Crosstalk Between the Angiotensin and Endothelin-System in the Cerebrovasculature

Juergen      Konczalla; Stefan      Wanderer; Jan      Mrosek; Patrick      Schuss; Johannes      Platz; Erdem      Güresir; Volker      Seifert; Hartmut      Vatter

doi:10.2174/15672026113109990030

Abstract

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.

Keywords: AT1-receptor, angiotensin, cerebrovasculature, crosstalk, ET(A)-receptor, ET(B)-receptor, endothelin, losartan.