Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat.

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.