Improvement of cardiac function with parecoxib, a cyclo-oxygenase-2 inhibitor, in a rat model of ischemic heart failure

OBJECTIVE: To assess changes in cardiac function in animals with ischemic congestive heart failure (CHF) treated with a selective cyclo-oxygenase-2 (COX-2) inhibitor. BACKGROUND: In patients with CHF, COX-2 expression was associated with features of worsening failure. However, evidence of beneficial or detrimental functional effects of COX-2 inhibition in ischemic CHF is lacking. METHODS: Thirty male Wistar rats underwent coronary ligation and were allowed to recover for 12 months. Five sham-operated animals were used as controls. After 12 months, six surviving animals underwent baseline echocardiogram to measure end-diastolic diameter (EDD), end-systolic diameters (ESD), fractional shortening (FS), and anterior and posterior diastolic and systolic wall thicknesses. The animals were thereafter treated by daily intraperitoneal parecoxib injections (0.75 mg/kg) for 7 days. On day 7, a repeat echocardiogram was performed. RESULTS: When compared to baseline, repeat echocardiography after 7 days of parecoxib treatment showed no changes in the EDD (9.4 +/- 0.4 mm vs. 9.4 +/- 0.3 mm, P = 0.9), a significant reduction of ESD (5.5 +/- 0.8 mm vs. 6.4 +/- 0.3 mm, P = 0.028), and a significant improvement in the FS (43 +/- 3% vs. 32 +/- 5%, P = 0.027). Improvement of FS was associated with a significant change in systolic thickness in the infarct zone (3.6 +/- 0.4 mm vs. 3.0 +/- 0.1 mm, P = 0.046), whereas no significant changes in systolic thickness in the remote area were observed. CONCLUSIONS: Administration of parecoxib in ischemic CHF provides functional improvement of the peri-infarct myocardium. This finding may prove useful in improving quality of life and, perhaps, survival in patients with ischemic heart disease.     

Bradykinin B2 receptor antagonism attenuates inflammation, mast cell infiltration and fibrosis in remote myocardium after infarction in rats

Bradykinin may interfere with myocardial remodelling by promoting inflammation and mast cell activation or, alternatively, by counteracting angiotensin II-dependent collagen accumulation. The aim of the present study was to investigate the role of bradykinin B2 receptor antagonism in inflammatory and mast cell infiltration, fibroplasia and fibrosis accumulation following myocardial infarction (MI). Myocardial infarction was produced by the ligature of the left coronary artery in male Wistar rats that were 10 weeks of age. Immediately after MI, rats received the B2 receptor antagonist Hoe140 (0.5 microg/kg per min, s.c.) or saline over a period of 3 days, 1 week or 4 weeks, constituting three separate groups and their respective controls. Coronal myocardial tissue sections underwent haematoxylin and eosin, Giemsa and picrosirius red staining, as well as immunohistochemistry for alpha-smooth muscle actin (SMA). Morphometric studies were undertaken in three different myocardial regions: MI, remote non-infarcted subendocardium (non-MI SE) and remote non-infarcted interventricular septum (non-MI IVS). The MI size was comparable between Hoe140-treated groups and their respective controls (day 3: 42 +/- 4%, n = 8, vs 43 +/- 3%, n = 6; week 1: 37 +/- 5%, n = 5, vs 39 +/- 2%, n = 5; week 4: 35 +/- 3%, n = 9, vs 36 +/- 3%, n = 7). At day 3, Hoe140 treatment reduced inflammatory cell reaction within the MI (585 +/- 59 vs 995 +/- 170 cells/mm2; P = 0.02), non-MI SE (77 +/- 12 vs 214 +/- 57 cells/mm2; P = 0.02) and non-MI IVS (93 +/- 16 vs 135 +/- 14 cells/mm2; P = 0.03) regions. Mast cells were reduced within the non-MI IVS region (0.8 +/- 0.1 vs 2.5 +/- 0.4 cells/mm2; P = 0.006), but not within the MI region. In non-MI SE, mast cells were rarely found. At week 1, Hoe140 treatment reduced alpha-SMA-positive myofibroblast infiltration within the MI (2535 +/- 383 vs 5636 +/- 968 cells/mm2; P = 0.01) and non-MI SE (222 +/- 33 vs 597 +/- 162 cells/mm2; P = 0.03) regions. In the non-MI IVS region, alpha-SMA-positive myofibroblasts were rarely found. At week 4, Hoe140 treatment reduced collagen volume fraction within the MI (37 +/- 4 vs 53 +/- 4%; P = 0.03), non-MI SE (1.3 +/- 0.2 vs 2.6 +/- 0.3%; P = 0.001) and non-MI IVS (1.1 +/- 0.2 vs 1.8 +/- 0.2%; P = 0.01) regions. Bradykinin promotes inflammation, fibroplasia and fibrosis after MI. Mast cells may have a role in fibrosis deposition through a bradykinin-related mechanism.     

Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart. When chronically infarcted hearts were subjected to programmed electrical stimulation, 1 mg/kg of clofilium inhibited the re-induction of either ventricular tachycardia or ventricular fibrillation in 5 of 6 animals and slowed the rate of the induced tachycardia in the sixth. Clofilium, however, failed to alter ventricular refractory periods of normal myocardium at either twice diastolic threshold current (176 +/- 5 ms control vs. 187 +/- 9 ms post-clofilium, P greater than 0.05) or at 10 mA (134 +/- 6 ms control vs. 137 +/- 13 ms post-clofilium, P greater than 0.05). In addition, chronic administration of clofilium (2 mg/kg, i.v., followed by 1 mg/kg every 12 h) was ineffective in decreasing mortality in a canine model of sudden coronary death. Of 10 saline-treated conscious animals subjected to an electrically-induced intimal lesion of the left circumflex coronary artery in the presence of a previous ischemic insult, all 10 died suddenly of ventricular fibrillation within 173 +/- 45 min after current application. Under similar conditions, 7 clofilium-treated animals died suddenly within 249 +/- 88 min (P greater than 0.05) after current application while 3 animals survived (P greater than 0.10). Clofilium did, however, elevate the effective refractory period in these animals (150 +/- 3 ms saline-treated vs. 195 +/- 7 ms clofilium-treated). It is concluded from our data that there is little relationship between clofilium's electrophysiologic actions in normal myocardium and antiarrhythmic effects. Furthermore, simple prolongation of refractoriness in normal non-ischemic myocardium may be insufficient for the prevention of ventricular fibrillation which develops in response to a transient ischemic event superimposed on a chronically injured myocardium.     

Peroxisome proliferator activated-receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction

1. Peroxisome proliferator activated receptor gamma (PPARgamma) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPARgamma agonists. Therefore, we examined the effect of pioglitazone, a PPARgamma agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2. Mice were treated with placebo or pioglitazone (20 mg x kg(-1) by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3. Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6+/-1.3 vs placebo MI 14.4+/-2.5 mm(2)). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8+/-2.9 mm(2), P=NS vs placebo). 4. Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPARgamma activation. 5. In conclusion, PPARgamma activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.     

Enhanced sympathetic neurotransmission in the tail artery of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX)-treated rats.

1. Sympathetic neurotransmission and noradrenaline content of the tail artery of Wistar rats treated for 7 days with the adenosine antagonist, 1,3-dipropyl-8-sulphophenylxanthine (DPSPX), were examined. 2. Systolic blood pressure of the DPSPX-treated rats (164.0 +/- 2.9 mmHg; n = 6) was significantly greater than saline-treated controls (140.0 +/- 2.8 mmHg; n = 5) after 7 days treatment. 3. The pressor responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4-64 Hz, for 1 s) were markedly enhanced in the DPSPX-treated compared with the saline-treated animals. Both noradrenergic and purinergic components of perivascular sympathetic neurotransmission were enhanced during DPSPX-induced hypertension. 4. Vasoconstrictor responses to exogenous noradrenaline (0.1-300 microM) and adenosine 5'-triphosphate (0.01-3 mM) were unaffected after DPSPX treatment, indicating prejunctional alteration of sympathetic cotransmission during DPSPX-induced hypertension. 5. Acute exposure to DPSPX (10 microM) did not modify vasoconstrictor responses to transmural nerve stimulation, thus supporting the claim that the enhancement of sympathetic neurotransmission only results from long-term DPSPX treatment. 6. The noradrenaline content of the tail arteries of DPSPX-treated (4.498 +/- 0.26 ng cm-1; n = 4) was significantly greater than saline-treated (3.440 +/- 0.30 ng cm-1; n = 5) animals. 7. These findings show that chronic inhibition of the actions of endogenous adenosine by DPSPX results in an elevation of systolic blood pressure accompanied by enhanced sympathetic cotransmission and enhanced noradrenaline content of the rat tail artery.     

