Landiolol enhances effect of ischemic preconditioning in isolated rabbit hearts.

The effect of the ultra-short-acting beta blocker, landiolol, on ischemic preconditioning was examined in isolated rabbit hearts. Ischemic preconditioned hearts received 2 episodes of 5 min each of global ischemia and reperfusion. The left anterior descending coronary artery was occluded for 1 hour and reperfused for 1 hour. Left ventricular end-systolic and end-diastolic pressures and infarct size were measured. Seven control hearts had no drug infused. Four groups of 6 hearts each were pretreated with 1 or 3 microM of landiolol or a combination of 1 or 3 microM landiolol and ischemic preconditioning. A further group of 6 hearts had ischemic preconditioning without landiolol. Ischemic preconditioning significantly reduced left ventricular end-diastolic pressure and infarct size compared to the controls. Landiolol alone did not change left ventricular end-diastolic pressure or infarct size, but landiolol 3 microM and ischemic preconditioning decreased left ventricular end-diastolic pressure more than preconditioning alone. These data suggest that pre-ischemic landiolol infusion may enhance the cardioprotective effect of ischemic preconditioning.

Activation of beta2-adrenergic receptor plays a pivotal role in generating the protective effect of ischemic preconditioning in rat hearts.

BACKGROUND: Ischemic preconditioning (IPC) protects hearts against ischemia by reducing infarct size. However, IPC does not preserve cardiac function, such as left ventricular peak developed pressure (LVPDP). Moreover, IPC fails to protect the post-myocardial infarct (MI) heart. DESIGN: Rat hearts were transfected with beta2-adrenergic receptor (B2AR) cDNA by the hemagglutinating virus of Japan-liposome method. After the gene transfer, the hearts were perfused in a Langendorff mode and preconditioned with two cycles of 5 min of ischemia and reperfusion. After 20 min of global ischemia, the hearts were reperfused under aerobic conditions for 90 min. LVPDP was measured as an indicator of the cardiac function. RESULTS: LVPDP of ischemic hearts was well preserved by the combination treatment of IPC and gene transfer of B2AR, but not IPC or gene transfer of B2AR alone. Moreover, the treatment was beneficial to even the post-MI heart. On the contrary, gene transfer of beta-adrenergic receptor kinase 1 (BARK1) reduced the protective effect of IPC. We also found that the mRNA ratio of B2AR and BARK1 was well correlated with the preservation of the LVPDP. CONCLUSIONS: The combination treatment of IPC and gene transfer of B2AR protects cardiac function against ischemia and it shows the beneficial effect also in post-MI hearts.

Simultaneous onset of mitral regurgitation requiring surgery due to primary chordal rupture in middle-aged identical twins.

Primary chordal rupture is a leading cause of severe mitral regurgitation requiring surgery. It has previously been documented that there is a high probability of the occurrence of primary chordal rupture in patients with histological evidence of myxysomatous changes in the mitral valve. The precise etiology of primary chordal rupture and/or myxysomatous changes remains obscure and the relative contribution of genetic factors is debated. We report a pair of middle-aged identical twins requiring surgery for mitral regurgitation due to primary chordal rupture, and discuss the etiology of primary chordal rupture and/or myxysomatous changes.

ATP regulation of ciliary beat frequency in rat tracheal and distal airway epithelium.

