Modification of blood flow in the HSN tumour and normal tissues of the ratby the endothelin ETB receptor agonist, IRL 1620

Activation of endothelin receptors on the vasculature can produce a variety of responses from potent vasoconstriction to mild vasodilation, depending on the receptor complement within the tissue. To elucidate the potential ro le of endothelin analogues as tumour blood flow modifiers, we have evaluate d the effect of the ETB receptor agonist, IRL 1620 ([Suc-(Glu(9), Ala(11),( 15))-ET-1(8-21)]) in CBH/CBi rats bearing an HSN fibrosarcoma. Tissue blood flow and vascular resistance were determined, 20 min following administrat ion of IRL 1620 (bolus intravenous), using the uptake of radiolabelled iodo antipyrine (I-125-IAP). Blood flow was unchanged in most tissues. However, at doses greater than or equal to 1.0 nmol kg(-1) IRL 1620, blood flow in t he brain and heart was increased, whereas in the small intestine it was red uced. Blood flow in the skeletal muscle was reduced at 1.0 nmol kg(-1) only . Tumour blood flow was significantly reduced at 3.0 and 5.0 nmol kg(-1). V ascular resistance was unchanged in most tissues although it was increased in the skeletal muscle at 1.0 nmol kg(-1), in the kidney at 1.0 and 3.0 nmo l kg(-1) and in the brain and heart, it was reduced at 5.0 nmol kg(-1) IRL 1620. Vascular resistance was significantly increased in the tumour and the small intestine at doses greater than or equal to 1 nmol kg(-1) IRL 1620. Pretreatment of rats with BQ-788, an ETB receptor antagonist, selectively a ttenuated the tumour vascular response to 3 nmol kg(-1) IRL 1620 with no ch anges observed in the normal tissue responses. Our results demonstrate that the HSN tumour vasculature is selectively responsive to IRL 1620 at doses > 1 nmol kg(-1) compared with the majority of normal tissues with the excep tion of the smalt intestine, and that only the tumour response is highly se nsitive to BQ-788 antagonism, under the experimental dosing regime investig ated. These differences may be exploitable for therapeutic benefit. (C) 199 9 Wiley-Liss, Inc.