Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine : A prospective, national, multicenter, non-interventional study-the HYPOTENS trial.

BACKGROUND: Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. METHODS: HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. RESULTS: A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. CONCLUSION: Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

Platelet surface membranes are highly mitogenic for coronary artery smooth muscle cells--A novel mechanism for sustained proliferation after vessel injury?

The effects of isolated platelet surface membranes on DNA synthesis and proliferation of bovine coronary artery smooth muscle cells (SMC) were studied. Platelet membranes were very potent mitogens for SMC. The potency was about 10-fold higher than the maximum effects of platelet-derived growth factor-BB (PDGF). Platelet membrane-induced mitogenesis was inhibited by rapamycin, wortmannin or heating for 15 min at 70 degrees C but not by the PDGF receptor antagonist SCH 13.929 or by neutralizing PDGF antibodies. Only a partial (30%) inhibition was seen with PD 98059. In contrast, PDGF-induced SMC mitogenesis was heat-stable but sensitive to SCH 13. 929, PDGF antibodies, and PD 98059. These findings provide evidence for a novel mechanism for platelet-induced SMC proliferation that is independent of PDGF secretion. Platelet membranes, attached to or incorporated into the vessel wall, could maintain sustained SMC proliferation following injury.

Patient-controlled versus staff-controlled analgesia with pethidine after allogeneic bone marrow transplantation.

Patients treated by allogeneic bone marrow transplantation (aBMT) suffer prolonged oropharyngeal mucositis pain. The aim of this study was to prospectively compare patient-controlled analgesia (PCA) with an established regimen of staff-controlled analgesia using pethidine (meperidine). Twenty patients undergoing aBMT for haematologic neoplasias or malignant lymphomas randomly received pethidine intravenously either continuously plus supplemental bolus doses on request through the transplant unit staff or by PCA. Pain intensity was assessed by patient self report using a visual analogue scale (VAS) and daily pethidine intake was documented. In addition, the pethidine consumption of 20 aBMT-patients receiving staff-controlled analgesia prior to initiation of the study, but not reporting pain, was compared retrospectively with that of patients receiving the same analgesia regimen under study conditions. PCA significantly diminished both pethidine consumption and pain intensity compared with staff-controlled analgesia. The maximum pethidine intake was 440.1 +/- 111.8 mg/24 h in the patient-controlled and 640.9 +/- 128.9 mg/24 h in the staff-controlled analgesia group (mean +/- 95% CI). Mean pain scores remained under 50% but reached 70% in the staff-controlled analgesia group. Pethidine dosage by staff-controlled analgesia increased under study conditions, suggesting that mere pain-assessment and a 'competing' analgesic method motivated the BMT-unit staff to administer higher pethidine doses. This observation is discussed as a possible Hawthorne effect. Previous studies using morphine demonstrated that PCA diminishes opioid requirement compared to continuous or staff-controlled application in bone marrow recipients. In contrast to these studies, PCA additionally improved pain relief in the present investigation.

Tolerance development to antimitogenic actions of prostacyclin but not of prostaglandin E1 in coronary artery smooth muscle cells.

This study compares the antimitogenic effects of iloprost and prostaglandin E1 on platelet-derived growth factor-BB stimulated DNA synthesis ([3H]thymidine incorporation) in bovine coronary artery smooth muscle cells. When added 20-24 h after stimulation with platelet-derived growth factor-BB (20 ng/ml), both iloprost and prostaglandin E1, concentration-dependently (IC50 3-5 nM) inhibited DNA synthesis. However, when added together with the growth factor (0-24 h), the inhibition of DNA synthesis by iloprost was markedly attenuated, indicating tolerance development. In contrast, no tolerance to antimitogenic effects of prostaglandin E1 or forskolin were observed. When added to iloprost-tolerant cells, both prostaglandin E1 and forskolin, still inhibited DNA synthesis. There was no evidence for transcriptional down-regulation of prostacyclin receptor gene by iloprost. The data demonstrate a tolerance development to antimitogenic actions of prostacyclin but not of prostaglandin E1 and suggest that the receptors, mediating the antiproliferative actions of these prostaglandins, may be different.

Thrombin-induced mitogenesis in coronary artery smooth muscle cells is potentiated by thromboxane A2 and involves upregulation of thromboxane receptor mRNA.

