[The clinical effect of ultrasonic bone curette-assisted "zoning" style laminectomy for the treatment of severe ossification of thoracic ligamentum flavum].

Objective: To investigate the safety and clinical efficacy of "zoning" style laminectomy by ultrasonic bone curette in patients with severe thoracic ossification of the ligamentum flavum(TOLF). Methods: The clinical data of 36 patients with severe TOLF treated by "zoning" style laminectomy at Department of Spinal Surgery,Zhengzhou Orthopaedic Hospital from October 2015 to October 2018 were respectively analyzed.There were 17 males and 19 females,aged(57.3±10.2)years(range:43 to 80 years).According to the anatomical characteristics of the thoracic ligamentum flavum and the pathological process of ossionization,each decompression segment was divided into the upper 1/3 area of the lamina,the bilateral area of the ossionum flavum,the transitional area,and the area of close contact between the ossionum flavum and the spinal cord.Different surgical strategies were used for decompression in turn.The modified Japanese Orthopedic Association (mJOA) was used to evaluate the neurological function status before and after surgery,to evaluate the surgical effect of patients,and to observe the surgical complications.Paired sample T test was used for data analysis. Results: All 36 patients successfully completed the operation,the operation time was (88.6±24.6) minutes(range:60 to 150 minutes).The intraoperative blood loss was (426.7±167.4) ml(range:250 to 800 ml).Follow-up time was (27.2±7.7) months(range:12 to 48 months).The mJOA score at the last follow-up was 9.0±1.5,which was statistically significant compared with the preoperative score 5.4±1.8 (t=13.59,P<0.01).The improvement rate of mJOA score was (65.7±22.1) %,of which 17 cases were excellent (47.2%),13 cases were good (36.1%),4 cases were normal (11.1%),2 cases were ineffective (5.6%).Ten patients had cerebrospinal fluid leakage during the separation or removal of dural ossification and were cured after a series of comprehensive conservative treatment.Two patients showed transient neurological deterioration,and the neurological function gradually recovered to the preoperative state after comprehensive treatment such as increasing the mean arterial pressure and using neurotrophic drugs.During the follow-up,no aggravation of neurological dysfunction and segmental kyphosis were found. Conclusions: The ultrasonic bone curette-assisted "zoning" style laminectomy for the treatment of severe TOLF can directly observed the position relationship between ossification of the ligamentum flavum and the spinal canal structure during the operation,and accurately guide the surgical decompression.It has the advantages of safe operation and complete decompression,which provides an important reference for the selection of clinical surgery.

Protease supplementation attenuates the intestinal health damage caused by low-protein diets in Pekin ducks.

The objective of this study was to investigate the effects of low-protein diets with low digestibility of feed ingredients on intestinal damage and to explore whether the protease supplementation can alleviate the damage in Pekin ducks. A total of 576 Pekin ducklings (6 replicate pens, 16 ducks/pen) were randomly assigned to 6 dietary treatments (3 × 2 factorial arrangement) in a randomized complete block design. Factors were CP levels (13.5%, 15.5%, and 17.5%) and protease (0 or 20,000U/kg). Compared with the diets containing 17.5% CP, low-protein diets (13.5% CP) showed suppressed (P < 0.05) growth performance and feed intake (FI); reduced (P < 0.05) serum-free arginine, isoleucine, leucine, methionine, phenylalanine, valine, and proline as well as the cecal acetate and propionate concentration; increased (P < 0.05) plasma and ileal mucosal tumor necrosis factor-α (TNF-α) concentration; and downregulated (P < 0.05) mRNA expression of TNF-α, nuclear transcription factor-κb, interferon gamma, and Occludin in ileal mucosa. Irrespective of the dietary CP levels, protease supplementation significantly increased (P < 0.05) the serum-free glutamic acid concentration while decreasing (P < 0.05) the plasma endotoxin, IL-6, and the cecal isovalerate concentration. A significant interactive effect was observed between low-protein diets and protease supplementation (P < 0.05) on serum-free arginine concentration, the ratio of ileal villus height to crypt depth, and the IL-6 concentration in ileal mucosa. These results indicated that low-protein diets could damage intestinal integrity to induce systemic inflammation response and at last to suppress growth performance. Protease supplementation could partly attenuate the negative effects on gut health caused by low-protein diets in Pekin ducks.

