Modulation by simvastatin of iberiotoxin-sensitive, Ca2+-activated K+ channels of porcine coronary artery smooth muscle cells.

BACKGROUND AND PURPOSE: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca2+-activated K(+) (BK(Ca)) channels. EXPERIMENTAL APPROACHES: Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BK(Ca) channel gatings of porcine coronary artery smooth muscle cells were evaluated. KEY RESULTS: Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 microM) (hydrophobic), but not simvastatin Na+ (hydrophilic), inhibited the BK(Ca) channels with a minimal recovery upon washout. Isopimaric acid (10 microM)-mediated enhancement of the BK(Ca) amplitude was reversed by external simvastatin. Simvastatin Na+ (10 microM, applied internally), markedly attenuated isopimaric acid (10 microM)-induced enhancement of the BK(Ca) amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 microM) and geranylgeranyl pyrophosphate (20 microM) only prevented simvastatin (1 and 3 microM)-induced responses. simvastatin (10 microM ) caused a rottlerin (1 microM)-sensitive (cycloheximide (10 microM)-insensitive) increase of PKC-delta protein expression. CONCLUSIONS AND IMPLICATIONS: Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BK(Ca) channels of the arterial smooth muscle cells through multiple intracellular pathways.

Video assisted thoracic surgery in the management of spontaneous pneumothorax: the current status.

Over the past decade, video assisted thoracic surgery (VATS) has changed the way spontaneous pneumothorax (SP) is managed. Benefits of VATS include less postoperative pain, shorter hospital stay, and attenuated postoperative inflammatory response are evident compared with open thoracic procedures. Furthermore, the increasing acceptance by patients and referring physicians is testament to its success. Recent studies and the authors decade of experience in management of SP by VATS show that it is quick, safe, and effective, with recurrence rates generally comparable to open procedures, with some exceptions. However, selecting the correct procedure and patient, as well as knowing the limitations of the surgeons and techniques are paramount for success. Even to this day, there are considerable variations in the treatment of SP and large scale controlled studies are needed to better define timing of surgery and the role of the different procedures in the treatment and prevention of SP.

Pulmonary ischaemia-reperfusion injury: role of apoptosis.

The central role of lung ischaemia-reperfusion injury in pulmonary dysfunction after cardiac surgery, particularly thoracic organ transplantation, has been well recognised. Lung tissue necrosis after prolonged ischaemia is known to worsen lung function, which was believed to be due largely to adjacent tissue inflammation. Recent studies suggest that lung apoptosis following ischaemia-reperfusion could be equally important in the development of post-operative lung dysfunction. The current literature on the mechanism and pathways involved in pulmonary dysfunction and, in particular, its relationship with apoptosis after lung ischaemia-reperfusion is briefly reviewed here. A better understanding of lung apoptosis, as well as the upstream pathways, may help in the development of therapeutic strategies that could benefit patients undergoing cardiac and lung transplantation.

Current indications and results of VATS in the evaluation and management of hemodynamically stable thoracic injuries.

OBJECTIVE: Thoracic injuries are among the most severe forms of trauma and also a leading cause of morbidity and mortality. Video Assisted Thoracic Surgery (VATS) has recently provided an alternative method to simultaneously diagnose and manage patients sustaining chest injuries. We analyze our experience with VATS in the setting of thoracic trauma detailing indications for exploration, procedures performed and results of surgery. METHODS: A 6-year single institution review of patients undergoing VATS due to injuries sustained from both blunt and penetrating chest trauma at a Level I trauma center and university teaching hospital. Comparisons were made between groups of blunt and penetrating trauma as to Injury Severity Score (ISS), presence of extra-thoracic injuries, initial thoracostomy drainage and length of postoperative stay. RESULTS: VATS was successfully performed in 19 consecutive patients without conversion to thoracotomy. Indications for exploration included acute hemorrhage, retained hemothorax, suspected diaphragmatic injuries (DI), suspected cardiac injury, intra-thoracic foreign body, persistent airleak and chronic empyema. Procedures performed consisted of evacuation of retained hemothorax, hemostasis of intra-thoracic bleeders, repair of DI, wedge lung resections and decortication. Mean postoperative length of stay was 5.86 days. There were no morbidities. One patient with severe intra-abdominal injuries expired on the first postoperative day. CONCLUSION: In hemodynamically stable patients with thoracic injuries, VATS provides an accurate assessment of intra-thoracic organ injury and can be utilized to definitively and effectively manage injuries sustained as a result of blunt or penetrating thoracic trauma. VATS should be used with caution in patients sustaining severe and life threatening intra-abdominal injuries.