BACKGROUND: Previous studies have shown that thrombin is a potent though slow-acting mitogen for vascular smooth muscle cells (SMC). Because thrombin generation in vivo is accompanied by platelet activation, it has been suggested that platelet-derived factors might enhance thrombin-induced SMC proliferation. No information is available so far on the possible role of thromboxane A2. METHODS AND RESULTS: Thrombin (1 U/mL) caused a threefold to fourfold increase of DNA synthesis in cultured bovine coronary artery SMC as assessed from [3H]thymidine incorporation. U 46619, a stable thromboxane A2 mimetic, had only a minor stimulating effect on its own but potentiated the thrombin effect sixfold to sevenfold above control (P<.05). These findings were paralleled by a 52+/-5% (P<.05) increase in cell number at 48 hours after addition of both mitogens as compared with 24+/-5% with thrombin alone and no change with U 46619 alone. Thromboxane A2 receptor mRNA was found to be upregulated sixfold 20 minutes after thrombin stimulation. Pretreatment of SMC with thrombin for 4 hours markedly increased U 46619-induced mitogen-activated protein kinase activity, indicating thrombin-induced upregulation of functional thromboxane receptors in SMC. CONCLUSIONS: Thrombin-induced proliferation of SMC is markedly enhanced by thromboxane A2. This might result in an enhancement of SMC proliferation by platelet-derived thromboxane A2 in vivo.

Antimitogenic effects of vasodilatory prostaglandins in coronary artery smooth muscle cells.

Vasodilatory prostaglandins (PGI2, PGE2, PGE1) are known inhibitors of proliferation of vascular smooth muscle cells (SMC) after stimulation with mitogenic factors. However, endogenous prostaglandins do not prevent SMC proliferation subsequent to vessel injury in vivo. Since vascular cells produce large amounts of antiproliferative prostaglandins, especially subsequent to COX-2 expression, insufficient vascular PGI2 formation is not likely to explain the failure of endogenous prostaglandins to prevent excessive SMC growth. In this paper we demonstrate a rapid development of tolerance to PGI2 in SMC, resulting in diminished antiproliferative activity. These findings may not only be relevant for the control of SMC growth by endogenously synthesized prostaglandins but also for clinical use of PGI2 mimetics.

Expression, function, and regulation of E-type prostaglandin receptors (EP3) in the nonischemic and ischemic pig heart.

The action of prostacyclin, prostaglandin E1 (PGE1), and their mimetics on myocardial function includes changes in contractility, electrophysiological properties, and protection from injury caused by transient myocardial ischemia. This study was undertaken to investigate the basic properties of myocardial E-type prostaglandin (EP) receptors. Ligand binding studies using an enriched preparation of sarcolemmal membranes prepared from pig hearts revealed a single class of binding sites for [3H]PGE1, with a Kd of 3.7 nmol/L and a Bmax of 92 fmol/mg protein. Competition experiments indicated highest affinity for EPs, suggesting an EP receptor. In addition, the EP receptor subtype-selective agonists sulprostone (EP1 and EP3) and M&B 28.767 (EP3) were active, suggesting the presence of an EP3 receptor subtype. PGE1 stimulated sarcolemmal GTPase and inhibited sarcolemmal adenylyl cyclase activity, indicating EP3 receptor coupling to an inhibitory G protein (Gi). Additional in vivo experiments showed that intracoronary infusion of PGE1 (1 nmol/min) decreased isoprenaline-stimulated left ventricular contractile activity without altering systemic vascular resistance. This inhibition of beta-adrenergic effects is compatible with the known myocardial anti-ischemic action of prostaglandins. Further experiments examined EP3 receptor density and G-protein coupling in sarcolemma from ischemic and reperfused ischemic myocardium. In anesthetized open-chest minipigs, occlusion of the left anterior descending coronary artery for 60 minutes increased EP3 receptor density by 50%, whereas receptor affinity was unchanged. This upregulation was prevented by pretreatment with colchicine (2 mg/kg i.v.), indicating microtubule-dependent receptor externalization. Northern hybridization showed comparable EP3 receptor mRNA expression in control and ischemic myocardium. The increase of receptor protein was reversed during 60 minutes of reperfusion. G-protein coupling proved to be intact in ischemic and reperfused ischemic myocardial tissue, as shown by preserved GTP-gamma-S-induced decrease of [3H]PGE1 binding. These data demonstrate for the first time that myocardial receptors for PGE1 belong to the EP3 subtype. The properties of this receptor include inhibition of adenylyl cyclase and upregulation during regional myocardial ischemia, suggesting an involvement in the anti-ischemic activity of E- and I-type prostaglandins.

