Effects on blood pressure in patients with refractory angina pectoris after enhanced external counterpulsation.

OBJECTIVE: Enhanced external counterpulsation (EECP) is a non-invasive technique that has been shown to reduce the frequency and severity of angina pectoris. Little is known how EECP affects the blood pressure. METHODS: 153 patients with refractory angina were treated with either EECP or retained on their pharmacological treatment (reference group). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP) and heart rate were measured pre- and post-treatment and at 12 months follow-up. RESULTS: EECP treatment altered the blood pressure in patients with refractory angina pectoris. A decrease in the blood pressure was more common in the EECP group compared with the reference group. In the reference group, an increase in the blood pressure was more common. A correlation between a decrease in blood pressure after EECP treatment and a higher baseline MAP, SBP and DBP was seen. No such correlation was seen in the reference group. The blood pressure response did not persist at 12 months follow-up. CONCLUSION: EECP treatment affects the blood pressure in patients with refractory angina pectoris. The decreased blood pressure may be a result of an improved exercise capacity, an improved endothelial function and vasoreactivity in general.

Protein kinase C in porcine retinal arteries and neuroretina following retinal ischemia-reperfusion.

PURPOSE: Identification of the intracellular signal-transduction pathways activated in retinal ischemia may be important in revealing novel pharmacological targets. To date, most studies have focused on identifying neuroprotective agents. The retinal blood vessels are key organs in circulatory failure, and this study was therefore designed to examine the retinal vasculature separately from the neuroretina. METHODS: Retinal ischemia was induced by elevating the intraocular pressure in porcine eyes, followed by 5, 12, or 20 h of reperfusion. Protein kinase C (PKC)alpha, PKCbeta1, and PKCbeta2 mRNA levels, and protein expression were determined using real-time PCR, western blot, and immunofluorescence staining techniques. RESULTS: The retinal arteries could easily be dissected free and studied separately from the neuroretina in this porcine model. The PKCalpha, PKCbeta1, and PKCbeta2 mRNA levels tended to be lower in ischemia-reperfused than in sham-operated eyes in both the retinal arteries and the neuroretina. This was most prominent after 5 h, and less pronounced after 12 h and 20 h of reperfusion. Likewise, the protein levels of PKCalpha, PKCbeta1, and PKCbeta2 were slightly lower following ischemia-reperfusion when compared to sham-operated eyes. PKCalpha, PKCbeta1, and PKCbeta2 immunostaining were observed in bipolar cells of the neuroretina and in endothelial cells, and to a low extent in the smooth muscle layer, of the retinal arteries. CONCLUSIONS: Retinal ischemia followed by reperfusion results in lower levels of PKC in both the neuroretina and retinal arteries. New targets for pharmacological treatment may be found by studying the retinal vasculature so as to identify the intracellular signal-transduction pathways involved in the development of injury following retinal circulatory failure.

Enhanced expression of contractile endothelin ET(B) receptors in rat coronary artery after organ culture.

Endothelin-1 is a potent vasoconstrictor mediating its effects via two receptor subtypes, the endothelin type A (ET(A)) preferentially situated on smooth muscle cells, mediating vasoconstriction and endothelin type B (ET(B)) mainly located on endothelial cells, mediating vasodilatation. In cardiovascular disease and in organ culture in vitro, endothelin ET(B) receptors are up-regulated on smooth muscle cells. The objectives of the present study were to characterise the endothelin receptor-induced vasoconstriction and quantify the endothelin receptor mRNA levels and immunoreactivity in fresh and cultured rat coronary arteries. We demonstrate that endothelin-1 induces strong and equal concentration-dependent contractions in fresh and cultured segments from the left anterior descending coronary artery. Sarafotoxin 6c, an endothelin ET(B) receptor agonist, had negligible effect in fresh arteries but produced significant vasoconstriction after organ culture. The endothelin ET(B) receptor mRNA level and the receptor protein immunoreactivity were increased, whereas the level of endothelin ET(A) receptor mRNA was down-regulated but not its receptor protein immunoreactivity after organ culture. Pharmacological inhibition of endothelium-derived dilatory mediators did not influence endothelin ET(A) or ET(B) receptor-mediated vasoconstriction in fresh segments. In cultured arteries, inhibition of endothelial vasodilators potentiated the effect of sarafotoxin 6c. In conclusion, endothelin ET(B) receptor stimulation in cultured coronary arteries elicits vasoconstriction. This is likely not related to endothelial dysfunction with putative loss of its vasodilator components, but rather explained by the up-regulation of contractile endothelin ET(B) receptors on smooth muscle cells.