Effects of dietary protein levels and protease supplementation on growth performance, carcass traits, meat quality, and standardized ileal digestibility of amino acid in Pekin ducks fed a complex diet.

This study aimed to investigate to the effects of dietary CP levels and protease supplementation on growth performance, carcass traits, meat quality, nutrients utilization, and standardized ileal digestibility of amino acid in Pekin ducks fed a complex diet. A total of 960 14-day-old male ducks were weighed and randomly allotted to a 2 × 5 factorial arrangement of 10 treatments with 6 replicate pens per treatment and 16 ducks per pen fed to 49 D of age. Experimental factors included five dietary CP levels ranging from 13.5 to 17.5% and with or without protease (200 mg/kg) supplementation. Between day 28 to 34, the digestible and metabolizable trials were performed. Significant CP × protease interactions (P < 0.05) on breast meat yield, DM, energy and nitrogen utilization, as well as standardized ileal digestibility values of 7 amino acids were observed. Regardless of protease supplementation, ducks fed 13.5, 14.5, and 15.5% CP had a poorer (P < 0.05) growth performance and breast meat yield than ducks fed with 16.5 and 17.5% CP. Ducks fed 13.5% CP had a positive effect (P < 0.05) on meat quality, dietary DM, energy and nitrogen utilization as well as standardized ileal digestibility of amino acids. Protease supplementation increased (P < 0.05) DM and phosphorus retention and decreased (P < 0.05) shear force of breast meat, regardless of CP level; when CP = 14.5%, protease significantly increased (P < 0.05) breast muscle yield. The optimal CP requirement without or with protease supplementation for BWG and FI were 17.02 or 16.53% and 16.64 or 16.75%, respectively, based on linear broken-line regression.

Development of Al-TiCN nanocomposites via ultrasonic assisted casting route.

This work provides a promising approach to achieve the uniform distribution of TiCN nanoparticles (NPs) in aluminum matrix via a combination of ultrasonic dispersion and fast cooling processing. Microstructure analysis demonstrates that as the cooling rate is increased, the NP distribution in the matrix varies from intergranular to intragranular at micro scale and the NP-matrix interface from incoherent to coherent at nano scale. An analytical model is proposed to unveil the effects of cooling rates on the behavior of NPs at the solidification front. The theoretical analysis reveals that the NP size and cooling rate are the two prominent factors determining the NP distribution during solidification of nanocomposites. The experimental results yield an insight into the understanding of NP-induced microstructural evolution and shed new light on the development of high-performance nanocomposites.

Dissecting x-ray-emitting gas around the center of our galaxy.

Most supermassive black holes (SMBHs) are accreting at very low levels and are difficult to distinguish from the galaxy centers where they reside. Our own Galaxy's SMBH provides an instructive exception, and we present a close-up view of its quiescent x-ray emission based on 3 megaseconds of Chandra observations. Although the x-ray emission is elongated and aligns well with a surrounding disk of massive stars, we can rule out a concentration of low-mass coronally active stars as the origin of the emission on the basis of the lack of predicted iron (Fe) Kα emission. The extremely weak hydrogen (H)-like Fe Kα line further suggests the presence of an outflow from the accretion flow onto the SMBH. These results provide important constraints for models of the prevalent radiatively inefficient accretion state.

Haemodynamic brain response to visual sexual stimuli is different between homosexual and heterosexual men.

The underlying neurobiological factors involved in sexual orientation are largely unknown. This study investigated whether neural circuits or different cognitive processes accounted for differences in brain activation in 14 heterosexual and 14 homosexual males. Brain scans were undertaken in each subject using functional magnetic resonance imaging while they viewed different sexual stimuli, i.e. heterosexual couple stimuli (HCS), gay couple stimuli (GCS), lesbian couple stimuli (LCS) and neutral stimuli (NS). Ratings of sexual attractiveness of the stimuli were assessed. Subjective sexual arousal was induced by HCS and GCS in heterosexual and homosexual men, respectively. Sexual disgust was induced by GCS and LCS in heterosexual and homosexual men, respectively. Compared with viewing NS, viewing sexual stimuli induced significantly different brain activations, most of which had the characteristics of cognitive processes. These observations suggest that different cognitive patterns may be the major cause of different subjective responses to sexual stimuli between heterosexual and homosexual men.

