PRESENCE OF CONTRACTILE ENDOTHELIN-A AND DILATORY ENDOTHELIN-B RECEPTORS IN HUMAN CEREBRAL-ARTERIES

OBJECTIVE: The aim of the present study was to elucidate the endotheli n receptor subtypes responsible for the endothelin-induced vasomotor r esponses of human cerebral arteries. METHODS: Human cerebral arteries with endothelium were mounted in in vitro tissue baths, and the vascul ar responses to endothelin-1 (ET-1) and sarafotoxin 6c (a selective ET (B) agonist) were studied in the presence or absence of endothelin blo ckers, bosentan (Ro 47-0203), a novel nonpeptide ET(A) and ET(B) recep tor antagonist, and FR139317, a selective ET(A) receptor antagonist. T he presence of messenger ribonucleic acid encoding the human ET(A) and ET(B) receptors in human cerebral arteries with intact endothelium an d in segments denuded of endothelium was studied by the use of reverse transcriptase-polymerase chain reaction. RESULTS: ET-1 induced concen tration-dependent contraction of human cerebral arteries; the pEC(50) value was 9.4 +/- 0.2. The vasoconstriction was significantly antagoni zed both by bosentan and by FR139317. The pA(2) values were 7.2 +/- 0. 4 and 7.4 +/- 0.4, respectively. Sarafotoxin 6c failed to cause contra ction of human cerebral arteries. In precontracted vessels, however, s arafotoxin 6c induced dilatation that was significantly inhibited by b osentan (10 mu mol/L), resulting in a pA(2) value of 6.0 +/- 0.2. Furt hermore, messenger ribonucleic acid encoding the human ET(A) and ET(B) receptors was detected in human cerebral arteries both with and witho ut endothelium. CONCLUSION: The ET-1-induced vasoconstriction of human cerebral arteries is primarily mediated by the ET(A) receptor, wherea s the sarafotoxin 6c-induced vasodilatation seems to be mediated via t he ET(B) receptor.