Video-assisted thoracic surgery for mediastinal extramedullary haematopoiesis.

Extramedullary haematopoiesis is a rare cause of an intrathoracic mass. We report a case of posterior mediastinal extramedullary haematopoietic mass in a 50-year-old man who presented with non-specific symptoms and a paravertebral mass on chest X-ray. Diagnosis was achieved by using video-assisted thoracic surgery.

Idiopathic localised bladder amyloidosis: rare cause of haematuria.

Idiopathic Localised Bladder Amyloidosis is a rare cause of haematuria and urinary tract symptoms. A review of the literature highlights the varied presentations and the appropriate investigations for this condition, with emphasise on the exclusion of a secondary cause. In addition, the range of treatment options is fully discussed. Our report on a 65-year old gentleman illustrates that a high index of suspicion is required for its diagnosis. Furthermore, conservative management can be an effective strategy in selected patients.

Giant pulmonary bulla.

The present report describes a case of a giant pulmonary bulla in a 32-year-old man that progressed to occupy almost the entire left hemithorax. This report is unique in documenting the natural history of progression of this condition. Bullectomy was performed using the video-assisted thoracoscopic surgery approach.

Thoracoscopy in the management of pneumothorax.

Spontaneous pneumothorax is a common condition that impacts significantly on healthcare expenditure. However, optimal management of spontaneous pneumothorax remains a subject of considerable controversy. A thoracic surgeon's perspective on the use of thoracoscopy and video-assisted thoracic surgery with a focus on surgical techniques in the current management of this condition is presented.

Place of video-thoracoscopy in thoracic surgical practice.

The advent of video-endoscopy revolutionizes the practice of surgery. Within a short span of time, video-assisted thoracic surgery (VATS) has become an acceptable approach to a wide range of thoracic procedures. The use of VATS as a diagnostic modality is now well established. For therapeutic procedures, VATS has also been generally accepted for the treatment of such conditions as primary spontaneous pneumothorax, loculated effusions, thoracodorsal sympathectomy, and resection of simple mediastinal cysts. Its roles in more complex procedures such as thymectomy and anatemic lung resections, however, remain poorly defined at present, even though the existing intermediate-term results are encouraging. VATS is still in evolution. Miniaturization of instruments promises to reduce access-induced trauma even further. On the other hand, attention to cost-containment is essential if VATS is to be applicable to patients in developing countries. Technology will continue to change. Carefully conducted clinical trials should precede the general acceptance of any new technology, no matter how attractive it may appear initially.

Macro-porosity is necessary for the reduction of neointimal and medial thickening by external stenting of porcine saphenous vein bypass grafts.