Beta-carotene supplementation attenuates cardiac remodeling induced by one-month tobacco-smoke exposure in rats.

OBJECTIVE: The objectives were to analyze the cardiac effects of exposure to tobacco smoke (ETS), for a period of 30 days, alone and in combination with beta-carotene supplementation (BC). Research methods and procedures: Rats were allocated into: Air (control, n = 13); Air + BC (n = 11); ETS (n = 11); and BC + ETS (n = 9). In Air + BC and BC + ETS, 500 mg of BC were added to the diet. After three months of randomization, cardiac structure and function were assessed by echocardiogram. After that, animals were euthanized and morphological data were analyzed post-mortem. One-way and two-way ANOVA were used to assess the effects of ETS, BC and the interaction between ETS and BC on the variables. RESULTS: ETS presented smaller cardiac output (0.087 +/- 0.001 vs. 0.105 +/- 0.004 l/min; p = 0.007), higher left ventricular diastolic diameter (19.6 +/- 0.5 vs. 18.0 +/- 0.5 mm/kg; p = 0.024), higher left ventricular (2.02 +/- 0.05 vs. 1.70 +/- 0.03 g/kg; p < 0.001) and atrium (0.24 +/- 0.01 vs. 0.19 +/- 0.01 g/kg; p = 0.003) weight, adjusted to body weight of animals, and higher values of hepatic lipid hydroperoxide (5.32 +/- 0.1 vs. 4.84 +/- 0.1 nmol/g tissue; p = 0.031) than Air. However, considering those variables, there were no differences between Air and BC + ETS (0.099 +/- 0.004 l/min; 19.0 +/- 0.5 mm/kg; 1.83 +/- 0.04 g/kg; 0.19 +/- 0.01 g/kg; 4.88 +/- 0.1 nmol/g tissue, respectively; p > 0.05). Ultrastructural alterations were found in ETS: disorganization or loss of myofilaments, plasmatic membrane infolding, sarcoplasm reticulum dilatation, polymorphic mitochondria with swelling and decreased cristae. In BC + ETS, most fibers showed normal morphological aspects. CONCLUSION: One-month tobacco-smoke exposure induces functional and morphological cardiac alterations and BC supplementation attenuates this ventricular remodeling process.     

Improving the cadmium-induced centriacinar emphysema model in rats by concomitant anti-oxidant treatment

1. The aim of the present study was to perform an evolutionary analysis of the morphometrical, biochemical and functional parameters of centriacinar emphysema induced by cadmium chloride (CdCl2) in rats and to determine the effects of concomitant N-acetylcysteine (NAC) administration. 2. Male Wistar rats were instilled orotracheally with either CdCl2 (n = 24) or saline (n = 24). One group of rats, consisting of both CdCl2- and saline-treated rats, was fed a normal diet (n = 24), whereas the other group received NAC (n = 24). 3. Changes in inspiratory capacity (IC), lung compliance (CL), expiratory flow at 75% (F75), forced vital capacity (FVC) and hydroxyproline content were assessed 2, 8, 21 and 45 days after instillation. Polymorphonuclear cells were evaluated 2 and 8 days after instillation and the mean linear intercept (Lm) was determined at 21 and 45 days. 4. Over time, CdCl2 instillation causes several changes that are bound up with centriacinar emphysema. The concomitant administration of NAC to CdCl2-treated rats partially reversed Lm at 21 days compared with CdCl2 alone (115 +/- 2 vs 127 +/- 2, respectively; P < 0.05). However, 45 days after instillation, NAC improved lung function in CdCl2-treated rats compared with that in the saline-treated control group (IC 14.64 vs 15.25, respectively (P = 0.054); FVC 16.94 vs 16.28, respectively (P = 0.052), F75 31.41 vs 32.48, respectively (P = 0.062)). In addition, 45 days after instillation, NAC reduced lung collagen content in both the saline-treated control (100 vs 81% alone and in the presence of NAC, respectively) and CdCL2-treated groups (213 vs 161% alone and in the presence of NAC, respectively). In addition, although the results were not significant, NAC tended to reduce Lm and enhance CL in NAC + CdCl2-treated rats. 5. In conclusion, NAC partially improved emphysematous changes and reduced collagen deposition, which diminished the CdCl2-induced fibrotic component of centriacinar emphysema.     

Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells

1. Acetaminophen, an analgesic and antipyretic drug with weak antiinflammatory properties, has been suggested to act as a tissue-selective inhibitor of prostaglandin H synthases (PGHSs) (e.g. COX-1 and COX-2) through its reducing activity, that is influenced by the different cellular levels of peroxides. 2. We have studied the effects of acetaminophen on inducible and constitutive prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate between the inhibitory effect of the drug on PGHS-isozymes vs PGE-synthases (PGESs), parallel measurements of PGE(2) and thromboxane (TX) B(2) were carried out. Since antioxidant enzymes and cofactors, present in plasma, may affect acetaminophen-dependent inhibition of prostanoids, comparative experiments in whole blood vs isolated monocytes were performed. 3. Acetaminophen inhibited LPS-induced whole blood PGE(2) and TXB(2) production, in a concentration-dependent fashion [IC(50) microM (95% confidence intervals): 44 (27-70) and 94 (79-112), respectively]. Therapeutic plasma concentrations (100 and 300 microM) of the drug more profoundly reduced PGE(2) than TXB(2) (71 +/- 3 vs 54 +/- 4 and 95 +/- 0.8 vs 78 +/- 2%, respectively, mean +/- s.e.mean, n = 6, P < 0.01). 4. Differently, in isolated monocytes stimulated with LPS, both PGE(2) and TXB(2) production was maximally reduced by only 60%. 5 At 100 and 300 microM, the drug caused a similar and incomplete inhibition of platelet PGE(2) and TXB(2) production during whole blood clotting (45 +/- 4 vs 54 +/- 4 and 75 +/- 2 vs 75 +/- 1%, respectively, mean +/- s.e.mean, n = 4). 6 In conclusion, therapeutic concentrations of acetaminophen caused an incomplete inhibition of platelet COX-1 and monocyte COX-2 but in the presence of plasma, the drug almost completely suppressed inducible PGE(2) biosynthesis through its inhibitory effects on both COX-2 and inducible PGES.     

宫腹腔镜联合检查患者应用帕瑞昔布钠的镇痛效果和满意度

目的评价宫腹腔镜联合检查患者术前用帕瑞昔布钠的镇痛效果和满意度。方法随机双盲、安慰剂对照试验,60例择期全麻下行宫腹腔镜联合检查患者随机分为帕瑞昔布组(D组)和生理盐水组(S组),各30例。麻醉诱导后、手术开始前静脉给予帕瑞昔布钠40 mg(D组)或等量生理盐水(S组)。术后记录停药后患者苏醒时间、睁眼时间和定向力恢复时间,记录患者在恢复室内的疼痛评分和术后6,24 h疼痛评分以及患者满意度。结果 2组患者的麻醉恢复时间和质量无显著性差异。与S组相比,D组患者24 h内最严重疼痛(3.9±3.8vs 5.6±4.6)和最轻微的疼痛程度(0.5±1.4 vs 1.4±1.8)较低,术后6,24 h差异无统计学意义,D组术后患者对疼痛治疗更为满意。结论术前用帕瑞昔布钠可有效控制宫腹腔镜联合检查患者的术后疼痛,显著提高患者的满意度。     

Parecoxib exhibits anti-inflammatory and neuroprotective effects in a rat model of transient global cerebral ischemia

