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Background: Extension of the elbow joint is maintained during shoulder flexion. In contrast, the arm starts from the flexed position of the elbow joint and the joint gradually extends during reaching elevation. Objectives: This study aimed to compare the kinematic elements and electromyographic (EMG) activities of the rotator cuff muscles between flexion and reaching elevation. Methods: The study included 10 healthy young men. (average age, 21.5 ± 3.4 years), and measurements were performed on their dominant arms. A three-dimensional motion analyzer was used to record the following elements during shoulder flexion and reaching elevation: the angles of glenohumeral joint elevation and scapular upward rotation, scapulohumeral rhythm, external rotation of the humerus, and glenohumeral plane shifting from the coronal plane. The EMG activities in the supraspinatus, infraspinatus, subscapularis, and teres minor were recorded simultaneously. Results: The plane of reaching elevation was retained at 60° from the coronal plane. The glenohumeral planes (P < 0 .01) and the external rotation angles of the humerus below 90° of elevation (P < 0.05) were significantly different between both the motions. The EMG activities in the supraspinatus (P < .01), infraspinatus (P < 0.05), and teres minor (P < 0.01) were significantly lower while reaching elevation than those during flexion. Conclusion: The motion plane at 60° from the coronal plane, movement of the humeral external rotation, and EMG activities of the rotator cuff muscles were different during reaching elevation and shoulder flexion.

Background/Aims Gastric acid secretion is suspected to be a pivotal contributor to the pathogenesis of functional dyspepsia. The present study investigates the potential association of the gastric acid secretion estimated by measuring serum pepsinogen with therapeutic responsiveness to the prokinetic drug acotiamide. Methods Dyspeptic patients consulting participating clinics from October 2017 to March 2019 were prospectively enrolled in the study. The dyspeptic symptoms were classified into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Gastric acid secretion levels were estimated by the Helicobacter pylori infection status and serum pepsinogen using established criteria and classified into hypo-, normo-, and hyper-secretion. Each patient was then administered 100 mg acotiamide thrice daily for 4 weeks, and the response rate to the treatment was evaluated using the overall treatment efficacy scale. Results Of the 86 enrolled patients, 56 (65.1%) and 26 (30.2%) were classified into PDS and EPS, respectively. The estimated gastric acid secretion was not significantly different between PDS and EPS. The response rates were 66.0% for PDS and 73.1% for EPS, showing no significant difference. While the response rates were stable, ranging from 61.0% to 75.0% regardless of the estimated gastric acid secretion level among subjects with PDF, the rates were significantly lower in hyper-secretors than in non-hyper-secretors among subjects with EPS (42.0% vs 83.0%, P = 0.046). Conclusion Although acotiamide is effective for treating EPS as well as PDS overall, the efficacy is somewhat limited in EPS with gastric acid hyper-secretion, with gastric acid suppressants, such as proton pump inhibitors, being more suitable.

The coronary venous system is an alternate route for drug delivery to the acutely ischemic myocardium when the coronary arterial blood flow is impeded. This study was designed to determine the effect of retrograde infusion of lipid microsphere containing prostaglandin E1 (lipo-PGE1), which is believed to prevent rapid destruction of PGE1, on myocardial infarct size after acute myocardial ischemia and reperfusion. Twenty-one open-chest porcine models were subjected to 45 minutes of left anterior descending coronary artery (LAD) occlusion followed by 4 hours of reperfusion. Group A (n=7), the control group, was given, into the great cardiac vein, 4 ml of vehicle dissolved in 36 ml of saline for 5 minutes starting before the onset of reperfusion. In group B (n=7), 20 µg/4ml of lipo-PGE1 was administered into the great cardiac vein in the same manner as in group A. Group C (n=7) was treated the same as group B, but lipo-PGE1 was injected into the inferior vena caval vein. Infarct size, expressed as a percentage of area at risk, was significantly smaller in group B (56.1±12.6%) than groups A (79.4±11.4%) and C (83.0±11.1%) (p

A 72-year-old male visited our hospital for further evaluation of esophageal varices. Telangiectasias were present in the stomach. He had recurrent epistaxis, which was also confirmed in his family's medical history. We diagnosed this case as Osler-Weber-Rendu disease. He had concomitant with hepatic nodular change. Abdominal angiography showed arterio-portal (A-P) shunts, superior mesenteric artery (SMA)-superior mesenteric vein (SMV) shunt, extension of SMV, and dilated and meandering portal vein. Esophageal varices were treated by endoscopic variceral ligation (EVL) and argon plasma coagulation (APC) therapy for prophylaxis of bleeding.

Background and Aim: A 70-kDa heat shock protein (stress-inducible HSP70, HSP72) has been reported to be a cytoprotectant in a variety of organs. It has been reported that HSP72 protected non-cirrhotic rats against endotoxemia. However, its cytoprotective effect against endotoxemia in cirrhotic rats has not yet been studied. In this study, we investigated the cytoprotective effect of HSP72 on lipopolysaccharide (LPS)-induced liver injury in carbon tetrachloride (CCl4)-induced cirrhotic rats. Methods: Liver cirrhosis was produced by an 8-week intraperitoneal injection of CCl4 in male Sprague–Dawley rats. Expression of HSP72 was investigated using western blot analysis. Cirrhotic rats were given an intraperitoneal injection of LPS (10 mg/kg) with or without hyperthermia (42.5°C, 15 min) preconditioning. Liver injury was assessed biochemically (aspartate transaminase, alanine transaminase, bilirubin, lactate dehydrogenase, creatinine) and histologically. The plasma tumor necrosis factor (TNF)-α level was determined. Results: Hyperthermia preconditioning induced a 4-fold increase in HSP72 in the cirrhotic rat liver. Pre-induction of HSP72 prevented LPS-induced liver injury, as evaluated using serum biochemical parameters and histology with reduced TNF-α response. Conclusion: These findings suggest that pre-induction of HSP72 may provide therapeutic strategies for Gram-negative sepsis-induced liver injury in liver cirrhosis.

An experimental study was performed to clarify the flame structure of a burning fuel droplet. Both OH and soot concentration distributions were measured along diametrical line passing through the center of fuel droplet and the front stagnation point of a fuel droplet flame in steady air stream.The laser induced fluorescence and the laser light scattering techniques were applied for the measurement of OH and soot concentration distributions, respectively. An Nd : YAG laser-pumped pulsed dye laser emitting monochromatic radiation at a wavelength of 283.56 nm was used as the light source for these measurements. Fuel employed were n-heptane, n-hexadecane, benzen, methanol and their mixtures. The results showed that the highly sooting region was located deep inside the flame front, and near the flame front was located the maximum of OH concentration. An increase in the relative humidity in the air stream caused the decrease of OH concentration.

Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium, clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during ischemia. The current study explored the pharmacokinetics of clevidipine when administered locally into the coronary circulation. Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to myocardial ischemia through ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls. Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a catheter distal to the LAD ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD ligation, or in the nonligated group following the drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of clevidipine from the femoral artery and the coronary vein during reperfusion and during drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts, clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of ischemia, very low levels of clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of clevidipine did not differ with the length of myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of clevidipine does not reach pharmacologically active levels. Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.

Off-pump coronary artery bypass grafting (CABG) has become a popular procedure. However, temporary occlusion of the target vessel is sometimes a threat to the patients. Although ischemic preconditioning (IP) has been proposed to reduce myocardial injury, its effects remain controversial. The coronary veins represent an alternate route for delivery of therapeutic agents and arterial blood to the acutely ischemic myocardium. The aim of this study was to investigate the protective effect against myocardial ischemia and reperfusion injury of combined IP and synchronized coronary venous retroperfusion (SCVR) in an off-pump CABG model. Twenty-one pigs were assigned to 3 groups of 7 animals. In the control group, the left anterior descending coronary artery (LAD) was occluded for 45 min followed by 2 h of reperfusion using a left intrathoracic artery (LITA) bypass circuit. In the IP group, LAD occlusion was done for 5 min with 15 min of reperfusion, followed by 45 min of LAD occlusion. In the SCVR group, pretreatment before LAD occlusion was the same as in the IP group. Then, SCVR was commenced just after the start of LAD occlusion for 45 min. The percent systolic shortening of ischemic myocardium (measured by sonomicrometry) after reperfusion via the LITA was significantly (p < 0.001) greater in the SCVR group (14.6 +/- 3.3%) than in the control group (-1.6 +/- 5.6%, 95%CI: -24.3 - -8.1) or the IP group (0.7 +/- 8.0%, 95%CI: -22.0 - -5.8) after 30 min of reperfusion, and this difference persisted throughout the reperfusion period. Infarct size (expressed as a percentage of the area at risk) was significantly (p < 0.001) smaller in the SCVR group (2.4 +/- 2.7%) than in the control group (83.0 +/- 2.3%, 95%CI: -99.0 - -62.4) or the IP group (42.0 +/- 23.0%, 95%CI: -58.0 - -21.3). Combined SCVR and IP had a potent myocardial protective effect in the present off-pump CABG model. This method may be clinically feasible and may be able to prolong a safe coronary occlusion.

