In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle.
5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic agent. Among the various toxicities associated with 5-FU, cardiovascular toxicity, consisting principally of acute myocardial ischemia and/or myocardial infarction, has been reported in up to 8.5% of patients treated with this drug. While 5-FU-induced coronary vasospasm has been considered as a potential basis for such clinical toxicity, this hypothesis remains unsubstantiated by laboratory investigation. Accordingly, the present study was designed to investigate the hypothesis that 5-FU induces reversible vasoconstriction of vascular smooth muscle and to study the cellular mechanisms of such vasomotor alterations. To investigate the effects of 5-FU on the vasoreactivity of vascular smooth muscle, 479 exposures were performed in 105 rings of aorta freshly isolated from 23 New Zealand white rabbits. Vasoconstriction was documented in 20 of 86 (23%) rings exposed to 5-FU at 7 x 10(-5) M, 45 of 83 (54%) rings exposed to 5-FU at 7 x 10(-4) M, and 41 of 49 (84%) rings exposed to 5-FU at 7 x 10(-3) M. In each case, 5-FU-induced vasoconstriction was endothelium independent. Pretreatment of rings with 10(-9) M staurosporine, a protein kinase C (PK-C) inhibitor, reduced 5-FU-induced vasoconstriction from 25.0 +/- 6.5 to 2.5 +/- 1.7 mg; staurosporine at a concentration of 10(-8) M abolished 5-FU-induced vasoconstriction. Pretreatment of rings with 10(-7) M phorbol-12,13-dibutyrate, an activator of PK-C, increased the magnitude of 5-FU-induced vasoconstriction 23-fold, from 49.7 +/- 11.1 mg before to 1163.6 +/- 276.4 mg after phorbol-12,13-dibutyrate (P = 0.0002). Neomycin, an inhibitor of phosphoinositide turnover, did not alter the magnitude of 5-FU-induced vasoconstriction. Membrane receptor blockers, including the alpha-adrenergic receptor blocker phentolamine, the beta-adrenergic receptor blocker propranolol, the H1 receptor inhibitor diphenhydramine, the H2 receptor inhibitor cimetidine, the Ca2+ channel blockers verapamil and diltiazem, and the cyclooxygenase inhibitor indomethacin all failed to alter the magnitude of 5-FU-induced vasoconstriction. Furthermore, the 5-FU-related compounds uracil and floxuridine did not produce vasoconstriction. Finally, 5-FU-induced vasoconstriction was abolished by nitroglycerin. These results indicate that (a) 5-FU causes direct, endothelium-independent vasoconstriction of vascular smooth muscle in vitro, (b) this vasomotor response involves activation of PK-C, and (c) this response is independent of vasoactive cell membrane receptors, phosphoinositide turnover, or activation of the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Medicine, St. Elizabeth's Hospital, Tufts University School of Medicine, Boston, Massachusetts 02135.
M
M
Mosseri
H J
HJ
Fingert
L
L
Varticovski
S
S
Chokshi
J M
JM
Isner
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005472:Fluorouracil / Q000037:antagonists & inhibitors / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000201:enzymology* / Q000503:physiopathology; D005996:Nitroglycerin / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000633:toxicity
D000970:Antineoplastic Agents; D015220:Calcium Channels; D010716:Phosphatidylinositols; D011941:Receptors, Adrenergic; D014662:Vasoconstrictor Agents; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D005996:Nitroglycerin; D005472:Fluorouracil