ABSTRACT

Transient global cerebral ischemia (tGCI) induces inflammation leading to secondary brain injury. Data suggested that cyclooxygenase-2 (COX-2) is involved in the occurrence and development of inflammatory reaction after reperfusion; however, the effectiveness of a highly selective COX-2 inhibitor, parecoxib, to counteract tGCI remains to be determined. Thus, the aim of this study was to investigate the potential protective actions of parecoxib in a rat model of tGCI and the role inflammation plays in this disorder. Adult male Sprague-Dawley rats were administered parecoxib 10 or 20 mg/kg intraperitoneally (ip) at 5 min, 24 or 48 hr after tGCI. Control rats received an equal volume of 0.9% saline. The rat model of tGCI was established using the method of bilateral common carotid artery occlusion combined with arterial hypotension. The following parameters were measured: Neurological Severity Score, morphological changes in the hippocampal CA1 region, Evans blue (EB) extravasation, brain water content, levels of matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), neuronal apoptosis, the protein expression of Bcl-2, Bax, COX-2, prostaglandin E2 (PGE₂), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). Parecoxib treatment significantly improved neurological function and morphological defects in the hippocampal CA1 region, reduced levels of COX-2, PGE₂, IL-1β, and TNF-α. In addition, parecoxib attenuated brain edema and BBB destruction as evidenced by increased ZO-1 expression and decreased MMP-9 expression. Further, parecoxib reduced neuronal apoptosis via diminished protein expression of Bax and enhanced expression of Bcl-2.     

Ventilatory response to single, high dose estazolam in healthy humans

The purpose of this study was to determine the effect of oral estazolam at two and three times the usually recommended dosage (2 mg) on ventilation and respiratory drive during wakefulness. Sixty healthy subjects were randomized to receive a single oral dose of either: 1) estazolam 4 mg; 2) estazolam 6 mg; 3) placebo; or 4) morphine 0.15 mg/kg. Predrug and postdrug measurements were obtained for ventilation, respiratory cycle timing, metabolic rate, temperature, and ventilatory and mouth occlusion pressure (P0.1) responses to exogenous CO2. No difference between placebo and the study drugs was noted during eupneic breathing. During administration of exogenous CO2, morphine caused a decrease in the slope of the ventilatory (-0.4 +/- 0.1 L/min/mm Hg, P = .008) and P0.1 (-0.22 +/- 0.06 cm H2O/mm Hg, P = .015) responses. Estazolam (4 and 6 mg) had no effect on the ventilatory response to exogenous CO2. However, estazolam (6 mg) caused the P0.1 at a PCO2 of 57 mm Hg to decrease (-0.67 +/- 0.30 cm H2O, P = .005). The preservation of ventilation with the highest dose of estazolam, despite the decrease in P0.1, indicates that a compensatory strategy independent of respiratory center drive may have been activated. Sedation was a common side effect of estazolam reported in 13% and 53% of subjects at the 4 mg and 6 mg doses, respectively. We conclude that a single, high dose of estazolam does not cause ventilatory depression during wakefulness in healthy subjects.     

Cannabinoid-mediated diversity of antinociceptive efficacy of parecoxib in Wistar and Sprague Dawley rats in the chronic constriction injury model of neuropathic pain

We studied nociceptive behavior and the effects of analgesics in Wistar (Wist) and Sprague Dawley (SPD) rats and in CB1 receptor-deficient mice with neuropathic pain experimentally. Neuropathic pain was induced by loose ligation of the sciatic nerve (chronic constriction injury, CCI). In CCI rats from both strains, cold allodynia and a reduced thermal pain threshold were detected, whereas no effect was found in the hot plate test. Thermal pain threshold was used to study the antinociceptive effects of morphine, gabapentin, and parecoxib 5 days after surgery. Doses of gabapentin and morphine which had no effect on sham-operated animals provoked antinociceptive activity in CCI rats from both strains. An antinociceptive effect of parecoxib was only found in CCI Wist rats. No pharmacokinetic differences were detected between the two strains in parecoxib metabolism. Antinociceptive activity caused by parecoxib was attenuated by the CB1 antagonist rimonabant. To further clarify parecoxib—CB1 interaction, the effect of parecoxib was investigated in CB1-deficient mice and wild-type animals. CCI did not affect thermal pain threshold and mechanical pain threshold was decreased. Parecoxib normalized the altered mechanical pain threshold in CCI wild-type animals, whereas it had only a marginal effect in CB1 receptor deficient mice. Receptor binding experiments showed increased CB1 binding in parecoxib-treated CCI Wist rats. Levels of the CB1 receptor mRNA remained constant in both strains of rats 5 days after surgery. Differences in antinociceptive activity might be due to modification of the cannabinoid system.     