Ciliary beat frequency (CBF) was measured by video-optical microscopy in rat tracheal and distal airway ciliary cells using a slice preparation. In tracheal ciliary cells (tracheal slice), ATP or 2-methylthio ATP (MeSATP) increased CBF, which was inhibited by suramin (100 microm, an inhibitor of purinergic receptor). Ionomycin (5 microm) or thapsigargin (2 microm) increased CBF similarly. Ca2+-free solution or addition of Ni2+ (1 mm) decreased CBF gradually by approximately 25% and subsequent stimulation with ATP (10 microm) increased CBF transiently. The purinergic agonist experiments demonstrated that ATP increases CBF in tracheal ciliary cells via both P2X and P2Y receptors. ATP increased the intracellular calcium concentration ([Ca2+]i) in tracheal ciliary cells. However, in distal airway ciliary cells (lung slice), ATP did not increase CBF and [Ca2+]i, although a Ca2+-free solution decreased CBF, and ionomycin (5 microm) or thapsigargin (2 microm) increased it. Moreover, acetylcholine (100 microm) did not increase CBF in distal airway ciliary cells, although it increased CBF in tracheal ciliary cells. Terbutaline (10 microm), a selective beta2-adrenergic agonist, increased CBF in both tracheal and distal airway ciliary cells. These observations suggest that the Ca2+-mobilization mechanisms via purinergic or muscarinic receptors of the distal airway ciliary cell may be different from those of the tracheal ciliary cell. In conclusion, the CBF increase is differently regulated in the tracheal and distal airway epithelia of the rat.

Axillo-axillary bypass for in-stent restenosis in Takayasu arteritis.

We report a patient with Takayasu arteritis (TA) who initially received stent placement (SP) following percutaneous transluminal balloon angioplasty for stenotic lesion of the left subclavian artery and subsequently had recurrent in-stent restenosis three times. Every time restenosis occurred, percutaneous transluminal rotational arterectomy (RA) was performed. After all, the patient underwent axillo-axillary bypass and has remained asymptomatic for 10 months after the surgery. We suggest that surgical treatment is beneficial for in-stent restenosis in patient with Takayasu arteritis.

A specific chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2-heptyl]acetamide (NK3201), suppresses development of abdominal aortic aneurysm in hamsters.

In this study, we investigated the effect of a specific chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[[3,4-dioxo-1-phenyl-7-(2-pyridyloxy)]-2-heptyl]acetamide (NK3201), in the development of abdominal aortic aneurysm in a hamster experimental model. The abdominal aortic aneurysm was induced by application of elastase onto the abdominal aorta in hamster. Each hamster was administered NK3201 (30 mg/kg/day p.o.) or placebo beginning 4 days before application of elastase and continuing through the experiments. Sham-operated hamsters received saline application onto the abdominal aorta. Two weeks after application of elastase, the aortic diameter in the placebo-treated group was significantly increased to 1.6-fold compared with the value for the sham-operated group, whereas that in the NK3201-treated group was significantly reduced. The chymase activities in the sham-operated and the placebo-treated groups were 0.35 +/- 0.01 and 3.44 +/- 0.62 mU/mg protein, respectively, and this difference was significant. NK3201 significantly reduced the chymase activity in the placebo-treated group. Here, we demonstrated for the first time that a chymase inhibitor prevented the development of abdominal aortic aneurysm in a hamster experimental model.

Stent-graft placement for mycotic aneurysm of the thoracic aorta: report of a case.

A 66-year-old man was found to have a mycotic aneurysm of the thoracic aorta. It was first suspected to be a pseudoaneurysm of the descending thoracic aorta on computed tomography scan, and the blood cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA). It was subsequently diagnosed as a mycotic aneurysm, but because the patient continued to do so poorly with septicemia, conventional surgery (ie, aortic exclusion and extraanatomic bypass, or surgical placement of in situ graft) was not performed. A stent-graft device composed of several units of self-expandable Z stents covered with ultra-thin woven Dacron was inserted through 21F sheath via the left external iliac artery and aortography showed successful deployment without blood endoleaks. The procedure was completed without incident and the patient has continued to do well. Endovascular stent-grafts may offer significant advantages for patients at high surgical risk.

Primary hemangiopericytoma of the trachea.

A 28-year-old man arrived at our hospital complaining of severe dyspnea. Bronchoscopic findings demonstrated that a tumor was located approximately 4 cm distant from the vocal cord, occupying most of the tracheal lumen. To urgently relieve the dyspnea, some parts of the tumor were cauterized with the neodymium:yttrium-aluminum garnet laser. Histopathologic examination of the cauterized specimen revealed malignant hemangiopericytoma. During the operation, the tumor was resected en bloc with a tracheal segment containing four tracheal cartilages. The patient's postoperative course was uneventful with no evidence of recurrence 1 year after the operation.