Patterns of brain activation during visually evoked sexual arousal differ between homosexual and heterosexual men.

BACKGROUND AND PURPOSE: Nowadays the mechanism of homosexuality is little known. Few studies have been carried out to explore the brain functional changes of homosexual men during sexual arousal. We used functional MR imaging (fMRI) to determine whether the patterns of brain activation in homosexual and heterosexual men differed during visually evoked sexual arousal. MATERIALS AND METHODS: To all the subjects (10 homosexual and 10 heterosexual), real-time visual stimulation was provided by 3-minute exposure to 3 types of erotic film: heterosexual couples (F-M), male homosexual couples (M-M), and female homosexual couples (F-F) engaged in sexual activity, during which time fMRI was used to determine the patterns of brain activation. Self-reports of level of sexual arousal were collected immediately afterward. RESULTS: Statistical parametric mapping showed that viewing erotic film excerpts that induced sexual arousal was associated, in both groups, with activation of the middle prefrontal gyrus, bilateral temporal lobe and postcentral gyrus, thalamus, insula, vermis, left precuneus, occipital cortex, parietal cortex, and cerebellum. In homosexual men, the left angular gyrus, left caudate nucleus, and right pallidum were activated; in contrast, heterosexual men showed no activation in these regions. However, heterosexual men showed activation in the bilateral lingual gyrus, right hippocampus, and right parahippocampal gyrus, areas not activated in homosexual men. In both groups, region-of-interest analysis revealed no correlation between the magnitude of amygdala or thalamus activation and the reported level of sexual arousal. CONCLUSION: Our findings indicate that different neural circuits are active during sexual arousal in homosexual and heterosexual men and may contribute to a better understanding of the neural basis of male sexual orientation.

Various inotropic effects of angiotensin II in post-ischaemic rat hearts depending on ischaemic time with possible involvement of protein kinase C.

AIMS: The present study investigated if the inotropic effect of angiotensin II (AngII) is altered during post-ischaemic reperfusion in hearts subjected to mild and severe ischaemia. The possible involvement of protein kinase C (PKC) in the change in the inotropic effect was also investigated. METHODS: Isolated Langendorff-perfused rat hearts were perfused under constant flow with oxygenated Krebs-Henseleit buffer and paced at 360 beats min(-1). A saline-filled balloon catheter inserted into the left ventricle was used for measurement of contractile force. In the first series of experiments, hearts were subjected to continuous perfusion, 15- or 25-min global ischaemia followed by 45-min reperfusion. At the end of reperfusion, 0.1 micromol L(-1) AngII was infused for 5 min. In a second series of experiments, AngII was infused in hearts subjected to 25-min ischaemia followed by 45-min reperfusion in the absence or presence of the PKC inhibitor chelerythrine chloride (5 micromol L(-1)). RESULTS: The current study demonstrates that AngII exerts a positive inotropic effect in normoxic hearts with an increase of left ventricular developed pressure (LVDP) by 11% (P<0.05 vs. prior to AngII infusion). In post-ischaemic hearts subjected to 15-min ischaemia no effect of AngII was observed. In hearts subjected to 25 min of ischaemia, however, AngII evoked a negative inotropic response with a decrease of LVDP by 18% (P<0.05 vs. prior to AngII infusion). The negative inotropic effect of AngII was inhibited by the PKC inhibitor chelerythrine chloride. CONCLUSIONS: AngII exerts negative inotropic effect in severely injured post-ischaemic heart, possibly through the PKC pathway.

Cyclic fluctuations in the cardiac performance of the isolated Langendorff-perfused mouse heart: pyruvate abolishes the fluctuations and has an anti-ischaemic effect.

