Clinical outcome and prognostic factors in recurrent oral squamous cell carcinoma after primary surgical treatment: a retrospective study.

OBJECTIVES: Survival for patients with recurrent oral squamous cell carcinoma is usually poor, and the most effective treatment has not yet been clearly defined. The present study evaluates the outcome in radiotherapy-naïve patients after recurrence of oral squamous cell carcinoma with respect to different treatment modalities including surgery, radiation, chemoradiation, and palliative treatment. PATIENTS AND METHODS: In this retrospective study, we included all patients with primary oral squamous cell carcinoma who received exclusively surgical therapy between 2010 and 2020 and who suffered from locoregional recurrence in their follow-up. Patients with previous adjuvant therapy were excluded from this protocol. Clinical and pathological parameters were collected and statistically evaluated. Survival analysis was performed according to Kaplan-Meier. The primary endpoints were overall and progression-free survival in dependance of treatment strategy for recurrent tumors. RESULTS: Out of a total of 538 patients with surgically treated primary oral squamous cell carcinoma, 76 patients met the inclusion criteria. The mean follow-up was 38 ± 32 months. Patients who received surgically based therapy had a significantly better outcome in terms of disease-free survival (DFS) and overall survival (OS) (DFS p < 0.001; OS p < 0.001). The presence of regional metastases and a short disease-free interval (DFI) between primary and recurrent cancer were significant predictors for adverse outcomes (DFI p < 0.001). CONCLUSION: We recommend primary surgical therapy for radiotherapy-naïve patients with recurrent oral squamous cell carcinoma, supplemented by risk-adapted adjuvant therapy. CLINICAL RELEVANCE: Surgical therapy continues to play a central role in the treatment of radiotherapy-naïve patients with recurrent oral squamous cell carcinoma.

The Role of Losartan as a Potential Neuroregenerative Pharmacological Agent after Aneurysmal Subarachnoid Haemorrhage.

BACKGROUND: Cerebral vasospasm (CVS) remains a major cause of delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage (SAH), making it a life-threatening type of stroke with high morbidity and mortality. Endothelin-1 is known as key player mediating a strong vasocontractile effect. Interestingly, losartan restores the impaired vasorelaxative ET(B1) receptor function in a non-competitive direct fashion. With this study, we aimed to investigate a potential losartan-dependent vasodilatory effect vice versa by inhibiting NO release through L-NAME, thus pushing forward concepts to alleviate vasospasm and possibly prevent ischaemia and neurodegeneration. METHODS: Cerebral vasospasm was induced by the use of an established double-injection rat model. Sprague-Dawley rats were culled on Day 3 after the ictus, and the vasospastic basilar artery was harvested for isometric investigations of the vessel tone. Ring segments were preincubated with and without L-NAME and/or losartan. RESULTS: Preincubation with L-NAME induced dose-dependent vasoconstriction via endothelin-1 in the non-SAH cohort, which was dose-dependently reduced by losartan. After SAH and dose-dependent endothelin-1 administration, maximal contraction was achieved in the control group without losartan. Furthermore, this maximal contraction was significantly decreased in the losartan group and was reversed by L-NAME. CONCLUSIONS: After SAH, losartan was shown to positively influence the ET(B1) receptor pathway in a non-competitive direct agonistic and indirect fashion. Losartan alleviated the maximum contraction triggered by endothelin-1. This effect was resolved due to NO inhibition by L-NAME. Considering this spasmolytic effect of losartan besides its already well-known effects (attenuating cerebral inflammation, restoring cerebral autoregulation and reducing epileptogenic activity) and alleviating early brain injury, losartan seems to have potential as a promising pharmacological agent after SAH.

Crosstalk between the angiotensin and endothelin system in the cerebrovasculature after experimental induced subarachnoid hemorrhage.

Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B1 receptor (ET(B1)-receptor) antagonist. Also, an increased ET(B1)-receptor-dependent relaxation to sarafotoxin S6c (S6c; an ET(B1)-receptor agonist) was detected by preincubation with losartan. Investigations after experimental induced subarachnoid hemorrhage (SAH) are still missing. Therefore, we analyzed losartan in a further pathological setup. Cerebral vasospasm was induced by a modified double hemorrhage model. Rats were sacrificed on day 3 and isometric force of basilar artery ring segments was measured. Parallel to physiological conditions, after SAH, the ET-1-induced vasoconstriction was decreased by preincubation with losartan. This reduced contraction has been abolished after preincubation with BQ-788, an ET(B1)-receptor antagonist. In precontracted vessels, ET-1 induced a higher vasorelaxation under losartan and the endothelin A receptor (ET(A)-receptor) antagonist BQ-123. After SAH, losartan caused a modulatory effect on the ET(B1)-receptor-dependent vasorelaxation. It further induced an upregulation of the NO pathway. Under losartan, the formerly known loss of the ET(B1)-receptor vasomotor function was abolished and a significantly increased relaxation, accompanied with an enhanced sensitivity of the ET(B1)-receptor, has been detected. Also, the dose-dependent antagonistic effect to the ET-1-induced contraction can be effected by angiotensin II type 1 receptor (AT1-receptor) antagonism due to losartan directly via the ET(B1)-receptor.

Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage.

BACKGROUND: Cerebral vasospasm following subarachnoid haemorrhage (SAH) remains one of the major factors contributing to poor overall patient outcome. Prostaglandin F2-alpha (PGF2a) induces vasoconstriction. After SAH, PGF2a leads to cerebral inflammation and enhanced vasoconstriction, resulting in cerebral vasospasm. Losartan is already known to have beneficial effects in stroke models and also on several cerebral inflammatory processes. Therefore, the aim of the study was to analyse the effect of losartan on PGF2a-enhanced vasoconstriction after SAH. METHODS: To investigate the effect of losartan on PGF2a-enhanced vasoconstriction after SAH, cerebral vasospasm was induced by a double-haemorrhage model. Rats were killed on day 3 and 5 after SAH followed by measurement of the isometric force of basilar artery ring segments in an organ bath. RESULTS: PGF2a induced a dose-dependent contraction. After pre-incubation with losartan, the maximum contraction (Emax) for sham-operated animals was significantly lowered [Emax 6% in losartan 3 × 10-4 molar (M) vs. 56% without losartan]. Also, after induced SAH, PGF2a induced no vasoconstriction in pre-incubated vessels with losartan 3 × 10-4 M on day 3 (d3) as well as on day 5 (d5). For the vasorelaxative investigations, vessel segments were pre-incubated with PFG2a. Cumulative application of losartan completely resolved the pre-contraction in sham-operated animals (non SAH: 95% relaxation). After SAH, losartan not only resolved the pre-contraction (d5: 103%), but also exceeded the pre-contraction (d3: 119%). Therefore, a statistically significantly increased and earlier relaxation was calculated for all losartan concentrations [Emax (d3/d5) and pD2 (d3/d5)] compared with the solvent control group. CONCLUSION: In a physiological and pathophysiological setup, losartan reduces a PGF2-induced vasoconstriction and reverses a PGF2a-precontraction completely. This fact can be integrated in pushing forward further concepts trying to antagonise/prevent cerebral vasospasm after SAH.

Correction to: Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage.

The original version of this paper unfortunately captured the names of Florian Gessler and Volker Seifert incorrectly and are now corrected in this paper.

Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage?

