Endothelin-1 is a potent long-lasting vasoconstrictor in dog peripheral vasculature in vivo

Endothelin-1 (ET-1), a 21 amino acid peptide, has recently been identified and shown to produce a potent and prolonged constriction of mammalian blood vessels in vitro. We have studied the effect of local infusion of this peptide on resistance vessels in the hindlimb of the anesthetized greyhound dog. Incremental doses of ET-1 (3-200 pmol/min) were infused into the left femoral artery. Doses above 10 pmol/min produced a slowly progressive reduction in hindlimb blood flow in a dose dependent fashion, maximally reducing flow by 79.5% +/- 3.2 from 152.3 +/- 29.1 ml/min to 27.8 +/- 5.8 ml/min (+/- SEM, p less than 0.015), with a concomitant rise in vascular resistance. In the control vessel (right femoral artery) there were no statistically significant changes in blood flow observed. Onset time of the response to ET-1 was 3 min, whereas spontaneous recovery of the flow occurred at 30 min following cessation of the infusion. We demonstrated transient reversal of constriction in this arterial model during coinfusion with endothelin-1 (100 pmol/min) of dihydropyridine calcium channel blocking agent nicardipine (0.5-20 nmol/min), substance P (0.5-50 fmol/min), adenosine (10-10,000 pmol/min), and isosorbide dinitrate (0.001-0.1 mg/min).