During the development of a Langendorff preparation of isolated mouse hearts, hitherto undescribed cyclic fluctuations in left ventricular pressure and coronary flow were independently observed in three laboratories. Isolated mouse hearts were perfused with crystalloid glucose-containing Krebs-Hensleit buffer in a constant pressure model, and left ventricular pressures were measured via an intraventricular balloon catheter. After acquiring technical skill in preparing the mouse hearts, the perfusionists observed that fluctuations in cardiac performance with a cycle period lasting 5-10 min occurred shortly after initiation of perfusion. Each fluctuation cycle consisted of a phase of increase and a phase of decrease. Synchronized with the fluctuations in left ventricular pressure, increases and decreases in dP/dt max took place. Analogous fluctuations in coronary flow occurred, with onset 1-2 min later than changes in left ventricular systolic pressure. In some preparations a gradual ST-segment elevation was seen on the electrocardiogram during the systolic pressure increase phase. The amplitude of the fluctuations could be augmented by increasing the perfusion pressure, and reduced, but not abolished, by lowering the pressure. Changes in buffer calcium, magnesium, or sodium concentration did not alter the fluctuations, nor did any change of anaesthetics, mouse strain, or left ventricular drainage. Altering the perfusion mode from constant pressure to constant flow did not prevent the occurrence of the cyclic fluctuations. The hearts became stable and the fluctuations disappeared when the buffer was supplemented with 2 mm pyruvate. In the present study, pyruvate given throughout stabilization and reperfusion also markedly attenuated the ischaemic insult, as evidenced by the delayed ischaemic contracture and a reduced magnitude of ischaemic contracture. A cardioprotective effect was only visible at early reperfusion, did not affect the final functional recovery. In conclusion, a phenomenon of cyclic fluctuations in left ventricular pressure followed by fluctuations in coronary flow was observed in isolated mouse hearts. These could be abolished by adding 2 mm pyruvate to the perfusion buffer. Pyruvate in the buffer also markedly attenuated the post-ischaemic deterioration of cardiac performance seen in this mouse model.

A faint discrete source origin for the highly ionized iron emission from the Galactic Centre region.

The origin of the X-ray emission for the central region of our Galaxy has remained a mystery. In particular, the relative spectral contributions of the diffuse emission and discrete sources, which are critical to understanding the high-energy phenomena in this environment, have been unclear because of the lack of sufficient spatial resolution. Here we report the results of a large-scale imaging survey of the Galactic Centre that resolves these components. We find that the Kalpha emission from iron that has been highly ionized (so that it has only two electrons left), which has previously been attributed to the diffuse component, actually arises mainly from discrete sources. This suggests that the presence of a large amount of hot gas (T approximately 108 K) is no longer required to explain the iron line emission. The spectra of the discrete sources indicate the presence of numerous accreting white dwarfs, neutron stars, and/or black holes in the region. The diffuse emission dominates over the contribution from the faint point sources, and is shown to be associated globally with interstellar features that have been observed at radio and mid-infrared wavelengths, suggesting that it is the product of recent massive star formation.

Relationship between ischaemic time and ischaemia/reperfusion injury in isolated Langendorff-perfused mouse hearts.

Myocardial functional recovery and creatine kinase (CK) release following various periods of ischaemia were investigated in isolated mouse hearts. The hearts were perfused in the Langendorff mode with pyruvate-containing Krebs-Hensleit (KH) buffer under a constant perfusion pressure of 80 mmHg, and were subjected to either continuous perfusion or to 5, 15, 20, 25, 30, 45 or 60 min of global ischaemia followed by 45 min of reperfusion. In hearts subjected to ischaemic periods of 5, 15 or 20 min, there was a transient reduction in the left ventricular (LV) dP/dt max during the early phase of reperfusion, while the recovery at the end of reperfusion reached a level similar to that in hearts subjected to continuous perfusion. In hearts subjected to longer ischaemic periods, i.e. 25, 30, 45 or 60 min, the decrease in the cardiac performance was more pronounced and persistent, with significantly lower recovery in LV dP/dt max and higher LV end diastolic pressure (LVEDP) at the end of reperfusion than in the non-ischaemic hearts. There were no significant differences in the recoveries in coronary flow or in heart rate (HR) between groups. Similarly to the functional recovery, the release of CK showed a clear ischaemic length-related increase. In conclusion, the Langendorff-perfused isolated mouse heart could be a valuable model for studies of myocardial ischaemia/reperfusion injury. Future studies using gene-targeted mice would add valuable knowledge to the understanding of myocardial ischaemia/reperfusion injury.

Sensitization of human colon cancer cells to TRAIL-mediated apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL), a novel member of the tumor necrosis factor (TNF) family, is thought to induce apoptosis preferentially in cancer cells; however, increasing evidence suggests that a number of cancers are resistant to TRAIL treatment. FLICE-like inhibitory protein (FLIP), which structurally resembles caspase-8, can act as an inhibitor of apoptosis when expressed at high levels in certain cancer cells. The purpose of our present study was to determine whether human colon cancer cells are sensitive to TRAIL treatment and, if not, to identify potential mechanisms of resistance. Colon cancer cells of different metastatic potential (KM12C, KML4A, and KM20) were found to be resistant to the effects of TRAIL when used as a single agent. FLIP expression levels were increased in all three KM cell lines. Treatment with either actinomycin D (Act D;10 :g/ml) or cycloheximide (CHX; 10 :g/ml) decreased FLIP expression levels in all three cell lines. The decrease in cellular levels of FLIP was associated with sensitization to TRAIL-mediated apoptosis, as demonstrated by enhanced cell death and caspase-3 activity compared with either Act D or CHX alone. Our findings suggest that reduction of FLIP levels by Act D or CHX renders TRAIL-resistant human colon cancer cells sensitive to TRAIL-mediated apoptosis. The combination of TRAIL along with agents such as Act D or CHX, which target proteins that prevent cell death, may provide a more effective and less toxic regimen for treatment of resistant colon cancers.

Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist clevidipine.

To test the hypothesis that calcium antagonists protect the myocardium from reperfusion-induced damage by local myocardial mechanisms just at the time of reperfusion, the myocardioprotective effects of the dihydropyridine clevidipine were investigated, taking advantage of its ultrashort-acting effect. Pigs were subjected to 45 min of myocardial ischemia by occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Either clevidipine (0.3 nmol/kg/min, n = 6) or the corresponding amount of vehicle (n = 6) was administered to the ischemic myocardium by retrograde coronary venous infusion over a 30-min period starting 10 min before reperfusion. Hemodynamic variables (heart rate, left ventricular systolic and end-diastolic pressure, max dP/dt, and mean arterial blood pressure) as well as coronary blood flow were measured throughout the experiment. At the end of reperfusion, the area at risk (percentage of left ventricle) was determined by infusion of Evans blue into the left atrium, and the infarct size, by triphenyl tetrazolium chloride (TTC) staining. The plasma level of endothelin-like immunoreactivity (ET-LI) was analyzed in blood from the aorta and the anterior coronary vein before ischemia and at different times during reperfusion. The area at risk was similar in the vehicle and the clevidipine groups. The infarct size, expressed as a percentage of the area at risk, was 80 +/- 9.2 in the vehicle group, whereas it was significantly reduced to 51 +/- 9.2% in the clevidipine group (p < 0.01). Clevidipine did not influence any of the hemodynamic variables measured throughout the study. A nonsignificant trend toward decreased total ET-LI overflow during 4-h reperfusion was observed in the clevidipine-treated pigs compared with vehicle-treated ones (5.3 +/- 1.4 vs. 7.1 +/- 3.4 pmol). These results demonstrate that, in this model of ischemia/reperfusion-induced myocardial infarction, clevidipine reduced the damage to the myocardium when given in association with reperfusion. The local administration of the compound together with its short blood half-life shows that clevidipine reduces reperfusion-induced damage by local mechanisms within the ischemic tissue rather than by peripheral mechanisms.

The role of the L-arginine/nitric oxide pathway in myocardial ischaemic and reperfusion injury.