BACKGROUND: Under physiological cerebral conditions, levosimendan, a calcium-channel sensitizer, has a dose-dependent antagonistic effect on prostaglandin F2alpha (PGF)-induced vasoconstriction. This circumstance could be used in antagonizing delayed cerebral vasospasm (dCVS), one of the main complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and ischemic neurological deficits. Data already exist that identified neuroprotective effects of levosimendan in a traumatic brain injury model and additionally, it has been proven that this compound prevents narrowing of the basilar artery (BA) luminal area after SAH in an in vitro rabbit model. Takotsubo cardiomyopathy, a severe ventricular dysfunction, is also a well-known complication after SAH, associated with pulmonary edema and prolonged intubation. METHODS: The polypeptide endothelin-1 (ET-1) plays a key role in the development of dCVS after SAH. Therefore, the aim of the present investigation was to detect functional interactions between the calcium-sensitizing and the ET-1-dependent vasoconstriction after experimental-induced SAH; interactions between levosimendan and a substrate-specific vasorelaxation in the BA were also examined. It was reviewed whether levosimendan has a beneficial influence on endothelin(A) and/or endothelin(B1) receptors (ET-(A) and ET-(B1) receptors) in cerebral vessels after SAH. We also examined whether this drug could have antagonistic effects on a PGF-induced vasoconstriction. RESULTS: Under treatment with levosimendan after SAH, the endothelin system seems to be affected. The ET-1-induced contraction is decreased, not significantly. In addition, we detected changes in the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway. Preincubation with levosimendan causes a modulatory effect on the ET-(B1) receptor-dependent vasorelaxation. It induces an upregulation of the NO-cGMP pathway with a significantly increased relaxation. Even after PGF-induced precontraction a dose-dependent relaxation was registered, which was significantly higher (Emax) and earlier (pD2) compared to the concentration-effect curve without levosimendan. CONCLUSIONS: After experimental-induced dCVS, levosimendan seems to restore the well-known impaired function of the vasorelaxant ET-(B1) receptor. Levosimendan also reversed the PGF-induced contraction dose-dependently. Both of these mechanisms could be used for antagonizing dCVS in patients suffering SAH. Levosimendan could even be used additionally in treating patients developing takotsubo cardiomyopathy.

Comparison of Antero-Lateral Thigh Flap and Vastus Lateralis Muscle Flap for the Treatment of Extensive Scalp Defects-A Retrospective Cohort Study.

Free flap reconstruction is the standard of care for extensive defects of the head and neck area. In this study, two types of free flaps, the antero-lateral thigh flap (ALT) and the vastus lateralis muscle flap, were compared. The primary endpoint was flap success, secondary endpoints were complication rates, hospitalization and surgery time. Cases with defect situations of the scalp and consecutive microvascular free flap reconstructions using either ALT flaps or vastus lateralis muscle flaps between 2014 and 2022 were retrospectively analyzed. Indications, perioperative handling and outcomes were compared. Twenty patients were included in the analysis. Ten patients (50%) received a free flap reconstruction using an ALT flap and ten patients (50%) received a vastus lateralis flap. A simultaneous two-team approach was possible in each case and the flap success rate was 100% with the need for one successful anastomosis revision. The mean defect size in our cohort was 147 ± 46 cm2. There were no significant differences in surgery time, duration of hospitalization or complication rate between both cohorts. Both free flaps, the ALT and the vastus lateralis flap, are suitable for the closure of large scalp defects. They provide high success rates, short surgery times without the need for patient repositioning and low donor-site morbidity. The vastus lateralis muscle flap bares the advantage of being perforator-independent and allows for the preparation of long vessels for anastomosis if needed while baring the disadvantage of a prolonged period of healing via granulation or the need for secondary surgery in terms of covering by split-thickness skin grafts which may interfere with necessary adjuvant treatment in oncological patients.

Levosimendan as a therapeutic strategy to prevent neuroinflammation after aneurysmal subarachnoid hemorrhage?

BACKGROUND: Poor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH. METHODS: Experimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV. RESULTS: After preincubation with LV 10-4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10-4 M, Emax 65%; LV 10-5 M, Emax 48%; no LV, Emax 53%). Interestingly, SAH D3 (LV 10-4, Emax 76%) and D5 (LV 10-4, Emax 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels. CONCLUSIONS: LV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy.

The Effect of Losartan on Neuroinflammation as Well as on Endothelin-1- and Serotonin-Induced Vasoconstriction in a Double-Haemorrhage Rat Model.

