Presence of contractile endothelin-A and dilatory endothelin-B receptors in human cerebral arteries.

Abstract

The aim of the present study was to elucidate the endothelin receptor subtypes responsible for the endothelin-induced vasomotor responses of human cerebral arteries. Human cerebral arteries with endothelium were mounted in in vitro tissue baths, and the vascular responses to endothelin-1 (ET-1) and sarafotoxin 6c (a selective ETB agonist) were studied in the presence or absence of endothelin blockers, bosentan (Ro 47-0203), a novel nonpeptide ETA and ETB receptor antagonist, and FR139317, a selective ETA receptor antagonist. The presence of messenger ribonucleic acid encoding the human ETA and ETB receptors in human cerebral arteries with intact endothelium and in segments denuded of endothelium was studied by the use of reverse transcriptase-polymerase chain reaction. ET-1 induced concentration-dependent contraction of human cerebral arteries; the pEC50 value was 9.4 +/- 0.2. The vasoconstriction was significantly antagonized both by bosentan and by FR139317. The pA2 values were 7.2 +/- 0.4 and 7.4 +/- 0.4, respectively. Sarafotoxin 6c failed to cause contraction of human cerebral arteries. In precontracted vessels, however, sarafotoxin 6c induced dilatation that was significantly inhibited by bosentan (10 mumol/L), resulting in a pA2 value of 6.0 +/- 0.2. Furthermore, messenger ribonucleic acid encoding the human ETA and ETB receptors was detected in human cerebral arteries both with and without endothelium. The ET-1-induced vasoconstriction of human cerebral arteries is primarily mediated by the ETA receptor, whereas the sarafotoxin 6c-induced vasodilatation seems to be mediated via the ETB receptor.