Neuroleptic malignant syndrome following cardiac surgery: successful treatment with dantrolene.

Neuroleptic malignant syndrome (NMS) is a rare idiosyncratic reaction to neuroleptic drugs, which is potentially fatal. It has been occasionally reported that NMS occurs subsequently after surgery. We report a case of a 53-year-old male patient who developed NMS following cardiac surgery due to the resumption of zotepine. The patient was attacked with hyperthermia, sweating, significant shivering, trembling of the fingers, disturbed consciousness and extreme muscle rigidity after the resumption of zotepine. Furthermore, laboratory measurements revealed increased levels of serum blood urea nitrogen, creatinine and creatine phosphokinase. In addition, elevation in white blood cell counts and myoglobinemia were also observed. After a diagnosis of NMS was established, administration of zotepine was stopped and treatments with administration of dantrolene and a large amount of fluid infusion intravenously were started. Following these treatments, the clinical symptoms subsided and the laboratory findings improved without need for hemodialysis. Dantrolene, which is able to effectively impede the abnormal flow of calcium from the sarcplasmic reticulum into the muscle cytoplasm, was beneficial to reduce the clinical symptoms of NMS. We hereby present a patient with NMS following cardiac surgery, and discuss its subsequent management.

Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences.

Expression of thrombomodulin (TM) in atherosclerotic lesions of the human aorta (8 cases of diffuse intimal thickening, 4 fatty streaks, 11 atheromatous plaques, and 5 fibrous plaques) as well as in undiseased aortas of 5 infants obtained at autopsy was studied immunohistochemically using a novel polyclonal antibody against human TM. TM was expressed in intimal smooth muscle cells (SMC) besides endothelial cells and foamy macrophages in almost all patients (26/28). In addition, medial SMC in adult cases over 27 years of age expressed TM. In young adults with diffuse intimal thickening under 26 years of age, medial SMC showed no TM expression whereas intimal SMC did show it. Both intimal and medial SMC in infants showed no TM expression. An immunofluorescence method showed TM expression in cultured adult human SMC. These findings indicate that TM expression in SMC may depend on patient age as well as lesion type of atherosclerosis.

Surgical treatment of traumatic thoracic aorta rupture: a 7-year experience.

OBJECTIVES: Traumatic aortic rupture is highly lethal and an ongoing therapeutic challenge. We review our 7-year experience with traumatic aortic disruption. METHODS: We treated 12 cases of traumatic rupture of the thoracic aorta (TRTA) from December 1994 to June 2001 at our institution. Of these, 9 were male, and the average age 26 years. Injuries were caused by traffic accidents in 9 cases and falls in 3. Contrast-enhanced helical computed tomography was used to diagnose10 cases and digital subtraction angiography to diagnose 2 at other hospitals. Six of 12 (50%) disruptions were located in the aortic isthms. All surgery was conducted under cardiopulmonary bypass. A percutaneous cardiopulmonary support system (heparin-bonded artificial lung and centrifugal pump) was used in 6 cases since 1998. RESULTS: Among the 12 patients, 6 had early surgical repair within 2 days after the accident, and all survived free of neurological problems. Six other had repair delayed more than 2 days and all were doing well. CONCLUSION: Immediate repair of aortic lesions should be the rule because the majority of deaths from TRTA occur within 24 hours. We believe, however, that immediate surgery may not be necessary for some patients with severe, multiple associated lesions who survive initial traumatic aortic disruption of the aorta.

Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta.

