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Biomedical subjects

Andreas Raabe

Publications and source records attributed to Andreas Raabe.

At least 19 recordsLinked to original sources
PubMed2007

Treatment related morbidity of unruptured intracranial aneurysms: results of a prospective single centre series with an interdisciplinary approach over a 6 year period (1999-2005).

OBJECTIVES: To review the angiographic and clinical outcome of patients with unruptured intracranial aneurysm(s) (UIA) with regard to complications and successful obliteration by surgical clipping or endovascular coiling. METHODS: Data were derived from a prospective database of intracranial aneurysms from June 1999 to May 2005. All patients were followed-up for 6 months using the modified Rankin Scale (mRS). Favourable outcome was classified as mRS 0-2. From a total of 691 patients included in the database, 173 harboured 206 UIA of whom 118 patients (133 UIA) were treated. RESULTS: Primary treatment assignment was surgical repair in 91 UIA and endovascular treatment in 42. In 3 UIA (7.1%), endovascular treatment was not feasible and had to be abandoned. Definite treatment was surgery in 94 UIA (81 patients) and endovascular obliteration in 39 UIA (37 patients). There were no deaths related to any treatment. Immediately after treatment, 6.4% of the surgical and 7.7% of the endovascular patients showed new neurological deficits, mainly related to cerebral ischaemia. After 6 months, 3 (2.3%) patients had a treatment related unfavourable outcome, defined as mRS >2, 2 patients after surgical and 1 patient after endovascular aneurysm repair (not statistically different, p = 0.3; Fisher's exact test). This led to an overall satisfactory outcome in 97.9% of surgically and 97.4% of endovasculary treated UIA. After surgical clipping, complete occlusion of the aneurysm was achieved in 88 (93.6%) and near complete (small residual neck) in 4 (4.3%) of 94 UIA. Two small posterior communicating artery aneurysms with a fetal type posterior communicating artery were wrapped. After endovascular treatment, obliteration was complete in 26 (66.7%). Small residual neck was seen in 13 (33.3%), but none of the UIA showed residual aneurysm filling. Five patients in the endovascular group (13.9%) underwent repeated endovascular treatment after aneurysm recanalisation. CONCLUSIONS: If patients are carefully selected and individually assigned to their optimum treatment modality, UIA can be obliterated by surgery or endovascular treatment in the majority of patients, with a low percentage of unfavourable outcomes. In this series, the outcome was not dependent on treatment. However, the rate of recanalisation of UIA is higher after endovascular obliteration. After diagnosis of an UIA, an individual interdisciplinary decision is essential for each patient to provide the optimum management.

Adult↗
PubMed2007

Persistence of the nitric oxide-dependent vasodilator pathway of cerebral vessels after experimental subarachnoid hemorrhage.

OBJECTIVE: Efficiency of the treatment of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) by interfering with the nitric oxide-cyclic guanosine monophospate (cGMP) pathway seems to be inconsistent. So far, it remains unclear whether or not insufficient access to the drugs or impaired reactivity of the vessels is responsible for this inconsistency. Therefore, the aim of the present investigation was to characterize this pathway on cerebral arteries during CVS. METHODS: CVS was induced using the rat double hemorrhage model and was determined by magnetic resonance perfusion weighted imaging. Rats were sacrificed on Day 3 and Day 5 after SAH. Immunohistochemical staining of the basilar artery for endothelial nitric oxide synthases and the alpha- and beta-subunits of the soluble guanylate cyclase was performed. Basilar artery ring segments on Day 5 were used for measurement of isometric force. Concentration effect curves for acetylcholine, sodium nitroprusside, and 8-bromo-cGMP were constructed and compared by maximum effect and pD2. RESULTS: The immunohistochemical expression of endothelial nitric oxide synthase was comparable in all groups. The soluble guanylate cyclase alpha- and beta-subunits were significantly diminished on Day 3, but recovered by Day 5. The relaxation attributable to acetylcholine and 8-bromo-cGMP was virtually identical in controls and during CVS. Relaxation attributable to sodium nitroprusside, however, was significantly enhanced after SAH (maximum effect, control: 88 +/- 12%; Day 5: 117 +/- 26%). CONCLUSION: The present investigations suggest the persistence of endothelium-, nitric oxide-, and cGMP-dependent relaxation during CVS. Therefore, the treatment of CVS interfering with this pathway seems not to be limited by alterations inside the vessel wall.

