title: Effects of chronic endothelin ET(A) receptor blockade on blood pressure and vascular formation of cyclic guanosine-3',5'-monophosphate in spontaneously hypertensive rats.
abstract: Endothelin (ET) mediates vasoconstriction in intact arterial blood vessels with functional endothelium via stimulation of ET(A) receptors, while ET(B) receptor stimulation leads to vasodilation via nitric oxide (NO) release and formation of cyclic guanosine-3',5'-monophosphate (cGMP). In spontaneously hypertensive rats (SHR) the cGMP-forming NO-receptor guanylyl cyclase (sGC) is downregulated. It is unclear whether ET contributes to the hypertensive phenotype of SHR, and whether this involves the disturbed cGMP signaling. The selective ETA receptor antagonist darusentan (CAS 171714-84-4), given orally via drinking water (10 mg kg(-1) d(-1)) for 12 weeks, significantly lowered systolic blood pressure of SHR as determined by radiotelemetry. Neither impaired endothelium-dependent relaxation to acetylcholine was restored nor sGC expression and activity affected when compared to control SHR. While these findings show a role for ETA receptors in blood pressure regulation in genetically elevated blood pressure, downregulation of sGC expression and cGMP-mediated vasorelaxant response in SHR were shown to be independent of ETA receptors. The findings suggest distinct mechanisms of gene expression affecting ET and cGMP mediated vasomotor functions.
authors.affiliation: Institute of Pharmacology and Toxicology, Ruprecht Karls University Heidelberg, Mannheim, Germany. kirchengastmichael@prantintl.com
authors.forename: Michael
authors.initials: M
authors.lastname: Kirchengast
authors.forename: Klaus
authors.initials: K
authors.lastname: Witte
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stolpe
authors.forename: Lothar
authors.initials: L
authors.lastname: Schilling
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Nedvetsky
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Björn
authors.initials: B
authors.lastname: Lemmer
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D006152:Cyclic GMP / Q000096:biosynthesis*; D065130:Endothelin A Receptor Antagonists; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D065130:Endothelin A Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan; D006162:Guanylate Cyclase; D006152:Cyclic GMP