Myocardial ischaemia followed by reperfusion (I/R) is associated with impaired endothelial function including diminished release and/or effects of nitric oxide (NO) which may contribute to the development of I/R injury. The aim of the present study was to investigate the role of the L-arginine/NO pathway in myocardial I/R injury. In isolated rat hearts subjected to global ischaemia followed by reperfusion L-arginine and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), but not D-arginine, significantly enhanced the recoveries of mycardial performance and coronary flow, and reduced the area of no-reflow and creatine kinase outflow. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the protective effects of L-arginine. Endothelium-dependent vasodilatation after I/R was preserved in L-arginine treated but not in vehicle hearts. Following I/R Ca2+-dependent NO synthase activity was reduced by 90% in comparison with non-ischaemic hearts. L-arginine but not D-arginine significantly increased NO synthase activity. In anaesthetized pigs, L-arginine given by local coronary venous retroinfusion reduced myocardial infarct size induced by 45 min of coronary artery ligation and 4 h of reperfusion to 35% of the area at risk from 76% in controls. The protective effect of L-arginine was blocked by L-NNA. Acetylcholine-induced coronary vasodilatation following I/R was attenuated in controls but not in L-arginine treated pigs. It is concluded that L-arginine or the NO donor SNAP reduces I/R-induced myocardial and endothelial injury. The protective effect of L-arginine seems to be mediated through maintained production of NO by preserving the function of Ca2+-dependent NO synthase in the heart.

Combination of a calcium antagonist, a lipid-peroxidation inhibitor, and an angiotensin AT1-receptor antagonist provides additive myocardial infarct size-limiting effect in pigs.

The calcium antagonist felodipine, the lipid-peroxidation inhibitor H290/51, and the angiotensin II type 1 (AT1)-receptor antagonist candesartan all exert beneficial effects on myocardial ischemia/reperfusion injury. This study was undertaken to test the hypothesis that a combination of these drugs with different pharmacologic properties could exert additive cardioprotective effects. Anesthetized pigs were subjected to 45 min of left anterior descending coronary artery occlusion followed by 240 min of reperfusion. Five groups of pigs were randomly given either 0.65 microM (7 nmol/kg) felodipine, 1.0 microM (3.1 microg/kg) H 290/51, 4.2 microM (20 microg/kg) candesartan, a cocktail of these three drugs, or vehicle (n = 6 for each) for 30 min starting at 5 min before reperfusion by coronary venous retroinfusion, which delivers drugs specifically to the ischemic regions. Systolic segment shortening (%SS) was measured by sonomicrometer. The myocardial area at risk and the final infarct size were determined by Evans blue and 2,3,5-triphenyl tetrazolium chloride staining. The hemodynamics did not change significantly during the study. In the vehicle group, the recovery of coronary flow was not maintained during reperfusion, and it was significantly lower after 240 min of reperfusion than during the preischemic period (p < 0.05). The coronary flow in the drug-treated groups was approximately the same by the end of the reperfusion period as that before the induction of ischemia. In the ischemic myocardium, %SS slightly recovered during reperfusion in the four drug-treated groups, but not in the vehicle group. The infarct size, expressed as a percentage of the myocardial area at risk, was smaller in all four drug-treated groups compared with the vehicle group. The infarct size in the cocktail group was significantly smaller than that in the groups given felodipine, H290/51, or candesartan alone. These results demonstrate that a combination of a calcium antagonist, a lipid-peroxidation inhibitor, and an angiotensin AT1-receptor antagonist has an additive effect on infarct limitation, indicating that combined therapy with agents having different pharmacologic modes of action may provide better cardioprotection than any of the drugs alone. The findings also support the view that reperfusion injury is possibly mediated by a combination of mechanisms.

The angiotensin II AT1 receptor antagonist candesartan at antihypertensive plasma concentrations reduces damage induced by ischemia-reperfusion.

