EFFECTS OF MEXILETINE ON TRANSMEMBRANE ACTION POTENTIALS AS AFFECTED BY EXTERNAL POTASSIUM CONCENTRATION AND BY RATE OF STIMULATION IN GUINEA-PIG PAPILLARY MUSCLES

1. The effects of mexiletine and quinidine were compared on transmembrane potentials in guinea-pig papillary muscles, using conventional microelectrode techniques. 2. Mexiletine (23–1 μ mol/1) decreased the maximum rate of rise of the action potential (V?max) and increased the ratio of the effective refractory period to the action potential duration at 90% repolarization level (ERP/APD90); these effects were prominent with elevation of the external potassium concentration ([K]_o) from 2–7 to 5–4, 81 and 100mmol/1. 3. The percentage decrease in V?max induced by 5 and 10 μmol/1 of quinidine was approximately constant in 2–7, 5–4 and 100 mmol/1 [K]_o solutions. 4. The decrease in V?max produced by mexiletine was progressively increased as the driving rate was raised from 0–25 to 5H z. This rate-dependent change was pronounced when the concentration was raised from 23–1 to 46–2 and 92–4 /μmol/1. 5. Mexiletine in concentrations of 23–1 and 92–4 μ miol/1 delayed the recovery of V?max in a premature action potential to the level of V?max in the conditioning action potentials at the driving rate of 0–25 Hz. 6. It appears that mexiletine exerts its anti-arrhythmic action by a selective depressant effect on depolarized cells (high [K]_o) and cells with high frequency discharges, as is the case with lignocaine.     

BLOOD FLOW AND RELATIVE TISSUE OXYGENATION OF NORMAL AND PARTIALLY ISCHAEMIC MYOCARDIUM: EFFECT OF CO2

1. Ischaemia of a portion of the myocardium in the dog heart was produced by tying off a small branch of a coronary artery: flow in the occluded region was reduced from 5 to 82% of the initial value. 2. The effect of inhalation of 5% CO₂ in air on relative tissue PO₂ and perfusion in normal and partially ischaemic myocardium was determined. 3. After 10 min inhalation of 5% CO₂, there was an increase in tissue perfusion as measured by hydrogen desaturation; the increase was inversely proportional to the degree of flow reduction. 4. Relative intramyocardial P_O² measured polarographicafly, decreased with occlusion and increased after CO₂ inhalation; the changes were inversely proportional to the degree of reduction in Po₂ 5. The increase in flow after CO₂ inhalation suggests that partially ischaemic myocardial tissue is capable of further vasodilation.     

HYPOXIC INHIBITION OF BREATHING AND MOTOR ACTIVITY IN THE FOETUS AND NEWBORN

In fetal animals hypoxia of rapid onset causes cessation of breathing movements, electro-ocular activity and decrease of muscle tone. These effects last several hours and are in contrast to the hypernoea and behavioural activation which occurs during hypoxia soon after birth and in the adult. Transection and lesion studies in fetal sheep suggest that hypoxia activates a descending inhibition of respiratory and other motor activities which either originates in the pons or is conveyed to medullary and spinal levels of the neuraxis by fibres through the pons in the region of the Kolliker-Fuse nucleus. Recently, using FOS immunohistochemistry we have identified cells in the medial parabrachial complex which are activated by hypoxia in fetal sheep, but not newborn lambs. It is proposed that these cells have descending inhibitory connections with respiratory and spinal motor pathways, but the precise anatomy and neuro-chemistry of such pathways is unknown. It is not known if the parabrachial cells are directly sensitive to low P o₂ or receive input from other centres or peripheral receptors which monitor arterial P o₂ in the foetus. Nor is it known why these cells are not activated by low P o₂ after birth.     

EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP

1. The angiotensin type 1 (AT₁) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P < 0.05), fetal PO₂ decreased (P < 0.01), PCO₂ did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT₁ receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

The effects of cibenzoline,an imidazoline derivative with antiarrhythmic properties,on systemic hemodynamics and regional myocardial performance

The effects of increasing doses of cibenzoline (-2(2,2-diphenylcyclopropyl)-2-imidazoline, Cipralan), a new compound with antiarrhythmic properties, on systemic hemodynamics and regional myocardial performance were studied in anesthetized pigs. Doses of 0.5–2.0 mg kg^?1 i.v. produced a 10–15% prolongation of the PP' interval, and a dose-dependent increase (up to 60%) in QRS width, with only minor changes in PQ and ST length. Stroke volume decreased dose dependently (20–35%) immediately after drug administration, due to a decrease in myocardial contractility and an increase in systemic vascular resistance. Renal blood flow was unchanged, despite the decrease in cardiac output. Coronary blood flow decreased, while myocardial O₂ extraction was unchanged. Hence myocardial O₂ consumption decreased parallel to the decrease in flow, a consequence of the lowered myocardial O₂ demand. Studies with radioactively labeled microspheres revealed that the decrease in myocardial blood flow was equally distributed over the transmural layers.     

ALTERATIONS IN FETAL URINE PRODUCTION DURING PROLONGED HYPOXAEMIA INDUCED BY REDUCED UTERINE BLOOD FLOW IN SHEEP: MECHANISMS

• 1 Our aim was to identify mechanisms whereby prolonged fetal hypoxaemia alters renal function and urine production in fetal sheep.
• 2 Fetal hypoxaemia was induced for 24 h by reducing uterine blood flow at 129.0±2.1 days of gestation (term 145–147 days), causing a reduction in fetal arterial O₂ saturation (SaO₂) from 52.5±2.3 to 22.0±1.3% (P<0.05). This hypoxaemia was initially associated with a mild acidaemia (pH 7.23±0.03).
• 3 The glomerular filtration rate (GFR) increased from a control value of 1.8±0.03 mL/min per kg to a maximal value of 2.8±0.6mL/min per kg (P<0.05) at 4–5 h of hypoxaemia, returning to control levels by 6–9 h of hypoxaemia. After 4 h of hypoxaemia renal blood flow was no different to control values (144±8 mL/min per 100 g kidney weight) but after 24 h of hypoxaemia it had increased to 190±8 mL/min per 100 g kidney weight (P<0.05). Fractional reabsorption of Na⁺ in the proximal tubules decreased from a control value of 81.5±2.2 to 65.2±3.9% at 2–3 h of hypoxaemia (P<0.05) and remained reduced (68.5±3.1%) at the end of hypoxaemia (P<0.05). Fetal mean arterial pressure transiently increased (P<0.05) but returned to control values by 4–5 h of hypoxaemia. Fetal renal vascular resistance was not significantly altered during hypoxaemia. Fetal urine production increased from a control value of 12.3±2.1 mL/h per kg to a maximal value of 19.1±4.2 mL/h per kg at 4–5 h of hypoxaemia (P<0.05) and returned to control by 24 h of hypoxaemia.
• 4 Our results indicate that prolonged fetal hypoxaemia leads to the inhibition of Na⁺ reabsorption in the proximal portion of the renal tubules. Changes in GFR induced by hypoxaemia were similar to those in fetal urine production and were not associated with changes in renal blood flow. We conclude that prolonged fetal hypoxaemia affects renal haemodynamics and the reabsorptive capacity of the renal tubules, resulting in a diuresis.

     

ACUTE EFFECTS OF ORAL GLIBENCLAMIDE ON BLOOD PRESSURE AND FOREARM VASCULAR RESISTANCE IN DIABETICS

1. To determine the effects of an acute oral dose of glibencla-mide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K⁺_ATP channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75–30 mg/kg per min) and noradrenaline (25–100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K⁺ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.     

EFFECTS OF 1400W AND/OR NITROGLYCERIN ON RENAL OXYGENATION AND KIDNEY FUNCTION DURING ENDOTOXAEMIA IN ANAESTHETIZED RATS

• 1 The pathogenesis of acute renal failure (ARF) in sepsis is multifactorial. The role of nitric oxide (NO) in septic ARF has been a source of controversy. We hypothesized that endotoxaemia‐induced exacerbation of inducible nitric oxide synthase (iNOS)‐related NO release impairs renal oxygenation and contributes to ARF in anaesthetized rats.
• 2 In the present study, rats received lipopolysaccharide (2.5 mg/kg) for 30 min. Two hours later, fluid resuscitation was started (HES130; 5 mL/kg per h after a 5 mL/kg bolus) supplemented either by the NO donor nitroglycerin (NTG; 0.5 µg/kg per min after a 2 µg/kg bolus), the selective iNOS inhibitor 1400W (3 mg/kg per h after a 3 mg/kg bolus) or both. Systemic haemodynamics and renal microvascular Po ₂ (µPo ₂) were recorded continuously. Furthermore, creatinine clearance, plasma NO_x (nitrate + nitrite + S‐nitrosothiols) levels and the expression of iNOS mRNA were measured.
• 3 Endotoxaemia reduced renal blood flow, decreased mean arterial pressure, resulted in anuria and was associated with an increase in plasma NO_x levels and renal iNOS expression. Renal µPo ₂ deteriorated gradually during endotoxaemia and there was a significant decrease in renal O₂ delivery and consumption. Manipulation of NO levels had no beneficial effect on systemic haemodynamics, renal µPo ₂ or creatinine clearance over standard fluid resuscitation. The application of 1400W+NTG significantly reduced plasma NO_x levels compared with fluid resuscitation and NTG alone.
• 4 Neither iNOS inhibition, NO donation nor a combination of both showed beneficial effects on systemic haemodynamics, renal oxygenation and renal function compared with fluid resuscitation alone. Our results question the proposed key role of NO in the pathogenesis of septic ARF in rats.

     

Rotenone partially reverses decreased BKCa currents in cerebral artery smooth muscle cells from streptozotocin-induced diabetic mice

• 1 Reactive oxygen species (ROS) cause vascular complications and impair vasodilation in diabetes mellitus. Large‐conductance Ca²⁺‐activated potassium channels (BK_Ca) modulate vascular tone and play an important negative feedback role in vasoconstriction. In the present study, we tested the hypothesis that ROS regulate the function of BK_Ca in diabetic cerebral artery smooth muscle cells.
• 2 Diabetes was induced in male BALB/c mice by injection of streptozotocin (STZ; 180 mg/kg, i.p., dissolved in sterile saline). Control and diabetic mice were treated with 12.7 µmol/L rotenone, an inhibitor of the mitochondrial electron transport chain complex I, or placebo every other day for 5 weeks. The whole‐cell patch clamp‐technique and functional vasomotor methods were used to record BK_Ca currents and myogenic tone of cerebral artery smooth muscle cells.
• 3 In the diabetic group, there was a significant decrease in spontaneous transient outward currents in cerebral artery smooth muscle cells compared with control. Although the currents were only moderately increased in rotenone‐treated diabetic mice, they remained significantly lower than in the control group. Furthermore, the macroscopic BK_Ca currents that were decreased in diabetic mice were partially recovered in rotenone‐treated diabetic mice (P < 0.05 vs untreated diabetic group).
• 4 The posterior cerebral artery from diabetic mice had a significantly higher myogenic tone than the control group, but this impaired contraction was partially reversed in the rotenone‐treated diabetic group (P < 0.05 vs untreated diabetic group).
• 5 The H₂O₂ concentration was significantly increased in cerebral arteries from diabetic mice compared with control. This increase in H₂O₂ was significantly blunted by rotenone treatment.
• 6 In conclusion, rotenone partially reverses the decreased macroscopic BK_Ca currents in STZ‐induced Type 1 diabetic mice and this reversal of BK_Ca currents may be related to the inhibitory effects of rotenone on H₂O₂ production. Reactive oxygen species, particularly H₂O₂, are important regulators of BK_Ca channels and myogenic tone in diabetic cerebral artery.

     

CROSSOVER COMPARISON BETWEEN THE DEPRESSOR EFFECTS OF LOW AND HIGH WORK-RATE EXERCISE IN MILD HYPERTENSION

1. The relationship between work-rate and the antihypertensive effect of exercise in hypertensives, and the mechanism of that effect, were investigated by a crossover clinical trial. 2. Ten mild hypertensives were randomly divided into two groups. One group performed low work-rate exercise (LWE) on a cycle ergometer for 10 weeks (blood lactate threshold; ～50% of maximum oxygen consumption [V?_O2max]). After a 10 week interval without exercise training, these subjects were then switched to a high work-rate exercise (HWE) regimen (4 mmol/ L of blood lactate; ～75% of V?_O2max) for another 10 weeks. In the other group, the order of exercise training was reversed. Since two patients withdrew from the protocol during HWE periods, statistical analysis was performed on the data from the remaining eight patients. There were no order effects observed in any of the data from the two groups. 3. During both LWE and HWE, resting blood pressure (BP) fell significantly after the initiation of exercise therapy (P<0.05). Furthermore, the overall effects of 10 weeks of LWE and HWE on BP were not significantly different. 4. The work-rate at the lactate threshold, which reflects physical fitness, had increased significantly by 16 W (P<0.01) after the LWE period and by 11 W (P<0.01) after the HWE. 5. During the LWE period, changes in haemodynamic and humoral variables were not significant, except for a reduction in plasma norepinephrine at week 10 (P<0.05). In the HWE period, changes in haemodynamic and humoral variables were not significant. 6. Based on these findings, LWE is recommended for mild hypertensives because of its safety.     

PKC-ERK1/2通路在臭氧预处理减轻大鼠肝缺血再灌注损伤的作用

目的 探讨PKC介导的ERK1/2信号通路在臭氧（ozone，O₃）预处理大鼠肝缺血再灌注中的作用。方法 60只大鼠随机分成6组：对照组、缺血再灌注组、O₃预处理组、O₃预处理+ERK抑制剂组（O₃+PD98059组）、O₃预处理+PKC抑制剂组（O₃+CHE组）、缺血再灌注+PKC激活剂组（IR+PMA组）。除对照组外，其余各组均进行肝缺血再灌注手术。O₃相关组予O₃预处理，调节剂组予相应的调节剂。分别检测各组的血清中丙氨酸氨基转移酶、天冬氨酸氨基转氨酶水平，进行病理学观察，Western blotting检测肝组织中的热休克蛋白70（heat shock protein 70，HSP70）、蛋白激酶C（protein kinase C，PKC）和细胞外调节蛋白激酶1/2（extracellular regulated protein kinases，ERK1/2）的表达水平。结果 与对照组相比，缺血再灌注组肝组织细胞损伤明显加重（P<0.05），肝组织中PKC、ERK1/2的磷酸化和HSP70的表达水平明显升高（P<0.05）。与缺血再灌注组相比，O₃相关组肝组织细胞损伤明显减轻（P<0.05），肝组织中PKC、ERK1/2的磷酸化和HSP70的表达水平明显升高（P<0.05）。与O₃预处理组相比，当使用PKC和ERK1/2抑制剂后，肝组织细胞损伤明显加重（P<0.05），肝组织中PKC、ERK1/2的磷酸化和HSP70的表达水平明显降低（P<0.05）。结论 O₃氧化预处理可通过激活PKC介导的ERK1/2信号通路，使HSP70的表达水平明显增加，使大鼠肝脏缺血再灌注损伤明显减轻。     

Novel application of pluronic lecithin organogels (PLOs) for local delivery of synergistic combination of docetaxel and cisplatin to improve therapeutic efficacy against ovarian cancer

The synergistic combination of docetaxel (DTX) and cisplatin (CIS) by local drug delivery with a pluronic lecithin organogel (PLO) to facilitate high drug concentrations at tumor sites and less nonspecific distribution to normal organs is thought to be beneficial in chemotherapy. In this study, using Capryol-90 (C90) with the addition of lecithin as the oil phase was developed to carry DTX, which was then incorporated into a PLO-containing CIS to formulate a dual-drug injectable PLO for local delivery. An optimal PLO composite, P₁₃L_0.15O_1.5, composed of PF127:lecithin:C90 at a 13:0.15:1.5 weight ratio was obtained. The sol–gel transition temperature of P₁₃L_0.15O_1.5 was found to be 33?°C. Tumor inhibition studies illustrated that DTX/CIS-loaded P₁₃L_0.15O_1.5 could efficiently suppress tumor growth by both intratumoral and peritumoral injections in SKOV-3 xenograft mouse model. Pharmacokinetic studies showed that subcutaneous administration of P₁₃L_0.15O_1.5 was able to sustain the release of DTX and CIS leading to their slow absorption into the systemic circulation resulting in lower area under the plasma concentration curve at 0–72?h (AUC_0–72) and maximum concentration (C_max) values but longer half-life (T_1/2) and mean residence time (MRT) values. An in vivo biodistribution study showed lower DTX and CIS concentrations in organs compared to other treatment groups after IT administration of the dual drug-loaded P₁₃L_0.15O_1.5. It was concluded that the local co-delivery of DTX and CIS by PLOs may be a promising and effective platform for local anticancer drug delivery with minimal systemic toxicities.     

