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 endothelin-B- (ET(B)) receptor gene that prevents expression of functional ET(B)-receptors. Gariepy and colleagues used tissue-specific ET(B) transgene expression to support normal enteric nervous system development. To determine functional consequences of ET(B)-receptor deficiency, studies were conducted to characterize the pressor response to endothelin-1 (ET-1) and the ET(B) agonist, sarafotoxin 6c (S6c) in transgenic rats homozygous for the ET(B)-deficiency (sl/sl). Similar transgenic rats heterozygous for the ET(B) 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 ET(B) agonist, S6c. These studies provide in vivo evidence that the rescued ET(B)-deficient rat lacks functional vasodilatory ET(B) responses in response to ET-1 but retains the vasoconstrictor response to ET(B)-receptor agonists.
Pollock
D M
DM
Vascular Biology Center, Medical College of Georgia, Augusta 30912-2500, USA.
Portik-Dobos
V
V
Procter
C
C
Gariepy
C E
CE
Yanagisawa
M
M
D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014757:Viper Venoms / Q000494:pharmacology*
D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6