PKC and MAPK signalling pathways regulate vascular endothelin receptor expression.

Up-regulation of vascular endothelin type A (ET(A)) and type B (ET(B)) receptors are implicated in the pathogenesis of cardiovascular disease. Culture of arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for in detail delineation of the regulation of endothelin receptors. We hypothesize that protein kinase C (PKC) and mitogen-activated kinases (MAPK) are involved in the regulation of endothelin receptors. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology, real-time PCR and immunofluorescence techniques. Sarafotoxin 6c and endothelin ET-1 were used to examine the endothelin ET(A) and ET(B) receptor effects. The involvement of PKC and MAPK in the receptor regulation was examined by culture in the presence of antagonists. Organ culture resulted in increased sarafotoxin 6c and endothelin-1 contractions, endothelin ET(A) and ET(B) receptor immunofluorescence staining intensities and endothelin ET(B), but not ET(A), receptor mRNA levels. The general PKC inhibitors, bisindolylmaleimide I (10 microM) or Ro-32-0432 (10 microM), inhibited these effects. Also, the increase in sarafotoxin 6c contraction, endothelin ET(B) receptor and mRNA levels and endothelin ET(A) and ET(B) immunofluorescence staining intensities were inhibited by MAPK inhibitors for extracellular signal related kinases 1 and 2 (ERK1/2), PD98059 (10 microM), C-jun terminal kinase (JNK), SP600125 (10 microM), but not by p38 MAPK, SB203580 (10 microM). In conclusion, PKC and MAPK seem to be involved in the regulation of endothelin receptor expression in porcine coronary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin receptor changes in cardiovascular disease.

Endothelin receptor-mediated vasodilatation: effects of organ culture.

Culture of intact arteries is a frequently employed experimental model for investigating the mechanisms governing the regulation of vascular endothelin receptors. Endothelin type A (ET(A)) and type B (ET(B)) receptors on vascular smooth muscle cells are up-regulated in organ culture and the enhanced vasoconstriction mimics the changes that occur in cardiovascular disease. The effect of organ culture on endothelial dilatory endothelin ET(B) receptors is not known. We hypothesize that organ culture decreases the endothelin receptor-mediated dilatation and that this is one possible mechanism by which the effects of the endothelin in blood vessels are altered during culture. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology and immunofluorescence. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET(A) and ET(B) receptor effects, and the antagonists, Nomega-nitro-l-arginine (l-NOARG) for nitric oxide (NO), indomethacin for prostaglandins and charybdotoxin in combination with apamin for endothelium-derived hyperpolarizing factor (EDHF), were used to study the endothelium-derived dilatory mediators. Organ culture induced up-regulation of the sarafotoxin 6c (ET(B) receptor agonist) and endothelin-1 (ET(A) receptor agonist) elicited vasoconstriction. The sarafotoxin 6c contraction was stronger after endothelium denudation, suggesting endothelium-dependent dilatation. The endothelin-1 contraction was not affected by endothelium denudation. The increase in sarafotoxin 6c contraction after removal of the endothelium was more pronounced before than after organ culture, suggesting down-regulated endothelial endothelin ET(B) receptors. Also, the immunofluorescence staining intensities for endothelial endothelin ET(B) receptors were higher before than after organ culture. Pre-incubation with inhibitors for dilatory mediators suggested that both NO and EDHF play a vasodilatory role, while prostaglandins are not involved. In conclusion, endothelial endothelin ET(B) receptors induce NO and EDHF mediated vasodilatation in porcine coronary arteries. In organ culture, endothelial endothelin ET(B) receptors are down-regulated, mimicking the changes that occur in cardiovascular disease. Down-regulation of endothelial endothelin ET(B) receptors may in part explain the increased endothelin ET(B) receptor-mediated vasoconstriction frequently studied in organ culture.

Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways.