Animals↗
PubMed2006

Comparison between clipping and coiling on the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Cerebral vasospasm is one of the most important complications of aneurysmal subarachnoid hemorrhage. The effect of aneurysm occlusion technique on incidence of vasospasm is not exactly known. The objective was to analyze surgical clipping versus endovascular coiling on the incidence of cerebral vasospasm and its consequences. Using the MEDLINE PubMed (1966-present) database, all English-language manuscripts comparing patients treated by surgical clipping with patients treated by endovascular coiling, regarding vasospasm incidence after aneurysmal subarachnoid hemorrhage, were analyzed. Data extracted from eligible studies included the following outcome measures: incidence of total vasospasm, symptomatic vasospasm, ischemic infarct vasospasm-induced and delayed ischemic neurological deficit (DIND). A pooled estimate of the effect size was computed and the test of heterogeneity between studies was carried out using The Cochrane Collaboration's Review Manager software, RevMan 4.2. Nine manuscripts that fulfilled the eligibility criteria were included and analyzed. The studies differed substantially with respect to design and methodological quality. The overall results showed no significant difference between clipping and coiling regarding to outcome measures. According to the available data, there is no significant difference between the types of technique used for aneurysm occlusion (clipping or coiling) on the risk of cerebral vasospasm development and its consequences.

Cerebral Infarction↗
PubMed2006

Sentinel headache and the risk of rebleeding after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The clinical significance of sentinel headaches in patients with subarachnoid hemorrhage (SAH) is still unknown. We investigated whether patients with a sentinel headache (SH) have a higher rate of rebleeding after SAH. METHODS: An SH was defined as a sudden, severe, unknown headache lasting >1 hour with or without accompanying symptoms, not leading to a diagnosis of SAH in the 4 weeks before the index SAH. Age, sex, smoking status, clinical grade, computed tomography (CT) findings, angiographic findings, placement of an external ventricular drain, and time to aneurysm obliteration were prospectively recorded. All rebleeding events were confirmed by CT. Outcome was assessed at 6 months according to the modified Rankin Scale. RESULTS: Of 237 consecutive patients with SAH, 41 (17.3%) had an SH. Rebleeding occurred in 23 (9.7%) of all patients. Patients with an SH had a 10-fold increased odds of rebleeding compared with patients without SH. Aneurysm size and the total number of aneurysms were also significantly associated with rebleeding. There were no differences in age, sex, smoking, CT or angiographic findings, external ventricular drain placement, or time to aneurysm obliteration between groups. Patients with rebeeding had a significantly worse outcome. Logistic regression revealed the presence of an SH as an independent risk factor for rebleeding. CONCLUSIONS: In our study, patients with SAH who had an SH constituted a special group of patients with a 10-fold odds for early rebleeding. The presence of an SH may select candidates for ultraearly aneurysm obliteration or drug treatment.

Adult↗
PubMed2006

Single-center experience with TruFill platinum coils for the embolization of cerebral aneurysms.

Endovascular coiling has become a powerful alternative to neurosurgical clipping of cerebral aneurysms. Apart from the Guglielmi Detachable Coil (GDC) (Boston Scientific, Galway, Ireland), there is limited published data about the newer generation of detachable platinum coils, e.g., TruFill (Cordis, Johnson and Johnson, Miami, Fl.). We report our initial clinical experience with the embolization of aneurysms by TruFill coils. Included in this retrospective study were 26 patients (age 55.4+/-14.5 years; 9 male, 17 female) with 28 aneurysms, 21 ruptured and 7 unruptured. All patients were treated exclusively by embolization with TruFill platinum coils. Immediate angiographic and 6-month angiographic follow-up results were documented. Acute clinical outcome was recorded. Of the 28 aneurysms, 16 (57%) were completely occluded by TruFill embolization, 11 (39%) were incompletely occluded with residual necks, and 1 (4%) was partially occluded as residual aneurysm. There were no aneurysmal ruptures during the procedures. Follow-up at 6 months after the procedure was available in 18 patients and 19 aneurysms. Of the 19 aneurysms, 2 of 12 initially completely occluded aneurysms (17%) and 1 of 7 aneurysms with initial residual necks (14%) showed recanalization at the 6-month follow-up. One recanalized aneurysm was subsequently recoiled with consequent residual neck and remained unchanged at the 1-year follow-up. Embolization by TruFill platinum coils has a comparable total aneurysmal occlusion rate to that with GDC. The mid-term reintervention rate is low, and will require verification by future long-term studies.