Aortic aneurysm is a chronic degenerative condition associated with atherosclerosis. Recent studies have revealed that angiotensin (Ang) II plays important roles in atherosclerosis. In this study, to investigate the relationship between aortic aneurysm and Ang II, we measured the activities of the angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase-like enzyme, in human aneurysmal and control aortae. Aneurysmal aortic specimens were obtained from 16 aneurysm patients and control aortic specimens were obtained from 16 patients who underwent coronary artery bypass surgery (8 patients in each group were administered ACE inhibitors). The ACE and chymase-like enzyme activities were determined using extracts from vascular tissues. Both the ACE and chymase-like enzyme activities in the aneurysmal aortae were significantly higher than those in the control aortae (p < 0.01). In the patients treated with ACE inhibitors, the ACE activity in the aneurysmal aortae tended to be low, but the chymase-like enzyme activity tended to be high. In the aneurysmal aortae, the chymase-like enzyme activity in the adventitia was significantly higher than that in the intimal or medial layers (p < 0.01), while differences in ACE activity were not observed. Our results suggest that increases in local Ang II formation induced by chymase-like enzymes may play important roles in the pathogenesis of aneurysmal formation.

Case of primary malignant hemangiopericytoma of the heart expressing basement membrane-degradable enzymes.

An echocardiogram demonstrated a large tumor in the left atrium of a 47-year-old woman with sudden heart failure. Emergent cardiotomy showed that the tumor arose from the left atrial wall, and almost entirely occupied the left atrium. Grossly, the tumor had partly undergone necrosis. Histologically, the tumor consisted predominantly of round to polygonal cells with ill-defined cell borders surrounding 'stag horn'-shaped blood vessels. Mitosis was frequently seen with abnormal mitotic figures. Immunohistochemically, the tumor cells diffusely expressed vimentin and focally expressed factor XIIIa and human leukocyte antigen-DR. A few tumor cells expressed S-100 protein or alpha-smooth muscle actin. Histopathological diagnosis was malignant hemangiopericytoma of the left atrium. Most tumor cells expressed matrix metalloproteinase (MMP)-2 and MMP-3, and several cells expressed MMP-9, all of which are capable of degrading a major component of basement membrane (i.e. type IV collagen). Furthermore, tumor cells expressed membrane type 1 MMP and tissue inhibitor of metalloproteinase-2, both of which are required for activation of proMMP-2. Fourteen months after the surgical removal, she died of systemic recurrent tumors.

Potent adenylate cyclase agonist forskolin restores myoprotective effects of ischemic preconditioning in rat hearts after myocardial infarction.

BACKGROUND: The purpose of this study was to determine whether ischemic preconditioning (IPC) provides myoprotective effects in post-myocardial infarction (MI) hearts, and whether beta adrenergic signaling is involved in IPC. METHODS: Rats were subjected to either ligation of the left anterior descending coronary artery (LAD) resulting in MI, or a sham operation. Two weeks later, hearts were isolated and perfused. Six groups (n = 7 each) were studied: group 1, control (sham operation); group 2, sham operation + IPC; group 3, post-MI; group 4, post-MI + IPC; group 5, post-MI + forskolin; group 6, post-MI + forskolin + IPC. IPC consisted of two cycles of 5 minutes of global ischemia. The adenylate cyclase agonist forskolin (1.0 x 10(-5) M) was administered in post-MI hearts either alone (group 5) or for 5 minutes before IPC (group 6). All hearts were then subjected to 20 minutes of global ischemia followed by 120 minutes of reperfusion, after which infarct size was measured. Concentrations of endogenous catecholamines and myocardial mRNA expression of beta 2 adrenergic receptor were measured in the post-MI model. RESULTS: (1) IPC reduced infarct size in shams, from 34.7 +/- 5.2% in group 1 to 21.4 +/- 3.8% in group 2, but did not affect infarct size in post-MI hearts (group 3 versus group 4). (2) Forskolin combined with IPC reduced infarct size in post-MI hearts to 29.3 +/- 3.4% (group 6), but not in group 5 where the value was 39.3 +/- 4.8%. (3) Beta 2 adrenergic receptor mRNA expression in post-MI hearts was significantly decreased as compared with sham-operated animals. CONCLUSIONS: The results indicate that downregulation of beta adrenergic receptors in post-MI hearts may be associated with ineffectiveness of IPC, and that beta adrenergic signaling, especially in relation to adenylate cyclase activation, may be required to generate the IPC response in post-MI hearts.