BACKGROUND: Up-regulation of vascular endothelin type B (ETB) receptors is implicated in the pathogenesis of cardiovascular disease. Culture of intact arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for, ex vivo, in detail delineation of the regulation of endothelin receptors. We hypothesize that mitogen-activated kinases (MAPK) and protein kinase C (PKC) are involved in the regulation of endothelin ETB receptors in human internal mammary arteries. METHODS: Human internal mammary arteries were obtained during coronary artery bypass graft surgery and were studied before and after 24 hours of organ culture, using in vitro pharmacology, real time PCR and Western blot techniques. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ETA and ETB receptor effects, respectively. The involvement of PKC and MAPK in the endothelin receptor regulation was examined by culture in the presence of antagonists. RESULTS: The endothelin-1-induced contraction (after endothelin ETB receptor desensitization) and the endothelin ETA receptor mRNA expression levels were not altered by culture. The sarafotoxin 6c contraction, endothelin ETB receptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 microM bisindolylmaleimide I and 10 microM Ro-32-0432), and (2) inhibitors of the p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 microM SB203580, 10 microM PD98059 and 10 microM SP600125, respectively). CONCLUSION: In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ETB receptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ETB receptor changes in cardiovascular disease.

Serotonin kinetics in patients with burn injuries: a comparison between the local and systemic responses measured by microdialysis-a pilot study.

OBJECTIVES: To investigate serotonin (5HT) locally in burned and uninjured skin (intracutaneous) by microdialysis, and simultaneously record urinary and blood values in the same subjects. For comparison, serotonin values were also measured in skin of healthy controls. DESIGN AND SETTING: An experimental study in burned patients with of more than 25% TBSA (total burn surface area) % in an 8-bed tertiary burns unit, serving about 3.5 million persons. PATIENTS AND METHODS: Six subjects with a median TBSA% of 59% (range 33.5-90), and five healthy controls were examined by intracutaneous microdialysis of the skin. RESULTS: 5HT was increased in burned patients, compared with controls. This increase was tenfold in skin and was noted both in uninjured and burned skin. The highest values were recorded on day 1 (median 16.1nmol in uninjured and 9.5nmol in burned skin) and day 2 (15.6nmol in uninjured and 13.4nmol in burned skin). A rapid reduction was noted on day 3 (4.9nmol in uninjured and 3.8nmol in burned skin). The corresponding value for control subjects was 1.3nmol. The 5HT in blood was twice normal on day 2, and gradually reduced on days 3 and 4 (3189, 3035 and 2573nmol, respectively). Urinary 5HT concentrations were increased only on day 2 at 1755nmol and thereafter returned to the normal range on days 3 and 4 (1248 and 1344nmol, respectively). CONCLUSIONS: We showed that microdialysis may be used in the critical care of burns, and local skin serotonin concentrations examined continuously for several days. The findings of significantly raised tissue serotonin concentrations, compared to that in blood and urine, suggests that serotonin may be important in local vascular control and formation of oedema.

Angiotensin II-induced vasodilatation in cerebral arteries is mediated by endothelium-derived hyperpolarising factor.

The angiotensin II-induced vasodilatation was evaluated in rat middle cerebral artery, especially regarding endothelium-derived hyperpolarising factor (EDHF), by use of a pressurised arteriograph. The angiotensin II dilatation was partly antagonised by inhibitors of nitric oxide synthase and cyclo-oxygenase. The remaining dilatation was inhibited by the potassium channel blockers, charybdotoxin and apamin, providing direct evidence that angiotensin II induces EDHF-mediated dilatation in cerebral arteries. The angiotensin II dilatation was blocked by the angiotensin AT1 and AT2 receptor blockers candesartan and PD 123319. Both angiotensin AT1 and AT2 receptors were detected on the endothelium by immunohistochemistry.

One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.