Cerebral Angiography↗
PubMed2006

Size and location of ruptured and unruptured intracranial aneurysms measured by 3-dimensional rotational angiography.

OBJECTIVE: The aim of the study was to report about accurate size and location of a consecutive series of ruptured and unruptured aneurysms taking the complex 3-dimensional (3D) anatomy and parent vessel morphology into consideration by using the newly developed 3D rotational angiography (3D-RA). METHODS: One hundred eighteen consecutive patients with 155 saccular intracranial aneurysms were included in the study and received 3D-RA reconstructions for measurement of maximal height and width of the aneurysmal sac. Statistical evaluation compared values for ruptured (n = 83) and unruptured (n = 72) aneurysms. RESULTS: Mean height and width of unruptured aneurysms were 5.7 and 5.7 mm; of ruptured aneurysms, 6.7 and 6.1 mm (not significant, P = .7 for height and P = .9 for width). The majority of ruptured aneurysms, 81.9% and 59%, were smaller than 10 and 7 mm; likewise, 81.9% and 68.1% of unruptured aneurysms were smaller than 10 and 7 mm. The difference in frequency of small (<10/<7 mm) aneurysms between unruptured and ruptured aneurysms was not significant (P = 1.0 and .32, respectively). The majority (69.4%) of small ruptured aneurysms (<7 mm) were located in the anterior circulation. Most ruptured aneurysms were in the size group 4 to 6 mm in height and 2 to 4 mm in width, and a critical threshold size for aneurysm rupture could not be identified. CONCLUSIONS: An automated calibration procedure applied to all images and excellent visualization of aneurysm and parent vessel morphology using 3D-RA allow accurate size measurement of intracranial aneurysms which may be smaller than previously thought. Small aneurysm (<7 mm), also in the anterior circulation, should be carefully evaluated for treatment.

Aneurysm, Ruptured↗
PubMed2006

Contemporary management of aneurysmal subarachnoid hemorrhage in germany: results of a survey among 100 neurosurgical departments.

OBJECTIVE: To assess the status quo of clinical management in patients with ruptured intracranial aneurysms in Germany. In addition to preferences in vascular treatment (i.e., surgical versus endovascular), the choice of diagnostics and treatment options in the pre- and postprocedural phase is emphasized. METHODS: A standardized questionnaire was used in a postal survey. Participants were representatives of neurosurgical departments in Germany (n = 130, total number of departments). Comparisons between groups of respondents were tested using chi statistics (Fisher's exact test, two-sided). RESULTS: The overall response rate was 77% (n = 100). Preoperative assessment is standard by computed tomography and conventional angiography. Currently, endovascular treatment options are available in 71% of all responding centers. On the basis of self estimates it is projected that 63% of all ruptured aneurysms are treated surgically, whereas 37% are treated endovascularly. For anterior circulation aneurysms, a significantly higher number of respondents commit to routine or frequent use of surgical techniques compared with endovascular treatment options (93 versus 52%, P < or = 0.05). In contrast, for posterior circulation aneurysms, endovascular treatment is preferred (24 versus 94%, P < or = 0.05). Acute posthemorrhagic hydrocephalus is treated by external ventricular drainage routinely (97%). Doppler sonography, monitoring of cerebral perfusion pressure, and electrophysiology are used by a significant number of respondents. Specific treatment of subarachnoid hemorrhage (SAH) patients includes calcium antagonists (70%), glucocorticosteroids (35%), and hemorheologic agents (30%). CONCLUSION: In Germany, aneurysmal subarachnoid hemorrhage remains a disease in which standardization of clinical management is highest in preoperative diagnostics, intensive care unit monitoring, and postoperative treatment. With respect to currently published guidelines for subarachnoid hemorrhage treatment, compliance is moderate. Preferred treatment for anterior circulation aneurysms is predominantly surgical, whereas endovascular treatment options are preferentially used in aneurysms of the posterior circulation. This survey serves as a basis to analyze future developments in the management of subarachnoid hemorrhage more effectively and as an aid in finding a consensus in treatment both nationally and internationally.