Poor patient outcome after aneurysmal subarachnoid haemorrhage (SAH) is due to a multifactorial process. Delayed cerebral vasospasm, ischemic neurological deficits, and infarction are the most feared acute sequelae triggered by enhanced synthesis of serotonin and endothelin-1 (ET-1). During the past decades, multiple drugs have been analysed for protective effects without resounding success. Therefore, the authors wanted to analyse the potential beneficial role of Losartan (LOS). Male Sprague Dawley rats were randomised into either a group receiving two injections of blood into the cisterna magna (SAH group) or a group receiving two injections of isotonic sodium chloride (sham group). The animals were culled on day five and basilar artery ring segments were used for in vitro tension studies. Sarafotoxin S6c caused a dose-dependent vasorelaxation in sham and SAH segments, which was more pronounced in sham segments. LOS, applied in a concentration of 10−3 M, was able to significantly reduce serotonin- (p < 0.01) and ET-1- (p < 0.05, p < 0.01) mediated vasoconstriction in sham segments. These findings, along with the well-known beneficial effects of LOS on restoring the impaired endothelin-B1-receptor function after SAH, as well as on the neuroprotectional and antiepileptogenic aspects, might be implemented in advancing tailored concepts to sufficiently ameliorate patients' functional outcome after SAH.

Full-Thickness Tumor Resection of Oral Cancer Involving the Facial Skin-Microsurgical Reconstruction of Extensive Defects after Radical Treatment of Advanced Squamous Cell Carcinoma.

Advanced tumors of the head and neck are challenging for the treatment specialist due to the need to synergize oncological and functional requirements. Free flap reconstruction has been established as the standard of care for defects following tumor resection. However, depending on the affected anatomic subsite, advanced tumors may impose specific difficulties regarding reconstruction, especially when full-thickness resection is required. This study aimed to evaluate reconstructive strategies and oncological outcomes in patients with full-thickness resection of the oral cavity. A total of 33 patients with extensive defects due to squamous cell carcinoma of the oral cavity were identified. Indications, reconstructive procedures, and clinical outcome were evaluated. Thirty-two patients (97%) presented locally advanced tumors (T3/T4). Complete tumor resection was achieved in 26 patients (78.8%). The anterolateral thigh flap was the most frequently used flap (47.1%), and the primary flap success rate was 84.8%. The cohort demonstrated a good local control rate and moderate overall and progression-free survival rates. Most patients regained full competence regarding oral alimentation and speech. Full-thickness tumor resections of the head and neck area may be necessary due to advanced tumors in critical anatomic areas. In many cases, radical surgical treatment leads to good oncological results. Free flap reconstruction has been shown to be a suitable option for extensive defects in aesthetically challenging regions.

Multiple Sequential Free Flap Reconstructions of the Head and Neck: A Single-Center Experience.

BACKGROUND: Free flap reconstruction is the standard of care in extensive defects of the head and neck area, and although most patients may be treated sufficiently with one flap, recurrence of a malignant tumor or failure of a previous reconstruction may make the use of a second (or more) flap necessary. The aim of this study was to evaluate the indications and success rates of multiple consecutive reconstructive procedures in a large cohort of patients. METHODS: Nine hundred ninety-six free flap reconstructions were retrospectively analyzed and cases of sequential reconstructions in the same patient were identified. Indications, success rates, perioperative procedures, and frequently used flaps were evaluated. RESULTS: Two hundred twenty cases of sequential microvascular reconstructions were identified, ranging from two to six flaps per patient. The overall flap success rate was 89.1 percent. A history of diabetes was identified as a risk factor for flap failure (p = 0.029). There was no association of flap loss with the number of reconstructive procedures per patient. CONCLUSIONS: The use of several free flaps in the same patient is a feasible option for patients suffering from recurrent tumors or to improve quality of life by a secondary reconstruction. A salvage free flap transfer to replace a lost transplant exhibits good success rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Treatment delay and tumor size in patients with oral cancer during the first year of the COVID-19 pandemic.

BACKGROUND: We set out to investigate how the ongoing coronavirus pandemic affected the size of tumors and the duration of treatment delay in patients with surgically treated oral squamous cell carcinoma. METHODS: Patients with surgically treated oral cavity squamous cell carcinoma were assessed retrospectively and divided into two groups depending on when they had first presented at our clinic. Patients presenting from 2010 to 2019, that is, before COVID-19 onset (n = 566) were compared to patients presenting in 2020 (n = 58). RESULTS: A total of 624 patients were included. Treatment delay was significantly longer in 2020 (median = 45 days) versus 2010-2019 (median = 35 days) (p = 0.004). We observed a higher pathological T classification in 2020 (p = 0.046), whereas pathological N classification was unchanged between groups (p = 0.843). CONCLUSIONS: While extraordinary efforts continue to be made in the context of the pandemic, it is imperative that this does not lead to significant disadvantages for many people with oral cancer.

3D-printed individualized tooth-borne tissue retraction devices compared to conventional dental splints for head and neck cancer radiotherapy: a randomized controlled trial.

BACKGROUND: Despite modern treatment techniques, radiotherapy (RT) in patients with head and neck cancer (HNC) may be associated with high rates of acute and late treatment-related toxicity. The most effective approach to reduce sequelae after RT is to avoid as best as possible healthy tissues and organs at risk from the radiation target volume. Even small geometric changes can lead to a significant dose reduction in normal tissue and better treatment tolerability. The major objective of the current study is to investigate 3D printed, tooth-borne tissue retraction devices (TRDs) compared to conventional dental splints for head and neck RT. METHODS: In the current two-arm randomized controlled phase II trial, a maximum of 34 patients with HNC will be enrolled. Patients will receive either TRDs or conventional dental splints (randomization ratio 1:1) for the RT. The definition of the target volume, modality, total dose, fractionation, and imaging guidance is not study-specific. The primary endpoint of the study is the rate of acute radiation-induced oral mucositis after RT. The quality of life, local control and overall survival 12 months after RT are the secondary endpoints. Also, patient-reported outcomes and dental status, as well as RT plan comparisons and robustness analyzes, will be assessed as exploratory endpoints. Finally, mesenchymal stem cells, derived from the patients' gingiva, will be tested in vitro for regenerative and radioprotective properties. DISCUSSION: The preliminary clinical application of TRD showed a high potential for reducing acute and late toxicity of RT in patients with HNC. The current randomized study is the first to prospectively investigate the clinical tolerability and efficacy of TRDs for radiation treatment of head and neck tumors. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04454697; July 1st 2020; https://clinicaltrials.gov/ct2/show/record/NCT04454697 .

Levosimendan Reduces Prostaglandin F2a-dependent Vasoconstriction in Physiological Vessels and After Experimentally Induced Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral vasospasm (dCVS) following aneurysmal subarachnoid hemorrhage (aSAH) is (next to possible aneurysm rebleeding, cortical spreading depression and early brain injury) one of the main factors contributing to poor overall patient outcome. Since decades, intensive research has been ongoing with the goal of improving our understanding of the pathophysiological principles underlying dCVS. Endothelin-1 (ET-1) and prostaglandin F2 alpha (PGF2a) seem to play a major role during dCVS. The synthesis of ET-1 is enhanced after subarachnoid hemorrhage (SAH) to mediate a long-lasting vasoconstriction, and PGF2a contributes to cerebral inflammation and vasoconstriction. Under physiological conditions, levosimendan (LS) demonstrates an antagonistic effect on PGF2a-induced cerebral vasoconstriction. Thus, the intention of the present study was to analyze potentially beneficial interactions in a pathophysiological situation. METHODS: A modified double hemorrhage model was used. Functional interactions between the calcium-sensitizing action of LS and the vasoconstrictive properties of PGF2a were investigated. RESULTS: After pre-incubation with LS, followed by application of PGF2a, a significant decrease in maximum contraction (Emax) for sham-operated animals was found (Emax 28% with LS, Emax 56% without LS). Using the same setting after SAH, the vessel segments did not reach a statistically significant contraction (but similar like the sham-operated vessels), neither for Emax nor pD2 (-log10EC50) nor EC50 (i.e., the concentration at which half of the maximal effect occurs). LS series in sham animals were performed by pre-incubation with PGF2a. The resultant Emax showed a statistically strong significance concerning a higher vasorelaxation compared with a solvent control group. Vessel segment relaxation was significantly stronger in the same experimental setup after SAH. CONCLUSION: Under physiological and pathophysiological circumstances, LS reduced and dosedependently reversed PGF2a-induced vasoconstriction. These results can be applied to further developing methods to antagonize dCVS after aSAH.