The laser-induced-fluorescence method has been employed for remote, non-intrusive and instantaneous measurements of a fuel droplet burning under microgravity. A fuel droplet was doped with naphthalene and TMPD. The fluorescence emission spectra from a droplet subjected to the incident nitrogen laser beam were measured with an image-intensifying optical multichannel analyser. The microgravity was generated in a capsule of a 100 m drop shaft. The results showed that the newly developed diagnostic system could be applied successfully for the simultaneous measurements of droplet temperature and diameters of the droplet, flame and soot shell under microgravity. The droplet temperature was determined from the measured ratio of fluorescence emission intensities at two different wavelengths. The soot shell was located in the vicinity of the droplet surface deep inside the flame during the early stage of the burning and moved away from the droplet with the elapse of time.

Objective: The objective of this study was to investigate the protective effects of nitric oxide synthase inhibitor, N g -nitro-l-arginine methyl ester hydrochloride, on reperfusion injury of the brain under hypothermic circulatory arrest. Methods: After cardiopulmonary bypass was established using 12 piglets each weighing about 30 kg, the animals were cooled to a brain temperature of 20° C and circulatory arrest was performed for 90 minutes followed by reperfusion for 120 minutes. The level of nitric oxide within the brain was measured with a needle electrode inserted into the brain. In the treatment group, N g -nitro-l-arginine methyl ester hydrochloride was administered with an intravenous injection of 1.5 mg/kg at the onset of the reperfusion followed by a 60-minute continuous venous infusion of 1.5 mg/kg/hr. Results: In the control group, nitric oxide levels within the brain increased not during ischemia but during reperfusion, and the level after 120 minutes of reperfusion increased significantly compared with that of before circulatory arrest. But in the treatment group, N g -nitro-l-arginine methyl ester hydrochloride administered at the onset of reperfusion inhibited nitric oxide production during reperfusion. A significant difference was observed between the groups regarding the nitric oxide level after 120 minutes of reperfusion. Regarding cerebral blood flow, excess lactate, and cerebral tissue water content, no significant difference was observed between the groups. However, recovery of somatosensory evoked potential after 120 minutes of reperfusion was detected in all six animals in the treatment group, but none in the control group ( p = 0.001). Conclusion: These data suggest that N g -nitro-l-arginine methyl ester hydrochloride protects the brain against reperfusion injury under hypothermic circulatory arrest. (J Thorac Cardiovasc Surg 1998;115:925-30)

In order to develop a natural gas fueled spark ignition engine with high thermal efficiency and clean exhaust gases, combustion characteristics of natural gas and air mixtures were examined using a rapid compression combustor. We concentrated on lean mixtures because of their potential for high efficiency and low pollutant emissions. To elucidate the effect of compression-induced physical aspects on the combustion process, the charge was kept quiescent before the start of the compression process. The results showed that an increased charge pressure increased the time required for combustion. A high compression ratio or piston speed tended to shorten the combustion time, but their effects were rather weak. An increased humidity in mixtures measurably increased the combustion time. The stratified charge, which was examined using the soap bubble method, markedly improved the combustion process of lean mixtures.