Germany↗
PubMed2006

Time course in the development of cerebral vasospasm after experimental subarachnoid hemorrhage: clinical and neuroradiological assessment of the rat double hemorrhage model.

OBJECTIVE: The "double hemorrhage" model in the rat is frequently used to simulate delayed cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in humans. However, an exact neurological and angiographic characterization of the CVS is not available for this model so far and is provided in the present investigation. Additionally, perfusion weighted imaging (PWI) at 3 tesla magnetic resonance (MR) tomography was implemented to assess the reduction in cerebral blood flow (CBF). METHODS: In a prospective, randomized setting CVS was induced by injection of 0.2 ml autologous blood twice in the cisterna magna of 45 male Sprague-Dawley rats. The surviving animals were examined on Days 2, 3, 5, 7 and 9 and compared to a sham operated control group (n = 9). Rats were neurologically graded between 0 and 3, followed by MRI and selective digital subtraction angiography (DSA). The relative CBF was set in relation to the perfusion of the masseter muscle. RESULTS: The neurological state was significantly worsened on Day 2 (Grade 3), 3 (Grade 3), and 5 (Grade 2) (medians). The relative CBF/muscle BF ratio (2.5 +/- 0.8 (SAH) versus 9.2 +/- 1.3 (sham) (mean +/- SEM) and the basilar artery (BA) diameter (0.15 +/- 0.02 mm (SAH) versus 0.32 +/- 0.01 mm (sham) were significantly decreased on Day 5. Correlation between relative CBF/muscle BF ratio and BA diameter was 0.70. CONCLUSION: A valid and reproducible CVS simulation was proven by neurological score, DSA, and PWI on Day 5. Furthermore, our data demonstrate the practicability and validity of MR PWI for the monitoring of CVS in a rat SAH model.

Angiography, Digital Subtraction↗
PubMed2006

Effects of balloon angioplasty on perfusion- and diffusion-weighted magnetic resonance imaging results and outcome in patients with cerebral vasospasm.

OBJECT: The aim of this study was to analyze the effects and outcome of transluminal balloon angioplasty (TBA) on brain tissue perfusion by using combined perfusion- and diffusion-weighted (PW/DW) magnetic resonance (MR) imaging in patients with cerebral vasospasm after subarachnoid hemorrhage. METHODS: Ten consecutive patients with cerebral vasospasm treated using TBA were included in this prospective study. Hemodynamically relevant vasospasm was diagnosed using a standardized PW/DW MR imaging protocol. Digital subtraction angiography was used to confirm vasospasm, and TBA was performed to dilate vasospastic arteries. The PW/DW imaging protocol was repeated after TBA. The evaluation of the passage of contrast medium after standardized application using the bolus tracking method allowed for the calculation of the time to peak (TTP) before and after TBA. Tissue at risk was defined based on perfusion delays in individual vessel territories compared with those in reference territories. In cases with proximal focal vasospasm, TBA could dilate spastic arteries. Follow-up PW/DW MR imaging showed the disappearance of, or a decrease in, the mismatch. A TBA-induced reduction in the perfusion delay of 6.2 +/- 1 seconds (mean +/- standard error of the mean) to 1.5 +/- 0.45 seconds resulted in the complete prevention of infarction; a reduction in the delay of 6.2 +/- 2.7 to 4.1 +/- 1.9 seconds resulted in the preservation of those brain tissue parts having only small infarcts in the vessel territories. Without TBA, however, the perfusion delay remained or even increased (11.1 +/- 3.7 seconds), and the complete infarction of a territory occurred. CONCLUSIONS: Angioplasty of vasospastic arteries leads to hemodynamic effects that can be quantified using PW/DW MR imaging. In cases of a severe PW/DW imaging mismatch successful TBA improved tissue perfusion and prevented cerebral infarction. The clinical significance of PW/DW MR imaging and the concept of tissue at risk is shown by cerebral infarction in vessels not accessible by TBA.

