EFFECTS OF ENDOTHELIN AND ENDOTHELIN RECEPTOR ANTAGONISM IN ARTERIOLAR AND VENOLAR MICROCIRCULATION

Background: Endothelin-1 (ET-I) is a potent endogenous vasoconstrictor potentially involved in several cardiovascular diseases. The effect o f ET-1 and the selective ETA receptor antagonist LU 135252 on skeletal muscle microcirculation in hypertensive rats was investigated. Method s: The cremaster muscle of anaesthetised spontaneously hypertensive ra ts was superfused with 10(-8) M ET-1 with and without pre-treatment wi th LU 135252 10 and 30 mg/kg iv. Vascular diameters were measured micr oscopically, recorded on videotape and quantified off-line. Results: S uperfusion with ET-I led to a pronounced arteriolar constriction, whic h was the stronger the smaller the arterioles were (Al: 45%, A4: 90%). Venolar vasoconstriction was much less pronounced and independent of the vessel size (V1-V4: approx. 25%). LU 135252 (IO and 30 mg/kg iv.) was able to block arteriolar vasoconstriction dose-dependently, most p ronouncedly so in the smallest arterioles. Venolar vasoconstriction wa s only antagonised by the higher dose. During the 30 minutes observati on period cardiovascular parameters were not changed significantly wit h either dose of LU 135252. Conclusion: Selective ETA receptor blockad e in hypertensive rats reduced ET-I induced arteriolar vasoconstrictio n in resistance arterioles to a much higher degree then venolar constr iction. As elevated ET-I bevels are seen in patients with primary hype rtension this new therapeutic principle may have promising clinical po tential to treat hypertension by reducing peripheral arterial resistan ce.