ACUTE EFFECTS OF ORAL GLIBENCLAMIDE ON BLOOD PRESSURE AND FOREARM VASCULAR RESISTANCE IN DIABETICS

1. To determine the effects of an acute oral dose of glibenclamide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K⁺atp channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75–30 mg/kg per min) and nor-adrenaline (25–100 ngkg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K⁺ atp channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.     

CEREBROVASCULAR AND METABOLIC EFFECTS OF BRADYKININ, ATP AND HYPERCAPNIA IN THE GOAT

1. Cerebral blood flow (CBF) and cerebral O₂ metabolism (CMRO₂) changes were measured in these studies during treatment with three reputed cerebral vasodilators: bradykinin, adenosine triphosphate (ATP) and increased arterial Pco₂. 2. Intracerebrovascular bradykinin infusions increased CMRO₂ and CBF to a similar degree. Intramaxillary ATP infusions increased CBF to an extent greater than that required for increases seen in CMRO₂. Hypercapnia increased CBF without a significant change in CMRO₂. 3. Results suggest that increases in cerebral metabolism may mediate most, some and none of the cerebrovascular changes produced by bradykinin, ATP or hypercapnia, respectively.     

脉君安片中主要成分对氢氯噻嗪在Caco-2细胞模型中转运的影响

利用人源结肠腺癌细胞系Caco-2细胞单层模型, 研究了脉君安片中主要降压活性成分葛根素、钩藤碱与氢氯噻嗪配伍使用前后对氢氯噻嗪体外吸收与转运的影响, 探讨了氢氯噻嗪与葛根素、钩藤碱配伍使用时在吸收阶段的药物相互作用。结果表明, 氢氯噻嗪在Caco-2单层细胞模型中的吸收可能存在由载体介导的主动转运, 葛根素能减少P-糖蛋白 (P-gp), 对氢氯噻嗪的外排, 钩藤碱对氢氯噻嗪的吸收转运无显著影响, 葛根素、钩藤碱与氢氯噻嗪合用能增强氢氯噻嗪的吸收。同时, 实验还发现氢氯噻嗪可能是P-gp的作用底物, 且pH值对氢氯噻嗪的转运有重要影响, 在弱酸性条件下, 氢氯噻嗪的吸收比在中性条件下好。     

EFFECT OF ARGININE VASOPRESSIN AND PARATHYROID HORMONE-RELATED PROTEIN ON RENAL FUNCTION IN THE OVINE FOETUS

1. The effects of intravenous infusions of arginine vasopressin (AVP), parathyroid hormone-related protein (PTHrP) and AVP + PTHrP on renal function in intact ovine foetuses at 100–125 days of gestation were examined. 2. A low dose of AVP (5.5 ± 0.9 pmol/h) increased plasma AVP concentrations from 0.6 pmol/L to 2.1 ± 0.4 pmol/L (mean ± s.e.m; n= 8). This dose caused a significant reduction in free water clearance (C_H2O; P<0.001), without any significant change in fetal arterial blood pressure, glomerular filtration rate (GFR), or the urinary excretion rates of sodium, calcium or 3', 5'-cyclic adenosine monophosphate (CAMP). 3. Infusions of PTHrP (1 nmol/h), with or without 1 nmol bolus dose, significantly increased (P<0.05) urine osmolality (Uosm), but did not synergize with AVP in reducing C_H2O. 4. It is concluded that AVP and PTHrP do not act synergistically on the kidney of the intact ovine foetus.     