Thromboxane A2 induces cell signaling but requires platelet-derived growth factor to act as a mitogen.

This study investigates thromboxane A2-induced cell signaling and mitogenesis of bovine coronary artery smooth muscle cells. The thromboxane mimetic U 46619 [(15S)-hydroxy-11,9-(epoxymethano) prosta-5Z,13E-dienoic acid] (10 microM) stimulated [Ca2+]i signals, phosphorylation of MAP kinase (mitogen-activated protein kinase), and expression of c-fos mRNA in smooth muscle cells. In contrast, no stimulation of DNA synthesis or cell proliferation by U 46619 was observed. However, platelet-derived growth factor-BB (20 ng/ml)-induced mitogenesis was potentiated by U 46619. Similar results were obtained with I-BOP [1S-(1 alpha,2 beta(5Z),3 alpha(1E,3R*), 4 alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo [2.2.1] heptan-2-yl]-5-heptenoic acid]. These potentiating effects were abrogated by a specific thromboxane receptor antagonist, suggesting that the potentiation of platelet-derived growth factor-BB-induced smooth muscle cell mitogenesis by U 46619 and I-BOP was mediated by thromboxane receptors. It is concluded that thromboxane A2 generated by blood platelets at the site of vessel injury induces cell signaling in smooth muscle cells but acts as a mitogen only in the presence of growth factor(s).

Thromboxane A2 potentiates thrombin-induced proliferation of coronary artery smooth muscle cells.

The activation of thrombin is the key event in clot formation after vascular injury. Thrombin itself, but also other clot-derived factors, such as thromboxane A2 (TXA2), are mitogenic for vascular smooth muscle cells. We have studied the possible interactions between thrombin and TXA2 in stimulation of coronary artery smooth muscle cell (SMC) proliferation. Thrombin (1 U/ml) caused a significant proliferatory response in SMC. U 46619, a stable TXA2 mimetic, had only a minor stimulating effect by its own but markedly potentiated the thrombin-induced mitogenesis. A possible mechanism for these potentiating effects is provided by the demonstration of a marked (6 fold) but transient (maximum after 20 min) increase in the expression of TXA2 receptor (TP receptor) mRNA in SMC by thrombin. Since a significant clot-related TXA2 generation was detected for at least 2 hours, the up-regulation of TP receptors by thrombin may represent a mechanism that is relevant for the in vivo situation of SMC proliferation after vessel injury.

Androstenedione increases thromboxane A2 receptors in human erythroleukemia cells.

Previous studies have demonstrated an increased thromboxane A2 (TXA2) receptor expression in human erythroleukemia (HEL) cells and rat aortic smooth muscle (RASM) cells in response to testosterone treatment. HEL cells have served as a model for megakaryocytes, the progenitor cell for platelets. Platelets have previously been shown to convert androstenedione to testosterone. This study investigated the effects of androstenedione on the TXA2 receptor density in HEL and cultured RASM cells. Both cell lines were incubated with vehicle, 150 nM testosterone or 250, 500 or 750nM androstenedione for 48 hours. Co-incubation with testosterone or androstenedione significantly (p<0.05) increased the maximum number of TXA2 binding sites (Bmax) in HEL cells compared to controls. There was no significant change in Kd values. In a separate series of experiments, HEL cells were incubated with the androgen receptor antagonist hydroxyflutamide (2.5mM). Treatment with androstenedione (500nM) significantly (p<0.05) increased the Bmax value by 35% compared to control and hydroxyflutamide completely antagonized this effect of androstenedione. Incubation with hydroxyflutamide alone had no effect on the Bmax values compared to control. RASM cells also showed an increase in Bmax values by 25% and 23% over control (95+/-6.6, 118+/-7.2 and 117+/-5.1 fmoles/mg protein, control, testosterone and androstenedione, n=3). Both cell lines converted androstenedione to testosterone. The results raise the possibility that the adrenal androgen, androstenedione can regulate the expression of TXA2 receptors either on its own or via conversion to testosterone and through an androgen receptor.

