ANALYSIS OF EFFECTS OF BOSENTAN (RO-47-0203), A NONPEPTIDE ENDOTHELINETA ETB RECEPTOR ANTAGONIST, IN THE HINDLIMB VASCULAR BED OF THE CAT/

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor a ntagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin I I, and arginine vasopressin were investigated in the hind-limb vascula r bed of the cat. Under constant-flow conditions, intraarterial inject ions of endothelin-1 and sarafotoxin 6c induced biphasic changes in hi nd-limb perfusion pressure characterized by an initial decrease follow ed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 a nd sarafotoxin 6c were reduced by bosentan, and the endothelin recepto r antagonist reduced baseline systemic arterial and hind-limb perfusio n pressures. Bosentan decreased vasoconstrictor responses to lower dos es of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, a cetylcholine, bradykinin, levcromakalim, PGE(1), adrenomedullin, and c alcitonin gene-related peptide were not altered. Vasoconstrictor respo nses to ET-1 were not altered by the angiotensin AT(1) receptor antago nist DuP 532 or the AT(2) receptor antagonist PD123,319. The results o f the present study show that bosentan attenuates vasodilator and vaso constrictor responses to endothelin-1 and sarafotoxin 6c and vasoconst rictor responses to lower doses of angiotensin II in the hind-limb vas cular bed of the cat. These results suggest that endothelin may be inv olved in mediating responses to lower doses of angiotensin II and in t he maintenance of baseline tone in the systemic vascular bed of the ca t.