Trandolapril reduces infarction area after middle cerebral artery occlusion in rats.

In this study, we investigated whether angiotensin-converting enzyme (ACE) is involved in the progression of cerebral infarct lesions after middle cerebral artery (MCA) occlusion in rats. After placebo or trandolapril was administered orally for 7 days, we infarcted in the territory of the right MCA by extracranial vascular occlusion and studied the effect of trandolapril on brain ACE activity and infarct size 7 days after MCA occlusion. In placebo-treated rats, brain ACE activity in the infarct side was increased by a significant 1.34-fold compared with that in the non-infarct side 7 days after MCA occlusion. Brain ACE activities in the infarct sides were suppressed to 39.8% by trandolapril treatment. The ratios of unilateral infarcts to the total coronal sectional areas in placebo- and trandolapril-treated rats were 48.1 +/- 3.3% and 37.4 +/- 2.3%, respectively, and the difference between these values was significant. These results demonstrate that inhibition of the increased brain ACE activity in infarct lesions can reduce the infarction area after MCA occlusion.

Increased local angiotensin II formation in aneurysmal aorta.

We investigated the levels and locations of angiotensin II-forming enzymes, angiotensin converting enzyme (ACE) and chymase, in aneurysmal and normal aortas. Aneurysmal aortic specimens (n = 14) were obtained at the time of operative aneurysm repair from 14 patients ranging in age from 57 to 84 y. Normal aortic specimens (n = 16) were obtained from 16 patients (48 to 72 y) who underwent coronary artery bypass surgery. The ACE and chymase activities were determined using each specimen. Sections of each specimen were immunostained with antibodies for ACE and chymase. The ACE activities in the aneurysmal and normal aortas were 0.82 +/- 0.10 and 0.14 +/- 0.05 mU/mg protein, respectively, and this difference was significant. The chymase activities in the aneurysmal and normal aortas were 17.9 +/- 2.40 and 1.02 +/- 0.18 mU/mg protein, respectively, and this difference was also significant. In the aneurysmal aorta, ACE-positive cells were detected with macrophages in the intima and media and chymase-positive cells were detected with mast cells in the media and adventitia, whereas positive ACE and chymase cells in the normal aorta were located only in the endothelium and adventitia, respectively. Angiotensin II-forming enzymes, chymase and ACE, were significantly increased in the aneurysmal aorta, and increased angiotensin II may be associated with the development of aneurysmal formations.

Oral hypoglycemic sulfonylurea glimepiride preserves the myoprotective effects of ischemic preconditioning.

BACKGROUND: To investigate whether the sulfonylurea glimepiride affects the myoprotective effects of ischemic preconditioning (IPC), isolated rabbit hearts were perfused with Krebs-Henseleit solution. METHODS: Eight hearts underwent IPC consisting of two cycles of 5 min global ischemia and reperfusion. Six hearts received a 5-min infusion of 10 microM glimepiride, six hearts received a 5-min infusion of 50 microM glimepiride, and seven hearts received a 5-min infusion of 10 microM glibenclamide before IPC. Seven hearts received a 5-min infusion of the selective mitochondrial K(ATP) channel opener diazoxide (50 microM). Other hearts received a 5-min infusion of 10 microM glimepiride (n = 6), 50 microM glimepiride (n = 6), or 10 microM glibenclamide (n = 7) before diazoxide. Seven hearts served as a control. All groups then were subjected to 1 h of regional ischemia, followed by 1 h of reperfusion. LV pressures, monophasic action potential duration (APD(50)), and infarct size were measured. RESULTS: Both IPC and diazoxide significantly prolonged APD(50) and preserved diastolic function at 60 min of reperfusion compared to control. In addition, both groups reduced infarct size compared to control. Glibenclamide, but not glimepiride reversed these effects. CONCLUSION: Glimepiride offers less cardiovascular effects than glibenclamide, possibly due to its lower affinity for the mitochondrial K(ATP) channels.