Modification of aortic contractility in the cardiomyopathic hamster.

1. The functional arterial response in the cardiomyopathic hamster compared with inbred control, was investigated in thoracic aortae. For this purpose, vessels were cut into 6-mm rings and mounted in 20-ml organ baths. 2. In a first experimental series, the function of the endothelium was evaluated. Dose-response curves to acetylcholine (0.1 nM-10 microM) on phenylephrine (0.3 microM)-preconstricted rings of cardiomyopathic hamsters and inbred age-matched controls were comparable (log[EC50] of -7.08 +/- 0.12 and -7.18 +/- 0.12, respectively; n = 4). 3. Changes in contractility of cardiomyopathic hamster endothelium-denuded aortae were investigated. Dose-response curves to phenylephrine (1 nM-0.1 mM), angiotensin II (10 pM-0.3 microM), 5-hydroxytryptamine (5-HT) (1 nM-0.1 mM) and KCl (1 mM-0.1 M) were performed. Increased sensitivity in cardiomyopathic hamster aortae, compared to controls, was observed with phenylephrine (log[EC50] of -7.25 +/- 0.05 and -6.83 +/- 0.05, respectively, n = 6, P < 0.001) and angiotensin II (log[EC50] of -8.67 +/- 0.07 and -8.26 +/- 0.06, respectively, n = 6, P = 0.001) but not with 5-HT or KCl. A decreased maximum response in cardiomyopathic, compared to control, was observed with 5-HT (1.28 +/- 0.06 g vs 1.56 +/- 0.07 g, respectively, n = 6, P = 0.03). Comparable results were found in aortae with an intact endothelium. 4. No difference in the maximum contractile response to the G-protein activator, NaF (3, 10 and 30 mM) was observed in either group of animals. 5. Phorbol 12-myristate 13-acetate (PMA, 1-10 microM) was used to assess changes in the activity of protein kinase C (PKC). Contractility to PMA was increased in cardiomyopathic hamster aortae compared to controls (0.22 +/- 0.02 g vs 0.07 +/- 0.03 g at 3 microM, respectively, n = 6, P = 0.003). 6. Finally, cardiomyopathic hamsters aortae were found to be less sensitive when exposed to increasing concentrations of Ca2+ (10 microM-1 mM) in KCl-depolarized rings (0.58 +/- 0.04 g in cardiomyopathic vs 0.79 +/- 0.06 g in control aortae at 0.3 mM, n = 8, P = 0.03). 7. In conclusion, aortae from cardiomyopathic hamsters are more sensitive to phenylephrine and angiotensin II, but not to 5-HT, than those of controls. The increase in sensitivity does not implicate Ca2+ channels or Ca2+ itself since cardiomyopathic hamsters aortae are not more sensitive to KCl- and Ca(2+)-induced contraction. The greater effect of PMA on cardiomyopathic hamster aortae suggests that the increase in sensitivity to phenylephrine and angiotensin II involves an enhanced activity of PKC.     

Parecoxib sodium, an injectable COX-2-specific inhibitor, does not affect unfractionated heparin-regulated blood coagulation parameters

The objective of this study was to evaluate the potential for hemostatic interaction between a full analgesic dose of parecoxib sodium (parecoxib), a prodrug of the COX-2 specific inhibitor valdecoxib, and unfractionated heparin (UFH) in healthy male subjects. This open-label, single-center study comprised two treatment periods. In treatment period I, fasted, eligible subjects (n = 18) received a UFH bolus (4000 U) followed by a 36-hour UFH infusion (start dose 10-14 U/kg). Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts were measured at regular intervals up to 24 hours after the end of the UFH infusion. After a 2-day washout, patients randomized to treatment period II received a full analgesic dosage of parecoxib 40 mg bid intravenously (IV) for 6 days (n = 18), with concomitant UFH (same regimen as treatment period I) on day 5 (n = 18). APTT, PT, and platelet counts were evaluated at regular intervals up to 24 hours after UFH infusion. Coadministration of parecoxib 40 mg bid IV with UFH (treatment period II) had no significant effect on aPTT, PT, or platelet counts, which were similar to those of participants receiving UFH alone (treatment period I) at all time points. These results show that a full analgesic dose of parecoxib, a COX-2-specific inhibitor available for parenteral administration, can be coadministered with UFH without affecting blood coagulation parameters. Therefore, parecoxib may be administered to patients who are receiving UFH for thromboprophylaxis.     