The aim of this study was to investigate if the angiotensin II AT1 receptor antagonist candesartan in antihypertensive plasma concentrations improves myocardial function and limits infarct size in anesthetized pigs. Animals were subjected to 45 min of regional ischemia and 240 min of reperfusion. Starting 60 min before ischemia, two groups of pigs (n = 6 in each) received either candesartan (25 micrograms/kg bolus followed by a continuous infusion at a rate of 14 micrograms/kg/h) or the corresponding volume of vehicle throughout the study period. Left ventricular systolic segment shortening (%SS) was measured by sonomicrometry, and infarct size was determined by triphenyl tetrazolium chloride staining. The plasma concentration of candesartan during the experiment was between 100 and 150 nmol/L, which was considered to be within the therapeutic range. Neither candesartan nor vehicle affected hemodynamics or coronary blood flow prior to ischemia. Compared to vehicle, candesartan improved recovery of %SS in the ischemic area. At 240 min of reperfusion, the %SS was significantly higher in pigs given candesartan than in pigs given vehicle (7.1 +/- 0.87% vs-1 +/- 1.79%; p < 0.01). In both groups the area at risk was approximately 20% of the left ventricle. Infarct size as a percentage of the area at risk was significantly smaller in the candesartan group than in the vehicle group (46 +/- 3.0 vs 73 +/- 3.6%; p < 0.01). The results suggest that angiotensin II AT1 receptor blockade, obtained in antihypertensive plasma concentrations, supports myocardial functional recovery and limits infarct size.

Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts.

Two angiotensin AT1 receptor antagonists with different receptor binding characteristics, candesartan (insurmountable antagonism) and losartan (surmountable antagonism), were compared as regards their effects on angiotensin II-induced vasoconstriction and on myocardial ischemia/reperfusion injury. In isolated rat hearts perfused under constant flow, it was found that at equipotent concentrations candesartan (10 nM) and losartan (3 microM) almost completely inhibited the angiotensin II-induced increase in coronary perfusion pressure. However, if a washout period was introduced before the angiotensin II challenge, the effect of losartan quickly vanished, while that of candesartan remained. In hearts subjected to 25 min of global ischemia and 45 min of reperfusion, pre-treatment with candesartan (10 nM) or losartan (3 microM) immediately prior to ischemia improved the recovery of left ventricular developed pressure as compared to the effect of vehicle (69 +/- 3.2 and 64 +/- 2.3 vs. 44 +/- 6.2%, respectively; mean +/- S.E.M, P < 0.05). When ischemia was initiated following 30 min of washout after drug administration, the recovery of left ventricular developed pressure was higher in the candesartan group (73 +/- 3.2%, P < 0.05), but not in the losartan group (63 +/- 2.8%), than in the vehicle group (58 +/- 4.8%). The cumulative creatine kinase release during the first 30 min of reperfusion in the washout experiments was lower in the candesartan group (28.5 +/- 2.30 U, P < 0.05), but not in the losartan (40.8 +/- 6.73 U) group, than in the vehicle group (48.1 +/- 4.35 U). No significant difference between groups in left ventricular end-diastolic pressure and coronary perfusion pressure was found. The present results demonstrate that angiotensin AT1 receptor antagonists at equipotent concentrations could differ in their cardioprotective effects in hearts subjected to ischemia/reperfusion. It is suggested that the insurmountable AT1 receptor characteristics of candesartan could provide more persistent cardioprotection than the surmountable receptor characteristics of losartan.

Cardiac inotropic vs. chronotropic selectivity of isradipine, nifedipine and clevidipine, a new ultrashort-acting dihydropyridine.

Cardiac effects of clevidipine, a new ultrashort-acting dihydropyridine Ca2+ channel antagonist were investigated in Langendorff-perfused rat hearts and compared to those of nifedipine and isradipine. The aim was to determine and compare the negative inotropic vs. chronotropic potency of these drugs. The hearts were perfused with oxygenated Krebs-Henseleit buffer at a perfusion pressure of 90 cm H2O. After stabilization, one concentration of each drug was administered for 45 min followed by a higher concentration for an additional 45 min. The concentrations of each drug in this study were 10(-9), 3 x 10(-9), 10(-8), 10(-7), 10(-6.5) and 10(-6) M for clevidipine and nifedipine, and 10(-10), 3 x 10(-10), 10(-9), 10(-8), 10(-7.5) and 10(-7) M for isradipine. Each concentration of each drug was tested in six hearts. Coronary flow, left ventricular dP/dt max, left ventricular systolic pressure and heart rate were recorded when the hearts were beating spontaneously and during pacing at a constant rate for 1 min. Spontaneous heart rate and atrio-ventricular conduction were not affected by clevidipine at any of the concentrations studied, while nifedipine and isradipine caused a concentration-dependent decrease. These two drugs caused atrio-ventricular block at high concentrations. All three compounds reduced cardiac contractility in a concentration-dependent manner. When isradipine was administered, at a given concentration, heart rate and contractility decreased proportionately. When clevidipine or nifedipine was given, at a given concentration, the proportionate reduction in left ventricular dP/dt max was greater than that in heart rate, resulting in a high inotropic vs. chronotropic selectivity. It is concluded that in contrast to nifedipine and isradipine, clevidipine does not impair atrio-ventricular conduction. Like nifedipine, clevidipine is selective for inotropic vs. chronotropic cardiac effects.