BACKGROUND: placing external non-restrictive macro-porous stents around porcine vein grafts prevents neointima formation and medial thickening in both the short and long term. Whether the porosity of the stent material influences this effect, however, has not been determined. Therefore, the effect on neointimal and medial thickening of external macro-porous (polyester) and micro-porous (polytetrafluorethylene) stents of equal diameter were compared. The effect on expression of platelet-derived growth factor (PDGF), a potent mediator of vascular smooth muscle cell migration and proliferation and its receptors was also investigated. METHODS AND RESULTS: saphenous vein-carotid artery interposition grafting was performed in Landrace pigs with external placement of 8 mm diameter macro- and micro-porous stents contralaterally. One month after surgery, graft wall dimensions, PDGF and PDGF receptor expression and cell proliferation using proliferating cell nuclear antigen (PCNA) were measured on histological sections. Macro-porous stents significantly reduced neointimal and medial thickening compared with micro-porous stents (0.1+/-0.02 vs. 0.25+/-0.03 mm, P<0.002, and 0.10+/-0.02 vs. 0.17+/-0.02 mm, P<0.014, respectively). Macro-porous stents significantly reduced the percentage of cells expressing PDGF and PCNA, compared with micro-porous stents (36+/-9 vs. 80+/-7, P < 0.002, and 11+/-3 vs. 21+/-2, P < 0.02, respectively). The percentage of cells expressing PDGF receptors was similar with both the stent types. Adventitial microvessel formation occurred across macro-porous stents but was markedly suppressed by micro-porous stents. CONCLUSIONS: porosity is crucial to the efficacy of external stents in reducing neointima formation in porcine vein grafts. Decreases in PDGF expression and cell proliferation accompany the reduction in neointima formation. In addition, macro-porous stents allow adventitial microvessels to connect with the vasculature outside the stent, thereby potentially improving oxygenation. Although external stenting is highly effective in reducing neointima formation after vein grafting, the properties of the stent material necessary for this effect have not been defined. This study establishes that macro-porosity is one essential feature required to reduce PDGF expression cell proliferation and neointima formation.

Effects of potassium channel opener aprikalim on the receptor-mediated vasoconstriction in the human internal mammary artery.

BACKGROUND: Arterial grafts for coronary artery bypass grafting such as the internal mammary artery (IMA) may develop spasm perioperatively. The purpose of this study was to investigate the effects of the potassium channel opener, aprikalim, on the receptor-mediated vasoconstriction in the human IMA in vitro. METHODS: We studied 160 IMA rings taken from coronary artery surgery in organ baths. The interaction between aprikalim and four vasoconstrictors 5-hydroxytryptamine (5-HT), norepinephrine (NE), endothelin-1 (ET-1), and angiotensin II (AII) was investigated in two ways. RESULTS: Aprikalim relaxed IMA rings precontracted by the vasoconstrictors to 66.40 +/- 5.9% for 5-HT (EC50: -6.78 +/- 0.26 LogM), 57.40 +/- 5.5% for NE (-6.54 +/- 0.39 LogM), 81.00 +/- 6.7% for ET-1 (-6.58 +/- 0.26 LogM), and 93.90 +/- 2.5% for AII (-7.80 +/- 0.23 LogM). The relaxation in endothelium-denuded rings contracted by AII was similar to that in the endothelium-intact rings. The relaxation was attenuated by glibenclamide (3 microM) in 5-HT or NE-precontracted IMA. Pretreatment with aprikalim at 1 microM depressed AII-induced contraction (33.20 +/- 7.5% versus 59.70 +/- 7.3%, p < 0.01) but only shifted the curves rightward for 5-HT or NE (EC50 3.1 or 4.3-folds higher, p < 0.05), whereas at 30 microM it also significantly depressed the maximal contraction for 5-HT (35.70 +/- 4.9% versus 103.30 +/- 9.8%, p < 0.001) and NE (90.60 +/- 15.6% versus 125.60 +/- 7.9%, p < 0.05). In contrast, aprikalim did not significantly depress the contraction induced by ET-1 (p > 0.05). CONCLUSIONS: We conclude that aprikalim has vasorelaxant effects on IMA and the effect is vasoconstrictor-selective and endothelium-independent. Aprikalim may provide clinically useful vasorelaxant effects in coronary bypass surgery.

ATP-sensitive potassium channel openers may mimic the effects of hypoxic preconditioning on the coronary artery.

