Endothelin vascular receptors and responses in deoxycorticosterone acetate-salt hypertensive rats.
The vasoconstrictor effect, the binding, and the response of inositol phosphates to endothelin-1 (ET-1) were investigated in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats within 2 weeks of development of hypertension and in uninephrectomized control rats. In DOCA-salt and uninephrectomized rats, plasma levels of endothelin were similar (1.2 +/- 0.1 fmol/ml). Thoracic aorta and mesenteric artery rings devoid of endothelium presented significantly decreased responses to increasing concentrations of ET-1. Binding of ET-1 to mesenteric artery membranes was significantly lower in DOCA-salt rats (106 +/- 22 fmol/mg protein) than in uninephrectomized rats (172 +/- 19 fmol/mg protein, p less than 0.05), whereas affinity was similar. Phosphoinositide metabolism was examined in aorta and mesenteric arteries after incubation with [3H]myoinositol. Inositol phosphates were separated by high-performance liquid chromatography. In response to 100 nmol/l ET-1, accumulation of inositol 1,4,5-trisphosphate after 20 seconds and of inositol monophosphate, inositol bisphosphate, and inositol 1,3,4-triphosphate after 30 minutes (in the presence of 25 mmol/l LiCl) were significantly lower in DOCA-salt hypertensive than in uninephrectomized control rats, in both aorta and mesenteric arteries. In conclusion, decreased density of ET-1 receptors in DOCA-salt hypertensive rats results in decreased activation of phospholipase C and, consequently, reduced vasoconstriction induced by ET-1. Because the decrease in vasoconstrictor effects of ET-1 is found in the absence of endothelium, it is likely that receptor downregulation rather than prior receptor occupancy underlies these findings.
Nguyen
P V
PV
Experimental Hypertension Laboratory, Clinical Research Institute of Montreal, Canada.
Parent
A
A
Deng
L Y
LY
Flückiger
J P
JP
Thibault
G
G
Schiffrin
E L
EL
D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure; D003900:Desoxycorticosterone; D016232:Endothelins / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000502:physiology; D017466:Receptors, Endothelin; D012083:Renin / Q000097:blood; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D007295:Inositol Phosphates; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D012083:Renin