Arterial pressure response to endothelin-1 and sarafotoxin 6c in rescued endothelin-B-deficient rats

The spotting lethal rat carries a naturally occurring deletion of the endot helin-B- (ETB) receptor gene that prevents expression of functional ETB-rec eptors. Gariepy and colleagues used tissue-specific ETB transgene expressio n to support normal enteric nervous system development. To determine functi onal consequences of ETB-receptor deficiency, studies were conducted to cha racterize the presser response to endothelin-1 (ET-1) and the ETB agonist, sarafotoxin 6c (S6c) in transgenic rats homozygous for the ETB-deficiency ( sl/sl). Similar transgenic rats heterozygous for the ETB deficiency were us ed as controls (sl/+). All rats were anesthetized with Inactin (100 mg/kg, i.p.) and a tracheostomy per formed. The right carotid artery and right jug ular 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 anesthetiz ed rats was similar during the baseline period. The sl/+ rats showed a clas sic dose-dependent presser response to ET-1; a transient vasodilation follo wed 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 presser response to the ETB agonist, S6c. These studies provide in vivo evidence that the rescu ed ETB-deficient rat lacks functional vasodilatory ETB responses in respons e to ET-1 but retains the vasoconstrictor response to ETB-receptor agonists .