BACKGROUND: Enhanced external counterpulsation (EECP) is a non-invasive technique that has been shown to be effective in reducing both angina and myocardial ischemia in patients not responding to medical therapy and without revascularization alternatives. The aim of the present study was to assess the long-term outcome of EECP treatment at a Scandinavian centre, in relieving angina in patients with chronic refractory angina pectoris. METHODS: 55 patients were treated with EECP. Canadian cardiovascular society (CCS) class, antianginal medication and adverse clinical events were collected prior to EECP, at the end of the treatment, and at six and 12 months after EECP treatment. Clinical signs and symptoms were recorded. RESULTS: EECP treatment significantly improved the CCS class in 79 +/- 6% of the patients with chronic angina pectoris (p < 0.001). The reduction in CCS angina class was seen in patients with CCS class III and IV and persisted 12 months after EECP treatment. There was no significant relief in angina in patients with CCS class II prior to EECP treatment. 73 +/- 7% of the patients with a reduction in CCS class after EECP treatment improved one CCS class, and 22 +/- 7% of the patients improved two CCS classes. The improvement of two CCS classes could progress over a six months period and tended to be more prominent in patients with CCS class IV. In accordance with the reduction in CCS classes there was a significant decrease in the weekly nitroglycerin usage (p < 0.05). CONCLUSION: The results from the present study show that EECP is a safe treatment for highly symptomatic patients with refractory angina. The beneficial effects were sustained during a 12-months follow-up period.

Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries.

BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor and a deleterious factor in cardiovascular pathophysiology. Ang II receptor blockers (ARBs) have recently been introduced into clinical practice for treatment of hypertension and congestive heart failure. AIMS: This study was undertaken to evaluate the inhibitory effects of ARBs on vasoconstriction in humans. METHODS: Vasomotor tone was analyzed in endothelium denuded, human coronary artery (HCA) segments. Ang II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Ang II was a potent vasoconstrictor (pEC(50) = 7.7). At 1 nM of the AT(1) receptor antagonists, candesartan and valsartan, the maximum contraction was depressed to 57 and 50% of Ang II, respectively, indicating insurmountability. Although generally considered surmountable, the presence of 100 nM losartan elicited a depression of the Ang II response to 32%. Its active metabolite, EXP 3174 (1 nM), abolished the Ang II contraction. The AT(1) receptor antagonists had the following order of blocking effect; EXP 3174 > candesartan = valsartan > losartan. The AT(2) receptor antagonist, PD 123319 (100 nM) significantly attenuated the Ang II contraction (E(max) = 62% of Ang II). RT-PCR of HCA smooth muscle cells demonstrated expression of both AT(1) and AT(2) receptor mRNA. CONCLUSIONS: Ang II contraction in HCA is mediated mainly by AT(1) but also involves AT(2) receptors. The active metabolite of losartan, EXP 3174, is the most efficacious AT(1) receptor antagonist in HCA.

Endothelin receptors in endothelium-denuded human coronary artery bypass grafts and coronary arteries.

BACKGROUND: Coronary artery bypass graft (CABG) surgery is hampered by deleterious vasospasm in the vessel wall, especially in vein grafts. Endothelin (ET) is a strong vasoconstrictor that can be observed in increasing concentrations during CABG surgery. METHODS: Endothelin-induced vasoconstriction was evaluated in isolated, endothelium-denuded vessel segments of the human saphenous vein (SV), left internal mammary artery (LIMA), and coronary arteries. The ET(A) and ET(B) receptor mRNA levels were quantified by real-time polymerase chain reaction (PCR) analysis. RESULTS: The ET(A) and ET(B) receptor mRNA levels were significantly higher in the SV than in the LIMA and the coronary arteries. ET-1 induced a more efficacious contraction in the SV and LIMA as compared with in the coronary arteries. The ET(B) receptor agonist, Sarafotoxin 6c (S6c) stimulated constriction of the LIMA and SV, while inactive in the coronary arteries. The concentration-response curve for S6c was biphasic, suggesting activation of ET(A) receptors at high concentrations as this response could be inhibited by FR139317 (10 micromol/L), and ET(B) at low concentrations as this response could be inhibited by BQ788 (0.1 micromol/L). CONCLUSIONS: Endothelin-induced vasoconstriction is mediated by ET(A) receptors alone in coronary arteries, while a combination of ET(A) and ET(B) receptors are of importance in SV and LIMA. Expression of contractile ET(B) receptors may be a pharmacologic disadvantage that contributes to the vasospasm during CABG surgery. The lower levels of ET(A) and ET(B) receptor mRNA in the LIMA and coronary arteries as compared with in the SV may provide one explanation for the better long- and short-term patency of LIMA as compared with SV grafts.

Ischemic heart disease down-regulates angiotensin type 1 receptor mRNA in human coronary arteries.

