Artikel
Vasorelaxant effect of losartan-potassium in basilar arteries of rats: a new therapeutic approach to prevent cerebral vasospasm?
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Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: Cerebral vasospasm (CVS) remains to be one of the substantial causes for worse outcome after subarachnoid hemorrhage (SAH). Endothelin-1 (ET-1) is known to play a leading role in the pathophysiological cascade leading to CVS. Clazosentan, an ET-receptor antagonist, is tested in a phase III-study. Some data show a contractile influence of ET-1 to an angiotensin II (ATII)-induced contraction. Therefore, the aim of the present study was to investigate the effect of the ATII-antagonist losartan-potassium (LOS), a save and established drug, to find an additive protective effect to avoid CVS.
Methods: Experimental SAH was induced by a rat double hemorrhage model. Autologous arterial blood was injected into the cisterna magna on day 1 and day 2, in sham operated rats (sham) sodium-chloride solution instead of blood was injected and basilar arteries tested on day 3 (d3) and day 5 (d5) after SAH induction in an organ bath. Concentration-effect curves (CECs) were constructed by cumulative application of ET-1. In rats without SAH (Sham) and after SAH day 3 (d3) and day 5 (d5) we tested the contraction without LOS (LOS-) and under LOS 3x10-4M (LOS+), given 30min prior to the first ET-1 contraction. CECs were compared by the maximum effect (Emax) and the pD2 (mean values [± standard error of the mean]). The pD2 is the negative decadic logarithm of the concentration producing the half maximal effect (-log10_EC50). A p ≤ 0.05 was considered statistically significant (*).
Results: Cumulative application of ET-1 induced a dose-dependent contraction, in controls, sham-operated rats and rats after SAH. The Emax was significantly lower in the LOS+ compared to the LOS- group for sham operated rats (sham LOS-: 118±3%, LOS 3x10-4M: 57±13%*, p<0,001). Also in the SAH groups the Emax was significantly lower in LOS+ versus the LOS- groups (SAH day 3 LOS-: 140±12%, LOS+: 102±6%*, p<0,05; SAH d5 LOS-: 130±8%; LOS+: 95±4%*, p<0,01). The pD2 wasn’t altered significantly, neither in the sham group (LOS-: -7,42; LOS+: -7,79) nor in the SAH-groups (SAH d3 LOS-: -7,64; LOS+: -7,28; SAH d5 LOS-: -7,54; LOS+: -7,63).
Conclusions: The present data indicate that LOS decreases the contractility of rat basilar arteries to ET-1 in control animals and animals after SAH, as an indirect sign for an ATII-dependent influence to an ET-1 induced contraction. The reduced contraction under LOS could be another additive therapeutic approach to prevent CVS after SAH.