The angiotensin II AT1-receptor antagonist candesartan improves functional recovery and reduces the no-reflow area in reperfused ischemic rat hearts.

It is not yet clear if cardiac angiotensin II is involved in the pathophysiology of myocardial ischemia/ reperfusion injury. The aim of this study was to investigate the effect of the angiotensin II AT1-receptor antagonist candesartan on myocardial functional recovery in isolated rat hearts subjected to ischemia and reperfusion. Three groups of hearts perfused in the Langendorff mode with Krebs-Henseleit buffer under constant pressure received either vehicle (n = 7), candesartan, 1 nM (n = 6), or 100 nM (n = 7) at the start of 30 min of global ischemia. The recovery of the double product was significantly higher in the candesartan, 100 nM, group (75+/-9.2%) than in the vehicle group (40+/-5.1%; p < 0.05). At the end of 30 min of reperfusion, left ventricular end diastolic pressure was lower in rats given candesartan, 100 nM, than in rats given vehicle (10+/-4.3 vs. 38+/-4.8 mm Hg; p < 0.05). After ischemia and reperfusion, there was a large no-reflow area in the vehicle group (28+/-3.1% of the left ventricle), which was reduced by candesartan, 100 nM (12+/-1.3%; p < 0.05). In rats given candesartan, 1 nM, there was a trend toward a higher recovery of the double product (73+/-13.4%), a lower left ventricular end-diastolic pressure (29+/-6.6 mm Hg), and a smaller no-reflow area (19+/-3.5% of the left ventricle) compared with the rats receiving vehicle. These trends did, however, not reach statistical significance. Our results demonstrate that candesartan reduces myocardial ischemia/reperfusion injury, thus indicating that endogenous cardiac angiotensin II is involved in the tissue injury after myocardial ischemia and reperfusion.

Effects of the angiotensin AT1 receptor blocker candesartan on myocardial ischemic/reperfusion injury.

The effect of the insurmountable angiotensin II AT1 receptor blocker candesartan on ischemic/reperfusion injury was investigated in isolated rat hearts and in anesthetized pigs. The possible additive effect of candesartan on the cardioprotection by a calcium antagonist and a lipid peroxidation inhibitor was also studied. In Langendorff-perfused rat hearts, candesartan, in a dose-related manner, improved left ventricular functional recovery and reduced the no-reflow area following global ischemia and reperfusion. A similar degree of cardioprotection by candesartan (10 nM) and an equipotent concentration of another AT1 receptor blocker losartan (3 microM) was observed when ischemia was begun immediately after drug pretreatment. When a washout period was implemented between pretreatment and ischemia, the protective effect of candesartan, but not that of losartan, remained, suggesting that candesartan may provide a more efficient cardioprotection than losartan. In anesthetized pigs subjected to 45 min of coronary artery occlusion followed by 240 min of reperfusion, local coronary venous retroinfusion (0.042, 0.42, and 4.2 microM) of candesartan starting just before reperfusion improved, in a dose-related manner, the recovery of myocardial segment shortening (sonomicrometer) and reduced infarct size without persistent effect on regional myocardial blood flow (microspheres). A combination of candesartan, felodipine, and the lipid peroxidation inhibitor H290/51 produced a more pronounced infarct limitation than each of these agents alone. In conclusion, candesartan exerts a cardioprotective effect, via a local mechanism within the ischemic myocardium. A combination of drugs with different pharmacologic profiles may provide a better cardioprotection in the setting of myocardial ischemic/reperfusion compared with each individual compound.