Angiotensin II is important in the development of cardiovascular disease. In the present study, angiotensin II receptor mRNA levels were quantified by real-time polymerase chain reaction (real-time PCR) in human coronary arteries from patients with ischemic heart disease and controls. Furthermore, the suitability of artery culture for studying angiotensin receptor changes was evaluated by in vitro pharmacology and real-time PCR. The angiotensin type 1 (AT1) receptor mRNA levels were down-regulated in human coronary arteries from patients with ischemic heart disease as compared to controls (P<0.05). Culture of coronary arteries for 48 h induced down-regulation of the angiotensin AT1 and AT2 receptor mRNA levels and also a less efficacious angiotensin II-induced vasoconstriction (Emax=103+/-2% before and 23+/-7% after artery culture, P<0.001). Artery culture may thus be a suitable method for studying angiotensin receptor regulation.

Ischemic heart disease induces upregulation of endothelin receptor mRNA in human coronary arteries.

Endothelin has been implicated in the pathogenesis of ischemic heart disease and congestive heart failure. The aims were to quantify endothelin type A (ETA) and type B (ETB) receptor mRNA levels in human coronary arteries from patients with ischemic heart disease, congestive heart failure and controls using real-time polymerase chain reaction (real-time PCR). In addition, the suitability of organ culture as a model mimicking endothelin receptor changes in cardiovascular disease was evaluated by in vitro pharmacology and real-time PCR. Endothelin ETA and ETB receptor mRNA levels were significantly higher in arteries from patients with ischemic heart disease (0.23+/-0.04 and 0.35+/-0.06) as compared to congestive heart failure (0.09+/-0.02 and 0.07+/-0.01) and controls (0.08+/-0.02 and 0.08+/-0.01). After organ culture, the endothelin ETB receptor mRNA levels were elevated, and the sarafotoxin 6c-induced vasoconstriction was more efficacious. Increased endothelin receptor activity may contribute to the increased vascular tone and development of atherosclerotic disease in ischemic heart disease in man.

Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries: effects of heart failure and age.

Angiotensin II is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, heart failure and atherosclerosis. In the present study, angiotensin II receptor mRNA expression levels were quantified by real-time polymerase chain reaction and the vasocontractile responses to angiotensin II were characterised by in vitro pharmacology in endothelium-denuded human coronary arteries. Angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression levels were significantly down-regulated in arteries from patients with heart failure as compared to controls. The angiotensin II-induced vasoconstriction diminished with increasing age in patients with heart failure (r(2)=0.31, P<0.05). Also, the AT(1) receptor mRNA expression levels decreased with increasing age in patients with heart failure (r(2)=0.74, P<0.05), while no such correlation could be shown in the control group (r(2)=0.04, P=n.s.). The AT(2) receptor mRNA expression levels did not correlate with age in patients with heart failure or controls. In conclusion, the diminished angiotensin II vasoconstriction with age in heart failure patients is most likely due to a lower density of AT(1) receptors and may result from a longer period of exposure to heart failure in older patients.

Sympathetic and sensory nerve activation during negative pressure therapy of sternotomy wounds.

Negative pressure wound therapy (NPWT) has been adopted as the first-line treatment for poststernotomy mediastinitis as a result of the excellent clinical outcome. The knowledge concerning the effects of NPWT on the cardiovascular system and homeostasis is still limited. The aim of the present study was to investigate whether the plasma levels of neurohormones change during NPWT. Six pigs underwent median sternotomy followed by NPWT at -125 mmHg. The plasma levels of noradrenaline, adrenaline, neuropeptide Y, substance P, vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP) were determined before (0 min) and 5, 20, 60 and 180 min after the application of NPWT. The results show a transient increase in the plasma levels of noradrenaline and adrenaline when NPWT was applied. The plasma level of the adrenergic co-transmitter neuropeptide Y was higher in NPWT--than in sham-treated pigs, after 180 min of negative pressure. After 180 min of NPWT there was an increase in the plasma levels of the sensory nerve transmitter substance P, while no such effect was observed for CGRP or VIP. In conclusion, the results suggest sympathetic nerve activation during NPWT. This may be the result of an increase in workload on the heart during the initial phase of NPWT.