[Preischemic infusion of alpha-human atrial natriuretic peptide elicits myoprotection through a nitric oxide-dependent mechanism].

OBJECTIVES: Alpha-human atrial natriuretic peptide (alpha-hANP) has been used to treat patients with heart failure due to its natriuretic and vasodilatory activities. Recent reports have suggested that alpha-hANP generates nitric oxide (NO) that is known to be involved in myoprotective mechanisms. In this study, the effects of preischemic infusion of alpha-hANP against reperfusion injury were evaluated. METHODS: Isolated rat (Sprague-Dawley rat, age 8-10 weeks, weight 260-340 g) hearts were subjected to Langendorff perfusion with buffered Krebs-Henseleit solution and were divided into three groups: Six hearts were treated with 0.1 microM of alpha-hANP for 10 min (Group H), six hearts with 1 mM of a NO synthetase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) for 5 min before alpha-hANP (Group L), and six hearts served as the controls with no interventions (Group C). All groups were then subjected to 20 min of global ischemia followed by 120 min of reperfusion. Left ventricular pressures and coronary flow were measured throughout the experiment and infarct size was evaluated at the end of the experiments. RESULTS: Treatment with alpha-hANP significantly reduced infarct size as compared to control hearts whereas pretreatment with L-NAME almost reversed the preventive effect (Group C = 42.7 +/- 2.3%, Group H = 26.1 +/- 2.8% *, Group L = 39.0 +/- 1.6%; * p < 0.01 vs Group C). There were no significant differences in left ventricular pressure and coronary flow between the three groups. CONCLUSIONS: Preischemic infusion of alpha-hANP may provide myoprotective effects against postischemic reperfusion, possibly through a NO-dependent mechanism.

HMG-CoA reductase inhibitor cerivastatin prolonged rat cardiac allograft survival by blocking intercellular signals.

BACKGROUND: The development of atherosclerotic cardiovascular complications caused by hyperlipidemia is a common and serious problem for long-term survivors of organ transplantation. However, adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and lymphocyte function-associated antigen (LFA)-1 are involved in allograft rejection, possibly by providing costimulatory signals. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin has been shown to suppress ICAM-1 expression in acute inflammatory responses. METHODS: In this study, we evaluated the immunosuppressive effects of cerivastatin in rat cardiac allografts. The hearts of Fischer rats were transplanted heterotopically into Lewis rats. Cerivastatin (2 mg/kg) was administrated intraperitoneally to recipients for 7 consecutive days from the day before transplantation. RESULTS: Graft survival in the cerivastatin-treated group (n = 8) was significantly longer than in controls (n = 10) (24.6 +/- 2.2 days vs 10.2 +/- 1.3 days, p < 0.05). Mixed lymphocyte reaction (MLR) showed that on Day 8 after grafting, the proliferative response of alloreactive T cells against F344 alloantigen in cerivastatin-treated rats was significantly more suppressed than in Lewis rats. The Interleukin-2 concentration of supernatant in MLR cultures in the cerivastatin-treated group was lower than in the control group. Immunohistochemical analysis showed that the percentage of CD4-positive cells to infiltrating mononuclear cells was less prominent in the cerivastatin-treated group (9.8% +/- 2.2%) than in the control group (20.9% +/- 3.2%). CONCLUSIONS: The HMG-CoA reductase inhibitor cerivastatin effectively suppressed acute graft rejection, possibly by blocking intercellular signals via ICAM/LFA-1, and cerivastatin may be a candidate for treating patients with hyperlipidemia who undergo organ transplantation.