Adult↗
PubMed2006

Three-dimensional rotational angiography guidance for aneurysm surgery.

OBJECT: The aim of this study was to investigate the feasibility of integrating three-dimensional rotational angiography (3D-RA) data into a surgical navigation system and to assess its accuracy and potential clinical benefit. METHODS: The study cohort consisted of 16 patients with 16 intracranial aneurysms who had been scheduled for routine or emergency surgery. Rotational angiography data were exported using a virtual reality modeling language file format and imported into the BrainLAB VectorVision2 image-guided surgery equipment. During 3D-RA the position of the head was measured using a special headframe. The authors also determined the accuracy of 3D-RA image guidance and the clinical benefit as judged by the surgeon, including, for example, early identification of branching vessels and the aneurysm. There was good correspondence between the 3D-RA-based navigation data and the intraoperative vascular anatomy in all cases, with a maximum error of 9 degrees of angulation and 9 degrees of rotation. In eight cases, the surgeon determined that the 3D-RA image guidance facilitated the surgical procedure by predicting the location of the aneurysm or the origin of a branching artery that had been covered by brain tissue and blood clots. CONCLUSIONS: The integration of 3D-RA into surgical navigation systems is feasible, but it currently requires a new perspective-registration technique. The intraoperative 3D view provides useful information about the vascular anatomy and may improve the quality of aneurysm surgery in selected cases.

Adult↗
PubMed2006

Alteration of the cerebrovascular function of endothelin B receptor after subarachnoidal hemorrhage in the rat.

The substantial role of endothelin-1 (ET-1) in the development of cerebral vasospasm (CVS) after subarachnoidal hemorrhage (SAH) has been demonstrated by numerous experimental and, recently, clinical investigations. Whether the expression or function of the ET(B) receptor is altered in CVS is still unclear, however. The aim of the present study was, therefore, to characterize the cerebroarterial ET(B) receptor function during CVS. Experimental CVS was induced by the rat double-hemorrhage model. Reduction of the cerebral blood flow (CBF) was confirmed by magnetic resonance perfusion-weighted imaging. Animals were sacrificed on days 3 (d3) and 5 (d5) after CVS induction. The basilar arteries (BA) were dissected, cut into ring segments, and prepared for measurement of isometric force in an organ bath. Concentration-effect curves (CECs) were constructed by cumulative application of ET-1, acetylcholine (Ach), or sarafotoxin S6c (S6c). Segments with (E+) endothelial function were used. CECs were compared by the maximum effect (E(max)), the pD2, and the shift calculated on the pD2 level. The pD2 is the negative decadic logarithm of the concentration producing the half maximal effect (-log10EC50). After SAH, the relative regional CBF in the d3 and d5 groups was reduced to 63% and 32%, respectively, of the CBF in controls. ET-1 induced a dose-dependent contraction of segments with and segments without CVS. In E+ segments, the E(max) for ET-1 was not significantly changed after SAH (mean values [ +/- SEM] of 104% +/- 4% for the control group, 106% +/- 4% for the d3 group, and 104% +/- 3% for the d5 group). The CECs, however, were significantly shifted to the left versus the control by factors of 2.4 in the d3 group and 3.6 in the d5 group. Relaxation by S6c was significantly reduced after SAH (E(max:) 73% +/- 11% in the control group, 21% +/- 13% in the d3 group, and 13% +/- 8% in the d5 group), whereas relaxation associated with Ach was not significantly changed (E(max): 45% +/- 7% in the control group, 56% +/- 6% in the d3 group, and 43% +/- 6% in the d5 group). Significant contraction by S6c was not observed in E+ and E - segments in any of the study groups. The present data indicate the loss of the ET(B) receptor-mediated relaxation of the cerebral arteries in cases of CVS, which is independent of the endothelial nitric oxide synthase level.

Acetylcholine↗
PubMed2005

Fourier analysis of intracranial aneurysms: towards an objective and quantitative evaluation of the shape of aneurysms.