Simvastatin preserves cardiac function in genetically determined cardiomyopathy

Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 +/- 3% vs 59 +/- 2%), higher LV end-diastolic volume (30 +/- 3 vs 6 +/- 2 mL/m2), and lower LV mass/volume ratio (0.5 +/- 0.04 vs 0.72 +/- 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 +/- 2%) and LV volume increased (38 +/- 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 +/- 0.02% vs 0.107 +/- 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.     

Delayed calcium channel blockade with diltiazem reduces paracetamol hepatotoxicity in mice.

1. Diltiazem (30 mg kg-1 body weight, intraperitoneally) given to mice 9 h after paracetamol (450 mg kg-1, orally) reduced liver damage, as judged by plasma aspartate aminotransferase activity (median 186, range 6-602 IU 1(-1), n = 18 vs 466, range 23-3872 IU 1(-1) in 18 saline-treated controls; P less than 0.05) with comparable reductions in mortality (14% vs 33%, respectively; NS). 2. Regenerative activity, as judged by mitotic figures in tissue removed at 30 h after paracetamol, was significantly higher in mice treated at 9 h with diltiazem (median 0.83 per high power field vs 0.1 in saline-treated controls; P less than 0.05). 3. Diltiazem administered earlier or later than 9 h showed reduced efficacy and in some cases potentiated toxicity, as did nifedipine (40 mg kg-1 in divided doses up to 9 h).     

Effects of angiotensins II and IV on blood pressure,renal function,and PAI-1 expression in the heart and kidney of the rat

The role of angiotensin II (AII) and angiotensin IV (AIV) as inducers of PAI-1 expression during hypertension was studied in vivo. A 2-week infusion of AII (300 ng/kg/min) via an osmotic pump increased systolic blood pressure (171 +/- 2 vs. 138 +/- 6 mm Hg), urinary protein excretion (32 +/- 6 vs. 14 +/- 2 mg/day), and renal (2.2 +/- 0.5 vs. 1.0 +/- 0.1) and cardiac (1.8 +/- 0.3 vs. 1.0 +/- 0.1) gene expression of plasminogen activator inhibitor 1 (PAI-1). AIV infusion did not affect any of the above with the exception of PAI-1 gene expression which was increased in the left ventricles (1.7 +/- 0.3 vs. 1.0 +/- 0.1). AII-infused rats displayed a decreased creatinine clearance (538 +/- 75 vs. 898 +/- 96 ml/min) and hypertrophic left ventricles (0.275 +/- 0.006 vs. 0.220 +/- 0.011 g/100 g). Our results demonstrate that AII but not AIV infusion is associated with increased renal PAI-1 gene expression.     

Impact of treatment with melatonin on cerebral circulation in old rats

Melatonin deprival in young rats induces alterations in cerebral arteriolar wall similar to those observed during aging: atrophy and a decrease in distensibility. In this study, we examined the effects of melatonin treatment on cerebral arteriolar structure and distensibility and on the lower limit of cerebral blood flow autoregulation (LLCBF) in old rats. We measured cerebral blood flow (arbitrary unit, laser Doppler, open skull preparation) prior to and during stepwise hypotension (SH) in adult (12/13 months) and old (24/25 months) IcoWI and WAG/Rij male rats. Old rats were untreated or treated for 3 months with melatonin (0.39 (IcoWi) and 0.44 (Wag/Rij) mg kg-1 day-1, drinking water). Stress-strain relationships were determined using cross-sectional area (CSA, microm2, histometry) and values of arteriolar internal diameter (microm) obtained during a second SH following arteriolar deactivation (EDTA, 67 mmol l(-1)). Aging induced (a) atrophy of the arteriolar wall in IcoWI (616+/-20 vs 500+/-27 microm2, P<0.05) but not in WAG/Rij rats (328+/-25 vs 341+/-20 microm2), (b) a decrease in arteriolar wall distensibility and (c) an increase in the LLCBF in both strains (67+/-10 mmHg in 12-month-old vs 95+/-6 mmHg in 24-month-old IcoWi, P<0.05 and 53+/-2 mmHg in 13-month-old vs 67+/-6 mmHg in 25-month-old WAG/Rij). Melatonin treatment induced in IcoWI and WAG/Rij rats (a) hypertrophy of the arteriolar wall (643+/-34 and 435+/-25 microm2, respectively), (b) an increase in arteriolar wall distensibility and (c) a decrease in the LLCBF (64+/-6 and 45+/-4 mmHg, respectively). Melatonin treatment of old rats induced hypertrophy of the arteriolar wall, prevented the age-linked decrease in cerebral arteriolar distensibility and decreased the LLCBF.British Journal of Pharmacology (2004) 141, 399-406. doi:10.1038/sj.bjp.0705629     

