Phorbol dibutyrate inhibits release and action of endothelium-derived relaxing factor(s) in canine blood vessels.
The effects of phorbol esters on endothelium-dependent relaxations evoked by ACh and the calcium ionophore A23187 were analyzed in isolated canine femoral and coronary arteries mounted in organ chambers or in a bioassay system. In rings of femoral and coronary arteries, phorbol 12,13-dibutyrate (PDBu) (10(-7) M) evoked contraction (ED50 2.9 x 10(-8) M) and depressed endothelium-dependent relaxations to ACh (4-fold increase in ED50 and 72% depression of maximal response). PDBu depressed maximal relaxations to A23187 by 50% but had no effect on ED50. The inactive phorbol ester 4-alpha-phorbol didecanoate (10(-7) M) did not evoke contractions and had no effect on endothelium-dependent relaxations to ACh or A23187. Endothelium-independent relaxations to sodium nitroprusside were not effected by PDBu (10(-7) M) in femoral or coronary arteries. In bioassay experiments, selective treatment of perfused femoral artery segments with PDBu (10(-8)-10(-6) M) caused concentration-dependent inhibition of basal and ACh- (10(-6) M) and A23187-(10(-6) M) induced release of endothelium-derived relaxing factor (EDRF) (as assessed by relaxation of superfused bioassay coronary artery rings without endothelium). PDBu inhibited these responses with different potency: basal (10(-8) M) greater than ACh (10(-7) M) much greater than A23187 (only partial inhibition at 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Rubanyi
G M
GM
Department of Pharmacology, Berlex Laboratories, Cedar Knolls, New Jersey.
Desiderio
D
D
Luisi
A
A
Johns
A
A
Sybertz
E J
EJ
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D005263:Femoral Artery / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide; D009599:Nitroprusside / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*
D001685:Biological Factors; D009599:Nitroprusside; D009569:Nitric Oxide; D015240:Phorbol 12,13-Dibutyrate; D000001:Calcimycin; D000109:Acetylcholine