Comparison of patients undergoing enhanced external counterpulsation and spinal cord stimulation for refractory angina pectoris.

INTRODUCTION: As more patients survive coronary events, the prevalence of patients with refractory angina pectoris is increasing. The aim was to evaluate the effects of enhanced external counterpulsation (EECP) and spinal cord stimulation (SCS) and compare with optimal medically treated patients with refractory angina. METHODS: 153 patients with refractory angina were treated with either EECP, SCS, or were retained on their pharmacological treatment (control). Glyceryl trinitrate usage and Canadian Cardiovascular Society classification were registered at baseline, 6 and 12 months after therapy. RESULTS: Both EECP and SCS reduced the angina as compared with controls (P<0.001). Patients treated with EECP showed a more effective reduction as compared with SCS patients (P<0.05). Both treatments resulted in significantly decreased glyceryl trinitrate usage at 6 and 12 months follow-up (P<0.001). The nitrate consumed was unaltered in the controls. DISCUSSION: The results from this study show that both EECP and SCS therapy reduce angina in patients with refractory angina pectoris; the response to EECP was slightly more effective than that to SCS. Thus, EECP can be used as an alternative treatment for patients not responding to electrical stimulation. The beneficial effects in the treated groups were maintained during the 12 months follow-up period.

Retinal function and PKC alpha expression after focal laser photocoagulation.

PURPOSE: To examine the effects of focal laser photocoagulation on general and local retinal function and to relate electrophysiological findings with changes in protein kinase C (PKC) alpha expression. METHODS: Twelve rabbits were treated with 70 spots of laser photocoagulation in the central cone-rich retina. The operated eyes were investigated with electroretinography (full-field ERG and multifocal electroretinography, mfERG) preoperatively and at 1, 3, and 5 weeks after surgery. The expression of PKC alpha was examined at all three time points using immunohistochemistry, and PKC alpha mRNA levels were quantified using real-time polymerase chain reaction (PCR). Immunohistochemistry for glial fibrillary acidic protein (GFAP) and hematoxylin and eosin staining was employed to monitor the extent and dynamics of the morphological response. RESULTS: The full-field ERG revealed a significant increase in b-wave amplitudes derived from the isolated rod response (blue light) at all three time points after surgery (p < 0.05). Supernormal b-wave amplitudes were also found for the combined rod-cone response at 3 weeks (white light), and for the isolated cone response (light-adapted 30-Hz flicker) at 5 weeks after treatment. In the mfERG, amplitudes derived from the central retina did not change postoperatively, while the implicit time was significantly increased at all time points. Immunohistochemistry for PKC alpha revealed a reduced expression of the enzyme in rod bipolar cells 1 and 3 weeks after laser treatment compared with untreated controls. Five weeks postoperatively, no PKC alpha labeling in rod bipolar cells was found in any part of the retina. Real-time PCR 1 and 3 weeks after treatment displayed a decreased level of PKC alpha mRNA compared to the controls. Immunolabeled tissue sections from laser-treated eyes displayed GFAP expression in Müller cells in the treated as well as untreated retina 1 week postoperatively. At 3 and 5 weeks, GFAP labeling was less pronounced and was concentrated around the laser-treated spots. CONCLUSIONS: Focal laser treatment in the rabbit eye induces local and wide-spread alterations in both rod- and cone-mediated retinal function in the form of supernormal b-wave amplitudes in the full-field ERG and increased latency in the mfERG. The electrophysiological abnormalities are accompanied by a progressive down-regulation of the PKC alpha isoenzyme in rod bipolar cells, reaching far beyond the treated area. PKC alpha is down-regulated directly by impaired protein synthesis, and also possibly indirectly by protein consumption related to GFAP up-regulation. The results indicate that focal laser photocoagulation interferes with PKC-alpha-mediated inhibitory regulation of inner retinal signal transmission.

Vacuum-assisted closure of the sternotomy wound: respiratory mechanics and ventilation.