SIMULTANEOUS ACTION OF THE FLAVONOID QUERCETIN ON CYTOCHROME P450 (CYP) 1A2, CYP2A6, N-ACETYLTRANSFERASE AND XANTHINE OXIDASE ACTIVITY IN HEALTHY VOLUNTEERS

• 1 Quercetin, one of the most abundant natural flavonoids, has been reported to modulate the activity of several drug‐metabolising enzymes. The aim of the present study was to investigate the effects of quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N‐acetyltransferase (NAT2) and xanthine oxidase (XO) activity in healthy volunteers using caffeine as a probe drug.
• 2 Twelve unrelated, healthy volunteers were recruited to the study. There were two phases to the study; in the first phase, each subject was given a single oral dose of caffeine (one 100 mg capsule) with 150 mL water; in the second phase, each subject was give a 500 mg quercetin capsule once daily for 13 continuous days and was coadministered a 100 mg caffeine capsule on the 13th day. Urinary caffeine metabolite ratios were used as indicators of the activity of CYP1A2, CYP2A6, NAT2 and XO. The pharmacokinetics of caffeine and its metabolites were determined by HPLC.
• 3 In the quercetin‐treated group, CYP1A2 activity was decreased by 10.4% (95% confidence interval (CI), 1.1–29.8%; P = 0.039), whereas increases were observed in CYP2A6 (by 25.3%; 95% CI, 6.2–34.5%; P = 0.002), NAT2 (by 88.7%; 95% CI, 7.1–160.2%; P = 0.010) and XO activity (by 15.0%; 95% CI, 1.6–21.6%; P = 0.007). Plasma C_max and the AUC_(0–24 h) of 1,7‐dimethylxanthine were decreased by 17.2% (95% CI, 6.4–28.0%; P = 0.024) and 16.2% (95% CI, 3.9–28.5%; P = 0.032), respectively. The urinary excretion of 1,7‐dimethylxanthine and 1‐methylxanthine was significantly decreased by 32.4% (95% CI, 2.5–62.1%; P = 0.036) and 156.1% (95% CI, 53.3–258.9%; P = 0.004), respectively. The urinary excretion of 1,7‐dimethylurate and 1‐methylurate was increased by 82.9% (95% CI, 56.0–165.4%; P = 0.030) and 97.8% (95% CI, 12.1–183.5%; P = 0.029), respectively. No changes were observed in the urinary excretion of caffeine and 5‐acetylamino‐6‐formylamino‐3‐methyluracil between the two study phases.
• 4 The results of the present study indicate that quercetin inhibits CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity. Simultaneously, some pharmacokinetic parameters relating to 1,7‐dimethylxanthine were affected by quercetin. Thus, we conclude that quercetin affects CYP1A2, CYP2A6, NAT2 and XO activity in vivo.

     

EFFECTS OF NITRIC OXIDE SYNTHASE INHIBITION AND ENDOTHELIN ETA RECEPTOR BLOCKADE ON HAEMODYNAMICS IN HYPERTENSIVE RATS

1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor N^G-monomethyl -l -arginine (l -NMMA) and the endothelin ET_A receptor antagonist BQ123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 μg/kg per min) was examined after l -NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. N^G-Monomethyl-l -arginine (20mg/kg) increased BP (26–48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11 %; P < 0.05). 3. N^G -Monomethyl-l -arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, l -NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following l -NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following l -NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, l -NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ET_A receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ET_A blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.     

Synthesis and evaluation of a glutamic acid-modified hPAMAM complex as a promising versatile gene carrier

Hyperbranched poly(amidoamine) (HPAMAM), structurally analogous to polyamidoamine dendrimer (PAMAM) dendrimers, has been suggested to be an effective carrier for gene delivery. In the present study, glutamic acid-modified hPAMAM was developed as a novel non-viral gene carrier for the first time. The hPAMAM was synthesized by using a modified one-pot method. DNA was found to be bound to hPAMAM at different weight ratios (W_hPAMAM/W_DNA). The resulting HPAMAM–Glu20 was able to efficiently protect the encapsulated-DNA against degradation for over 2?h. In addition to low cytotoxicity, the transfection efficiency of hPAMAM–Glu20 represented much higher (p?<?0.05) than that of Lipofectamine 2000 in both MCF7 and MDA-MB231 cells. Cellular uptake of the hPAMAM–Glu20 in MDA-MB231 cells, 173.56?±?1.37%, was significantly higher than that of MCF7 cells, 65.00?±?1.73% (p?<?0.05). The results indicated that hPAMAM–Glu20-mediated gene delivery to breast cancer cells is a feasible and effective strategy that may provide a new therapeutic avenue as a non-viral gene delivery carrier. In addition, it was found that hPAMAM–glutamic amino acid (Glu)-based gene delivery is an economical, effective and biocompatible method.