BACKGROUND: This study was designed to investigate the effects of the potassium channel opener KRN4884 in mimicking hypoxic preconditioning on coronary arteries and to explore the possible mechanisms. METHODS: In the organ chamber, porcine coronary artery rings (n = 96) were studied in 6 groups (n = 16 in each group): I. CONTROL: normoxia (pO2 > 200 mmHg); II. Hypoxia-reoxygenation: 60-minute hypoxia (pO2 < 15 mmHg) followed by 30-minute reoxygenation; III. Preconditioning: 5-minute hypoxia followed by 10-minute reoxygenation prior to hypoxia-reoxygenation; IV. KRN4884-pretreatment: KRN4884 (30 microM) was added into the chamber 20 minutes before hypoxia-reoxygenation; V. 5-HD-pretreatment: sodium 5-hydroxydecanoate (5-HD, 10 microM) was given 20 minutes prior to KRN4884-pretreatment; and VI. GBC-pretreatment: glibenclamide (GBC, 3 microM) was added 20 minutes prior to KRN4884-pretreatment. Concentration-contraction curves for U46619 (n = 8 in each group) were constructed. Concentration-relaxation curves for bradykinin (n = 8 in each group) related to endothelium-derived hyperpolarizing factor (EDHF) were established in the rings precontracted with U46619 (30 microM) in the presence of Nomega-nitro-L-arginine (L-NNA, 300 microM) and indomethacin (7 microM). RESULTS: The maximal relaxation induced by bradykinin was reduced in hypoxia-reoxygenation (54.6 +/- 4.3% versus 85.2 +/- 5.7% in control, p = 0.001). This reduced relaxation was recovered in KRN4884-pretreatment (78.9 +/- 3.7%, p = 0.014) or preconditioning (79.9 +/- 3.7%, p = 0.009). 5-HD- but not GBC-pretreatment abolished the effect of KRN4884-pretreatment (78.9 +/- 3.7% versus 53.5 +/- 4.7%, p = 0.009). CONCLUSIONS: Hypoxia-reoxygenation reduces the relaxation mediated by EDHF in the coronary artery. This function can be restored by either hypoxic preconditioning or the potassium channel opener KRN4884. The mechanism of such effect is mainly related to the mitochondrial ATP-sensitive K+ channels.

Direct measurement of nitric oxide release from saphenous vein: abolishment by surgical preparation.

BACKGROUND: Surgical preparation (distension) of the saphenous vein (SV) is applied routinely during harvesting in coronary artery bypass grafting (CABG). However, mechanical distension may impair the endothelium, which plays an important role in long-term patency. The present study investigated the effect of surgical preparation of the SV on nitric oxide (NO) release from the endothelium by direct measurement of NO. METHODS: Saphenous vein segments taken from CABG patients were cut open longitudinally and placed in an organ chamber. An NO-sensitive electrode and NO meter were used to directly measure NO release induced by acetylcholine (ACh) and bradykinin (BK) from the surgically prepared veins (PV) compared with the control (nondistended) veins. RESULTS: The basal release of NO in the PV group was significantly lower than that in the control group (3.4 +/- 1.4 nM, n = 9 versus 9.9 +/- 2.8 nM, n = 13, p = 0.002). The maximum concentrations of NO release induced by ACh and BK in the PV group were also significantly lower than those in the control veins (for ACh 10(-6) mol/L: 9.6 +/- 3.1 nM, n = 8 versus 41.9 +/- 11.2 nM, n = 12, p = 0.005; for BK 10(-8) mol/L: 8.3 +/- 3.7 nM, n = 7 versus 37.9 +/- 6.1 nM, n = 9, p = 0.003). Further, the duration of NO release in the PV group was significantly shorter than that in control veins (1.5 +/- 1.3 minutes, n = 8 versus 8.1 +/- 1.9 minutes, n = 8, p < 0.001). CONCLUSIONS: Surgical preparation almost abolishes NO release by the SV and this may significantly contribute to the low long-term patency rate of the vein graft.