Crosstalk between the angiotensin and endothelin-system in the cerebrovasculature.

Investigations have shown a multifactorial process as cause for the poor outcome after subarachnoid hemorrhage (SAH), including inflammation, early brain injury, cortical spreading depression, lack of cerebral autoregulation and the cerebral vasospasm (CVS) itself. Losartan may have a beneficial effect after SAH - preventing CVS, restoring cerebral autoregulation, reducing inflammation and early brain injury. Also some data is available for an AT1-receptor-upregulation and upregulated gene expression after subarachnoid hemorrhage, but the functional role of angiotensin on the cerebrovascular contractility is still not completely understood. Therefore, the aim of the present investigation was to detect functional interactions between the AT1-receptor blockade (by losartan) and the endothelin-1 (ET-1) dependent vasoconstriction and vasorelaxation in the basilar artery. To investigate the functional role of losartan on rat's basilar artery, changes of the vasoreactivity in an organ bath were determined. Under losartan the ET-1 induced contraction is decreased. After incubation with BQ-788, an ET(B)-receptor antagonist, the lowered contraction is abolished. In precontracted vessels under losartan and BQ-123, an ET(A)-receptor antagonist, ET-1 induced a higher relaxation. AT1-receptor antagonism causes a modulatory effect in ET(B)-receptor-dependent vasorelaxation in the basilar artery. AT1-receptor antagonism due to losartan induces the upregulation of the NO-pathway with a significantly increased relaxation accompanied with enhanced sensitivity of the ET(B)-receptor. Losartan has a dose-dependent antagonistic effect to the ET-1 induced contraction, which seems to ET(B)-receptor dependent. This antagonistic effect could be another beneficial effect after subarachnoid hemorrhage, additionally to the known effects after stroke: preventing CVS, restoring cerebral autoregulation, reducing inflammation and early brain injury.

Functional effects of levosimendan in rat basilar arteries in vitro.

Levosimendan is a novel calcium sensitizer that is an established treatment for congestive heart failure. In coronary vessels, levosimendan has a vasorelaxant, endothelium-independent effect and an antagonistic effect on endothelin-1 (ET-1). There is also some data for a neuroprotective effect in a traumatic brain injury model, and levosimendan can prevent the reduction of the luminal area of the basilar artery. We considered that patients who suffer heart attack after subarachnoid hemorrhage (SAH) might respond well to levosimendan, which might also be useful to induce hypertension in patients with cerebral vasospasm.However, the functional effects of levosimendan in the cerebrovasculature are unknown. Here, we investigated the functional role of levosimendan on rat basilar artery by assessing vasocontractile reactivity in response to ET-1, sarafotoxin S6c, acetylcholine, sodium nitroprusside, cGMP, and prostaglandin F2α (PGF).Contrary to observations in coronary vessels, levosimendan did not affect the ET-1 system in cerebral arteries; neither ET(A)-receptor-induced contraction nor ET(B)-receptor-dependent relaxation were changed. For the nitric oxide (NO) pathway, only a slight increase was detected. Rather, levosimendan caused significant and dose-dependent relaxation after PGF precontraction.To our knowledge, this is the first report that describes levosimendan-induced functional changes of cerebrovascular contractility and relaxation. Under physiological conditions, levosimendan did not influence ET(A)/ET(B)-receptor signaling or the NO pathway. Interestingly, levosimendan seemed to affect the prostaglandin system and dosedependently reversed PGF- induced contraction. We did not detect a vasospastic potential for levosimedan in cerebral arteries, suggesting that it would be safe for use in SAH patients.