Evidence that tryptophan reduces mechanical efficiency and running performance in rats

It has been reported that exercise increases brain tryptophan (TRP), which is related to exhaustive fatigue. To study this further, the effect of increased TRP availability on the central nervous system (CNS) with regard to mechanical efficiency, oxygen consumption (VO(2)) and run-time to exhaustion was studied in normal untrained rats. Each rat was anesthetized with thiopental (30 mg/kg ip b. wt.) and fitted with a chronic guiding cannula attached to the right lateral cerebral ventricle 1 week prior to the experiments. Immediately before exercise, the rats were randomly injected through these cannulae with 2.0 microl of 0.15 M NaCl (n=6) or 20.3 microM L-TRP solution (n=6). Exercise consisted of running on a treadmill at 18 m min(-1) and 5% inclination until exhaustion. TRP-treated rats presented a decrease in their mechanical efficiency (21.25+/-0.84%, TRP group vs. 24.31+/-0.98%, saline-treated group; P< or =.05), and increased VO(2) at exhaustion (40.3+/-1.6 ml kg(-1) min(-1), TRP group vs. 36.0+/-0.8 ml kg(-1) min(-1), saline group; P< or =.05), indicating that the metabolic cost of exercise was higher in the former group. In addition, a highly significant reduction was also observed in run-time to exhaustion of TRP animals compared to those of the saline-treated group (15.2+/-1.52 min, TRP group vs. 50.6+/-5.4 min, saline group; P< or =.0001). It can be deduced from the data that intracerebroventricular TRP injection in rats increases O(2) consumption and reduces mechanical efficiency during exercise, diminishing running performance.     

Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury

Ischemia-reperfusion injury (IRI) is a common event in organ transplantation, being implicated as a potential contributor for the development of chronic allograft nephropathy. There are new evidences showing a tissue inflammatory response following renal IRI. Cyclooxygenases (COX) 1 and 2 can be detected in tissue submitted to IRI and may have impact on organ function outcome. We evaluated the role of COX inhibition on the renal tissue damage that follows IRI. Mice were submitted to 45 min of renal pedicle ligature and allowed to reperfuse for 24, 48, 72 and 120 h. Blood and kidney samples were collected at reperfusion times. mRNA was extracted from the kidney samples to amplify COX-1, COX-2 and beta-actin genes. Animals were pretreated with indomethacin or rofecoxib before the surgery. Indomethacin treatment induced a better renal function (serum urea) when compared to control animals at 24, 48 and 72 h (219+/-54.5 vs. 338+/-51 mg/dl; 106+/-51 vs. 326+/-86 mg/dl; 94+/-14 vs. 138+/-38 mg/dl, respectively). Surprisingly, rofecoxib use was associated with even better renal improvement following IR. Animals treated with the later drug showed lower urea values at 24 h post reperfusion compared to indomethacin-treated animals (128+/-33 vs. 219+/-54.5 mg/dl, P<0.05). Blockade of COX-1 and -2 resulted in a decrease of tubular necrosis. mRNA COX-2 was up-regulated post IRI and considerable inhibited after indomethacin or rofecoxib treatment. Our data show COX-1/-2 participates in the inflammatory tissue response to IR injury and its inhibition is associated with an improvement in renal function.