versus 122.3 ± 19.1, n=8, respectively, P < 0.05; at 0.5 g: 24.0 ± 1.0, n=6 versus 49.0 ± 5.9, n=8, respectively, P < 0.05). 5 Maximal responses to noradrenaline were markedly decreased by cytochalasin B (50 μM ) (to 15.2 ± 6.0%, n=6, at 3 g and 2.8 ± 1.9%, n=6, at 0.5 g in SHR; to 11.8 ± 2.3%, n=4, at 3 g and 4.3 ± 1.3%, n=4, at 0.5 g in Wistar rats). Cytochalasin B at a lower concentration (4 μM ) produced a less marked decrease in responses to noradrenaline in both strains of rats. The presence of cardiovascular structural changes in SHR was confirmed by the fact that the heart weight (mg):body weight (g) was higher in SHR (3.37 ± 0.06, n=10) than in Wistar rats (2.40 ± 0.12, n=11) (P < 0.05). 6 It is concluded that in 6‐month‐old SHR the contractile capacity of the aortic tissue is reduced. However, the differential sensitivity of aortic smooth muscle at the two different levels of tension remains present. This difference may depend on filament interaction. Contractions to noradrenaline in the rat aorta are highly dependent on actin polymerization.     

Remote per‐conditioning reduces oxidative stress,downregulates cyclo‐oxygenase‐2 expression and attenuates ischaemia–reperfusion‐induced acute kidney injury

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Surgery‐induced changes in rat IL‐1β and acetylcholine metabolism: role of physostigmine

Pharmacological enhancement of cholinergic activity following administration of physostigmine is known to induce protective effects generally. However, it is unclear whether the effect of physostigmine on inflammation and acetylcholine (ACh) metabolism is related to different types of surgical intervention or anaesthesia alone. To investigate this, rats were subjected to partial liver resection (PLR) or sham surgery, with a control group receiving anaesthesia alone. Half of each treatment group received a single intra‐operative dose of physostigmine (0.04 mg/kg); the others received placebo. Acetylcholinesterase (AChE) activity and plasma and brain concentrations of interleukin (IL)‐1β and ACh were determined. Both PLR and sham operation induced a time‐dependent increase in plasma concentrations of IL‐1β compared with rats receiving anaesthesia alone (3.9‐ and 4.8‐fold increases, respectively). In the brain, IL‐1β concentrations had increased approximately twofold after surgery compared with the control group. Blood AChE was transiently decreased after surgery. Brain AChE activity increased 1.3‐fold (P = 0.014) only after PLR; consequently, cerebral ACh concentrations were significantly reduced. Physostigmine administration significantly reduced IL‐1β and AChE levels. Cerebral ACh concentrations were markedly increased from 544 ± 122 ng/mg protein following placebo administration to 654 ± 93 ng/mg protein after physostigmine administrations (P < 0.001). We conclude that a single dose of physostigmine intra‐operatively has a sustained anti‐inflammatory effect (up to 120 min after injection) that is especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts a neuroprotective action by increasing levels of the neurotransmitter ACh.     

LONG-TERM OUABAIN ADMINISTRATION DOES NOT ALTER BLOOD PRESSURE IN CONSCIOUS SPRAGUE-DAWLEY RATS

1. We tested the ability of ouabain to cause chronic hyper tension by continuously infusing ouabain for 28 days (mini-osmotic pump implantation; i.p.). The blood pressure and metabolic effects of sham (150 mmol/L NaCI; n= 12) or ouabain infusion (10 μg/kg per day; n= 14; 100 μg/kg per day; n = 14) were examined in conscious Sprague-Dawley rats. 2. Plasma ouabain concentrations measured after 28 days of ouabain infusion were as follows: sham, not detectable (n= 11); ouabain 10 μg/kg per day, 0.60 ± 0.07 nmol/L (n= 14); and ouabain 100 μg/kg per day, 7.17 ± 0.57 nmol/L (n= 14; P < 0.001). 3. Sham or ouabain infusion did not alter food intake, bodyweight, water intake or urine output in conscious rats. 4. Blood pressure was not altered by sham treatment. Ouabain at 10 μg/kg per day or 100 μg/kg per day did not produce consistent rises in blood pressure. Ouabain at 10 μg/kg per day increased blood pressure on treatment day 12 only (+ 6mmHg; P < 0.05), while at 100μg/kg per day blood pres sure increased on treatment days 16 (+ 9 mmHg; P < 0.05) and day 18 (+ 8mmHg; P < 0.05) only. There was no significant difference in blood pressure between sham and ouabain groups. 5. Renal blood flow was decreased in rats infused with ouabain at 10 μg/kg per day (2.0 ± 0.3 mL/min per 100 g body-weight; n= 5; P < 0.01) and 100 μg/kg per day (2.2 ± 0.4 mL/ min per 100 g bodyweight; n= 7; P < 0.05) compared with sham treatment (3.5 ± 0.2 mL/min per 100 g bodyweight; n= 6). Renal vascular resistance was increased in rats treated with ouabain at 10 μg/kg per day (65.5 ± 12.6 mmHg/mL per min per 100 g bodyweight; n= 5; P < 0.01) and 100 μg/kg per day (66.0 ± 15.6 mmHg/mL per min per 100 g bodyweight; n= 7; P < 0.05) compared with sham treatment (32.6 ± 2.5 mmHg/mL per min per 100 g bodyweight; n= 6). 6. High plasma concentrations of ouabain do not cause consistent increases in blood pressure in conscious Sprague-Dawley rats.     

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.