Twenty-three cases of aortic arch aneurysm, over the past 10 years, were divided into 3 groups of similar age and sex for comparison of operative technique. The aortic arch was reconstructed under normothermic femoral bypass via left posterolateral thoracotomy in 9 patients (group II), under hypothermic circulatory arrest via left posterolateral thoracotomy in 7patients (group II) and under hypothermic circulatory arrest with ascending aorta cannulation and brief retrograde systemic perfusion immediately after finishing reconstruction of the aortic arch via median sternotomy in 7 patients (group III). Surgical mortality in groups I, II and III was 33.3% (3/9), 14.3%(1/7)and14.3%(1/7), respectively. Cerebrovascular complications occurred in 1 of 8 patients (12.5%), excluding an intra-operative death, in group II, and in 4 of 7 cases (57%) in group II, of whom 2 were restored to consciousness. There were no cerebrovascular complications in group III (p< 0.005 v. group II). The patient in group III who died of a lung complication 11 days postoperatively was restored to consciousness. Circulatory arrest time was 30.7 ± 17 and 33 ± 17 minutes in groups II and III, respectively. This study demonstrated that normothermic bypass (group II) resulted in an unsatisfactory surgical outcome, and femoral artery cannulation (group II) caused increased cerebrovascular complications compared with ascending aortic cannulation (group III), suggesting that the retrograde aortic flow, but not circulatory arrest per se, predisposed cerebrovascular morbidity. Vascular embolism by debris could be prevented by normograde perfusion via the ascending aorta and brief retrograde systemic perfusion immediately after finishing reconstruction of the aortic arch.

Objective Local recurrence after radiofrequency ablation (RFA) is a major problem that needs to resolved to increase the survival rate of hepatocellular carcinoma (HCC). CE-US with Sonazoid®, the second-generation contrast media, can detect smaller HCC lesions and the detection rate of ultrasonically unrecognized hypervascular HCC was improved by CE-US. The aim of the present study was to evaluate the role of CE-US with Sonazoid® in improving radicality and reducing local recurrence after RFA for HCC. Patients and Methods A total of 102 nodules treated by RFA at our hospital from January 2006 to October 2009 were enrolled: 31 nodules were treated without CE-US, since CE-US was not yet available (Group A), and 71 nodules were treated with a combination of RFA and CE-US with Sonazoid® (Group B). Results The clinical characteristics (sex, virus marker, Child-Pugh grade, with or without transcatheter arterial infusion chemotherapy with lipiodol, and T factor) did not differ significantly between group A and group B. Mean age was significantly older and tumor size was significantly larger in group B. Group B had significantly better radicality compared with group A. The non-local recurrence rate was significantly higher in group B as compared with group A. Conclusion CE-US with Sonazoid® greatly helps to improve RFA efficacy in HCC treatment. We suggest that the ability of CE-US with Sonazoid® to detect an accurate area of HCC before RFA and to immediately detect a residual tumor during RFA might contribute to an increase of the radicality and reduction of local recurrence after RFA.

The biocompatibility of the cardiopulmonary bypass (CPB) circuit, in which an oxygenator is solely heparinized, was assessed by systemic inflammatory reactions as an indicator during CPB. Fourteen patients, 11 males and 3 females, underwent coronary artery bypass surgery and were randomly divided into 2 groups of 7 patients each. For the heparin–coated oxygenator group (Group H), a heparin–coated membrane oxygenator was used in the CPB circuit, and in the control (Group C) an uncoated membrane oxygenator was employed. Systemic inflammatory reactions, such as platelet activation, prostaglandin production, complement activation, and activated granulocyte released substance, were measured prior to, during, and 6 h after CPB. The number of platelets decreased after protamine administration in both groups (14. 5 ±4. 7 times 104/μl in Group H and 13. 8 ± 8. 7 times 104/μd in Group C) and returned to baseline levels in Group H while it remained decreased in Group C at 6 h after CPB. The platelet factor 4 level was significantly lower in Group H (181 ± 40 ng/ml) than in Group C (297 ±131 ng/ml) after protamine administration. Thromboxane–B2 (TXB2) rose during CPB in both groups; however, there were significantly different levels of TXB2 between the 2 groups at 60 min after CPB (293±258 pg/ml in Group H versus 408 ± 120 pg/ml in Group C) and after protamine administration (259 ± 122 pg/ml in Group H versus 709 ± 418 pg/ml in Group C). Plasma concentrations of granulocyte elastase were significantly lower in Group H at 30, 60 and 90 min, immediately after, and post–CPB than those of Group C. Although the oxygenator was solely heparinized in the CPB circuit, it was sufficiently effective to reduce inflammatory reactions during coronary artery bypass operation, and the heparin–coated surface seems to be more endothelium–like.