BACKGROUND: Numerous authors have reported promising results with the use of vacuum-assisted closure therapy in poststernotomy mediastinitis. The negative pressure applied to the anterior mediastinum substantially exceeds the normal negative pressure in the pleural cavities, and interaction with respiratory physiology cannot be excluded. The aim of the present study was to evaluate whether the application of six clinically relevant negative pressures between -50 mmHg and -175 mmHg to the sternotomy wound affects respiratory parameters in a porcine model. METHODS: A midline sternotomy was performed in six mechanically ventilated pigs weighing 70 +/- 3 kg. Vacuum-assisted closure therapy was applied with continuous negative pressure in a randomized order to the sternotomy wound. The following respiratory parameters were monitored by a carbon dioxide-based noninvasive monitoring system connected to the ventilator: carbon dioxide elimination, peak inspiratory pressure, peak expiratory flow, alveolar minute volume, alveolar tidal volume, expired tidal volume, static compliance, and airway resistance. RESULTS: All pigs survived the treatment, and there was no significant change in the respiratory parameters investigated at any of the six negative pressures applied. A tendency toward increased airway resistance was noted when -175 mmHg was applied, although this change was not significant. CONCLUSIONS: The application of negative pressure therapy in the treatment of deep poststernotomy infections is a novel modality gaining increased attention. In this study, no impairment in respiratory mechanics, ventilation, or oxygenation was detected when comparing applied pressures ranging from -50 mmHg to -175 mmHg in the sternotomy wound.

Triptans induce vasoconstriction of human arteries and veins from the thoracic wall.

A common side effect of migraine treatment with triptans is chest symptoms. The origin of these symptoms is not known. The aim of the present study was to examine the vasocontractile effect of triptans in human arteries and veins from the thoracic wall and in coronary artery bypass grafts. In vitro pharmacology experiments showed that the 5-hydroxytryptamine (5-HT) type 1B and 1D receptor agonists, eletriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan, induced vasoconstriction in the thoracic blood vessels from 38% to 57% of the patients. 5-carboxamidotryptamine (5-CT) and sumatriptan elicited a vasoconstriction that was antagonized by the 5-HT1B receptor antagonist SB224289, whereas the 5-HT1D receptor antagonist BRL115572 had no effect. 5-HT induced a contraction that was inhibited by the 5-HT2A receptor antagonist ketanserin. 5-HT2A, 5-HT1B, and 5-HT1D receptor mRNA levels were detected by real-time PCR in all blood vessels studied. In conclusion, triptans induce vasoconstriction in arteries and veins from the thoracic wall, most likely by activation of 5-HT1B receptors. This response could be observed in only 38% to 57% of the patients, which may provide an explanation for why a similar number of patients experience chest symptoms as a side effect of migraine treatment with triptans.

Blood flow responses in the peristernal thoracic wall during vacuum-assisted closure therapy.

BACKGROUND: Vacuum-assisted closure (VAC) therapy is a recently introduced method for the treatment of poststernotomy mediastinitis. The aim of this study was to examine the effects of negative pressure on peristernal soft tissue blood flow and metabolism because the mechanisms by which vacuum-assisted closure therapy promotes wound healing are not known in detail. METHODS: Microvascular blood flow was examined by laser Doppler velocimetry in an uninfected porcine sternotomy wound model. Microvascular blood flow was examined in the muscular and subcutaneous tissue, at different distances from the wound edge, after the application of -50 to -200 mm Hg. Wound fluid pH, partial pressures of oxygen and carbon dioxide, bicarbonate, and lactate were analyzed after 0, 30, and 60 minutes of continuous negative pressure. RESULTS: Vacuum-assisted closure therapy induced an increase in the microvascular blood flow a few centimeters from the wound edge. In muscular tissue, the distance from the wound edge to the position at which the blood flow was increased was shorter than that in subcutaneous tissue. Close to the wound edge, relative hypoperfusion was observed. The hypoperfused zone was larger at high negative pressures and was especially prominent in subcutaneous tissue. Wound fluid partial pressure of oxygen and lactate levels were increased after 60 minutes of vacuum-assisted closure therapy, which may be the result of changes in the microvascular blood flow. CONCLUSIONS: Vacuum-assisted closure therapy induces a change in microvascular blood flow that is dependent on the pressure applied, the distance from the wound edge, and the tissue type. It may be beneficial to tailor the negative pressure used for vacuum-assisted closure therapy according to the wound tissue composition. Wound fluid partial pressure of oxygen and lactate levels increased during vacuum-assisted closure therapy. This combination is known to promote wound healing.