Effects of endothelin and endothelin receptor antagonism in arteriolar and venolar microcirculation.
BACKGROUND
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor potentially involved in several cardiovascular diseases. The effect of ET-1 and the selective ETA receptor antagonist LU 135252 on skeletal muscle microcirculation in hypertensive rats was investigated.


METHODS
The cremaster muscle of anaesthetised spontaneously hypertensive rats was superfused with 10(-8) M ET-1 with and without pre-treatment with LU 135252 10 and 30 mg/kg i.v. Vascular diameters were measured microscopically, recorded on videotape and quantified off-line.


RESULTS
Superfusion with ET-1 led to a pronounced arteriolar constriction, which was the stronger the smaller the arterioles were (A1: 45%, A4: 90%). Venolar vasoconstriction was much less pronounced and independent of the vessel size (V1-V4: approx. 25%). LU 135252 (10 and 30 mg/kg i.v. was able to block arteriolar vasoconstriction dose-dependently, most pronouncedly so in the smallest arterioles. Venolar vasoconstriction was only antagonised by the higher dose. During the 30 minutes observation period cardiovascular parameters were not changed significantly with either dose of LU 135252.


CONCLUSIONS
Selective ETA receptor blockade in hypertensive rats reduced ET-1 induced arteriolar vaso-constriction in resistance arterioles to a much higher degree then venolar constriction. As elevated ET-1 levels are seen in patients with primary hypertension, this new therapeutic principle may have promising clinical potential to treat hypertension by reducing peripheral arterial resistance.
Hergenröder
S
S
Research and Development, Preclinical Cardiology, Knoll AG, Ludwigshafen, Germany.
Münter
K
K
Kirchengast
M
M
D000818:Animals; D001160:Arterioles / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014661:Vasoconstriction / Q000187:drug effects; D014699:Venules / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan