The spotting lethal rat carries a naturally occurring deletion of the endothelin-B- (ETB) receptor gene that prevents expression of functional ETB-receptors. Gariepy and colleagues used tissue-specific ETB transgene expression to support normal enteric nervous system development. To determine functional consequences of ETB-receptor deficiency, studies were conducted to characterize the pressor response to endothelin-1 (ET-1) and the ETB agonist, sarafotoxin 6c (S6c) in transgenic rats homozygous for the ETB deficiency were used as controls (sl/+). All rats were anesthetized with Inactin (100 mg/kg, i.p.) and a tracheostomy performed. The right carotid artery and right jugular veins were catheterized for measuring mean arterial pressure (MAP) and infusion of peptides, respectively. Following baseline measurement of MAP, hexamethonium was infused (10 mg/kg) to block sympathetic reflex responses. After a 10-15 min stabilization period, ET-1 or S6c was infused at 0.1, 0.3 and 1.0 nmol/kg at 10 min intervals. MAP in the two groups of anesthetized rats was similar during the baseline period. The sl/+ rats showed a classic dose-dependent pressor response to ET-1; a transient vasodilation followed by prolonged vasoconstriction. In contrast, the vasodilation was absent in sl/sl rats. Furthermore, ET-1 was more potent in sl/sl compared to the sl/+ rats. The response to S6c was qualitatively similar to ET-1 in the sl/+ rats. However, the sl/sl rats also had a significant pressor response to the ETB agonist, S6c. These studies provide in vivo evidence that the rescued ETB-deficient rat lacks functional vasodilatory ETB responses in response to ET-1 but retains the vasoconstrictor response to ETB-receptor agonists.
*Vascular Biology Center and †Departments of Surgery and Physiology & Endocrinology, Medical College of Georgia, Augusta, Georgia, and ‡Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
Address correspondence and reprint requests to David M. Pollock, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500, U.S.A.
© 2000 Lippincott Williams & Wilkins, Inc.