Shape irregularities of intracranial aneurysms may indicate an increased risk of rupture. To quantify morphological differences, Fourier analysis of the shape of intracranial aneurysms was introduced. We compared the morphology of 45 unruptured (UIA) and 46 ruptured intracranial aneurysms (RIA) in 70 consecutive patients on the basis of 3D-rotational angiography. Fourier analysis, coefficient of roundness and qualitative shape assessment were determined for each aneurysm. Morphometric analysis revealed significantly smaller coefficient of roundness (P < 0.02) and higher values for Fourier amplitudes numbers 2, 3 and 7 (P < 0.01) in the RIA group, indicating more complex and irregular morphology in RIA. Qualitative assessment from 3D-reconstructions showed surface irregularities in 78% of RIA and 42% of UIA (P < 0.05). Our data have shown significant differences in shape between RIA and UIA, and further developments of Fourier analysis may provide an objective factor for the assessment of the risk of rupture.

Adult↗
PubMed2005

Brain surface reformatted images for fast and easy localization of perirolandic lesions.

OBJECT: The goal of this study was to evaluate a novel form of brain surface representation that allows simple, reliable mapping of the surface neuroanatomy for the preoperative evaluation of the spatial relationship between a focal lesion and the precentral gyrus. METHODS: High-resolution three-dimensional (3D) magnetic resonance (MR) imaging data sets were postprocessed using a curved multiplanar reformatting technique to create brain surface reformatted (BSR) images. These BSR images were reconstructed in less than 5 minutes and demonstrated the entire central sulcus with adjacent surface structures in one view. Two experienced neuroradiologists determined the localization of lesions near the central sulcus in 27 patients on standard MR images in three orthogonal planes and on BSR images. In addition, these observers judged whether the lesions were easy or difficult to localize on standard MR and BSR images, and whether diagnoses based on these methods were certain or doubtful. Anatomical localization based on BSR images was compared with that based on functional MR (fMR) images or intraoperative mapping of motor function. The BSR images yielded a perfect concordance with the fMR images and intraoperative mapping (Cohen kappa 1.0) and optimal diagnostic accuracy in localizing perirolandic lesions (both sensitivity and specificity were 100%). Localization was judged to be easy for 48 of 54 diagnoses based on BSR images compared with 26 of 54 based on standard MR images. Diagnoses were assessed as certain for 52 cases based on BSR images and 34 cases based on standard MR images. CONCLUSIONS: Brain surface reformatted imaging improves the diagnostic accuracy of standard anatomical MR imaging for localizing superficial brain lesions in relation to the precentral gyrus. The complementary use of this technique with standard two-dimensional imaging is supported by the fast and simple postprocessing technique and may provide useful information for preoperative surgical planning.

Adult↗
PubMed2005

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: inhibitory effect on endothelin(A) receptor-mediated contraction.

OBJECT: The central role of endothelin (ET)-1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ET(A) receptor antagonists. Clazosentan is a selective ET(A) receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ET(A) receptor-mediated contraction in the cerebrovasculature. METHODS: Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E-) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10(-9), 10(-8), and 10(-7) M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E-) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E-). CONCLUSIONS: The present data characterize clazosentan as a potent competitive antagonist of ET(A) receptor-mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

Animals↗
PubMed2005

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: effect on endothelin(B) receptor-mediated relaxation.

OBJECT: The disturbed balance between nitric oxide and endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ET(A) receptor-dependent contractile effect, ET-1 also has ET(B) receptor-mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ET(A) receptor-selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature. METHODS: Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10(-9) to 10(-6) M) after a precontraction was induced by prostaglandin F2alpha. The inhibition by clazosentan was estimated by the value of the affinity constant (pA2). The relaxation induced by sarafotoxin S6c, ET-1, and big ET-1 was inhibited in a competitive manner by clazosentan, yielding pA2 values of 7.1, 6.7, and 6.5, respectively. The selectivity to the ET(A) receptor in the cerebrovascular system was approximately two logarithmic units. CONCLUSIONS: The present investigation shows a competitive inhibition of ET(B) receptor-mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations. Thus, additional clinical trials should be undertaken to evaluate clazosentan concentrations in cerebrospinal fluid. Furthermore, the present data may be taken to describe the pharmacological properties for an ET receptor antagonist specifically tailored for the treatment of pathological conditions of impaired cerebral blood flow.

Animals↗