Thrombin receptor activating peptide-induced cellular effects: comparative studies on human platelet activation and endothelium-dependent relaxation of porcine pulmonary arteries.

The thrombin receptor activating peptides with 6 and 14 amino acids (TRAP-6,TRAP-14) caused aggregation of washed platelets as well as of platelets in citrated and hirudin plasma. Stimulation of platelets was associated with an increase in cytosolic Ca2+ and formation of thromboxane. In porcine pulmonary arteries they induced reversible endothelium-dependent relaxation of precontracted vessels via release of endothelium-derived nitric oxide. TRAP-6 and TRAP-14 did not differ in their intrinsic activity. Both peptides possess thrombin-like activity, but their potency is more than three orders of magnitude lower than that of thrombin.

Potentiation of PDGF-induced growth responses in coronary artery smooth muscle cells by thromboxane.

Mitogenic effects of TXA2 in vascular smooth muscle cells are discussed to be dependent on the age of the donor organism. The present study investigates the contribution of TXA2 on PDGF-induced proliferation of bovine coronary artery smooth muscle cells (BCA-SMC) isolated from adult animals. Radioligand binding studies revealed high affinity TXA2 binding sites (Kd = 1.6 nM) in these cells. TXA2-mimetics alone showed no proliferative effect in BCA-SMC, assessed by [3H]thymidine incorporation. However, PDGF-stimulated proliferation was potentiated two-fold receptor-dependently by TXA2-mimetics. Thus, vasoconstrictory eicosanoids released from activated platelets might aggravate proliferation of vascular smooth muscle cells at sites of vessel injury in the adult organism.

Iloprost-induced inhibition of proliferation of coronary artery smooth muscle cells is abolished by homologous desensitization.

In addition to inhibition of platelet function, prostacyclin and its stable analogues are reported to attenuate vascular smooth muscle cell proliferation. However, desensitization of prostacyclin responsiveness is a known phenomenon in platelets. In this study we investigated the time-dependent effects of the prostacyclin-mimetic iloprost and of PGE1, respectively, on PDGF-induced proliferation of cultured coronary artery smooth muscle cells. Proliferation, assessed by [3H]thymidine incorporation was markedly inhibited by coincubation with iloprost (100 nM) and PGE1 (100 nM) for 4 h. In contrast, addition of iloprost (100 nM) for 24 h did not decrease smooth muscle cell proliferation, whereas inhibition by PGE1 or by forskolin was not diminished. These results suggest a homologous desensitization of anti-mitogenic effects of iloprost in coronary artery smooth muscle cells, probably at receptor-level.

[Low-dose midazolam reduces the alfentanil demand in elderly but not in young patients during extracorporeal shock wave lithotripsy]. / Niedrig dosiertes Midazolam reduziert den Alfentanilverbrauch bei alten, nicht aber bei jungen Patienten während extrakorporaler Stosswellenlithotrypsie.

To evaluate whether midazolam has analgesic properties in humans after intravenous injection we studied the influence of a subhypnotic dose of midazolam (50 micrograms/kg) on the cumulative alfentanil consumption in 53 patients during extracorporeal shock wave lithotripsy (ESWL) using a patient-controlled analgesia system (PCAS). In a randomised double blind fashion all patients received either midazolam or an equal volume of saline (placebo) prior to ESWL. Heart rate and arterial blood pressure were measured before and during ESWL. Alfentanil consumption was assessed 20 minutes after injection of midazolam or placebo, respectively. All patients received oxygen via face mask. In patients older than 60 years (median: 70 years, range: 61-88 years) pretreatment with midazolam resulted in a significantly lower cumulative alfentanil consumption (0.41 vs 0.97 mg; p = 0.027) compared with patients younger than 60 years after midazolam pretreatment (0.84 vs 0.71 mg; p = 0.27). Mean arterial pressure also was significantly lower in the former compared with the latter group, while heart rate remained unchanged. In contrast, in patients younger than 60 years (median: 47 years, range: 24-56 years) no significant differences were observed between the midazolam and the placebo group. Thus, low dose intravenous midazolam pretreatment led to a significant decrease of alfentanil consumption in patients beyond 60 years of age. We conclude that subhypnotic doses of midazolam are capable of reducing alfentanil demand in elderly but not in younger patients during ESWL.