A 78-year-old man complaining of chest pain was admitted to a nearby hospital with a diagnosis of acute myocardial infarction on March 26 1992. After discharge chest pain recurred and the patient was re-admitted to the same hospital with a diagnosis of angina pectoris after infarction, where internal treatment failed to control the pain. He was transferred to the hospital. On admission his condition was grade N according to NYHA classification. Based on test data, physiological age, and quality of life of the patient, it was thought that he was a possible candidate for operation. Coronary angiogram showed 99% stenosis of the left anterior descending artery and 99% stenosis of the right coronary artery. Aortogram showed severe aortic insufficiency. Emergency surgery was carried out on combination of coronary arterial bypass grafting and replacement of the aortic valve. The postoperative course was uneventful. In decision-making of operative indication for aged patients, we should consider the physiological age rather than real age, and perform operation aggressively, if the indication is reasonable.

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glisson's capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patient's prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Mao is one component of various traditional herbal medicines. We examined the effects of Mao on an acute liver failure model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). The lethality of mice administrated Mao with GalN/LPS was significantly decreased compared with that in mice without Mao. Hepatic apoptosis and inflammatory cell infiltration were slight in Mao-treated mice. Serum alanine aminotransferase (ALT) and total bilirubin (T.Bil) activity, tumor necrosis factor alpha (TNF-alpha) levels and caspase 8, 9, and 3 activity in the liver were significantly lower in mice administrated Mao. But, Serum interleukin-6 (IL-6), IL-10 levels and signal transducers and activators of transcription 3 (STAT3) activity in the liver were significantly higher in mice administrated Mao. To investigate the effect of STAT3, we used AG490, which selectively inhibits the activation of Janus kinase (JAK) family tyrosine kinase and inhibits the constitutive activation of STAT3. There was significant aggravation in hepatic apoptosis treated with Mao and AG490 compared with Mao alone. In conclusions, Mao significantly suppressed hepatic apoptosis by inhibition of TNF-alpha production and caspase activity. Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.

Genipin is a metabolite derived from the herbal medicine Inchinko-to. Little is known about the mechanism of genipin action on acute liver injury through inflammatory cytokines. We examined the effects of genipin on production of TNF-alpha in vivo and in vitro. Mice were given GalN/LPS with or without genipin treatment. All mice not given genipin died within 12h. But in mice given genipin, 8 of 15 mice survived for 24h after GalN/LPS administration. Histologically, hepatic necrosis and inflammatory cells infiltration were significantly slight in mice given genipin. Serum AST and ALT activity were significantly lower in mice given genipin. Serum and liver homogenate TNF-alpha levels were significantly lower in mice given genipin. However, in IL-6 and IL-1beta, there were no significant differences in mice given and not given genipin. TNF-alpha, NF-kappaB activation and TNF-alpha mRNA expression in a cultured mouse macrophage-like cell line J774.1 were significantly suppressed by genipin administration. In conclusion, the present findings suggest that genipin, a metabolite derived form the herbal medicine Inchinko-to improved acute liver dysfunction by suppressive effect of TNF-alpha production.

Previous studies have shown moderate or severe phlebitis at the site of venipuncture in some patients who receiving prostaglandin E1 (PGE1) infusion therapy. Such phlebitis is sometimes severe enough to necessitate the cessation of PGE1 therapy. This study investigated how to continue PGE1 infusion therapy for 3 weeks with tolerable phlebitis. Although a 60 μg dose of PGE1 is usually dissolved in 500 mL of fluid to avoid phlebitis, we used 200 mL to prevent volume overload. This PGE1 solution was neutralized to pH 7.4 with 4 mL of 7% sodium bicarbonate. We examined the frequency and severity of phlebitis among patients who received a 2-h PGE1 infusion twice daily. Eighteen patients who were hospitalized for peripheral vascular disease between June 1998 and May 1999 were studied. All of them were men and their mean age was 63.3 ±8.9 years (range: 47-78 years). Fourteen patients had arteriosclerosis obliterans and four had Buerger's disease. When the severity of phlebitis was determined according to Dinley's criteria, two patients (11%) had grade 0, four patients (22%) had grade 1, eleven patients (61%) had grade 2, and one patient (6%) had grade 3 phlebitis. Usually, PGE1 infusion therapy is stopped when phlebitis reaches grade 4 or more, but there were no such cases in this study. We also found that aging was significantly correlated with a decrease in the severity of phlebitis (Spearman's rank correlation test: r = -0.545, p = 0.0193).

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.

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.