979-34 Adriamycin May Impair Vascular Smooth Muscle Relaxation via a Nitric Oxide-Related Mechanism

Abstract

The free radical-dependent cardiac toxicity of adriamycin (ADR) is well known. Recently we observed that ADR is also able to affect vascular function, reducing endothelium-dependent relaxation. Moreover, endotheliumindependent relaxation to nitroglycerin (NTG) was also impaired. Therefore, we wanted to investigate the mechanism through which ADR induces impairment of vascular smooth muscle function. In isolated rings of rabbit thoracic aorta preconstricted with 1 μM phenylephrine, maximal relaxation to NTG was decreased after 1 h incubation with ADR is a dose-dependent manner. In 6 experiments relaxation to NTG was 103 ± 3% in control rings, and was reduced to 97 ± 5% (p = NS), 85 ± 8 (p = NS) and 77 ± 8% (p < 0.05) in presence of 30 μM, 90 M and 150 μM ADR. As a consequence, ED 50 increased from -7.93 ± 0.11 Log Mol NTG in controls to -7.81 ± 0.11 (p = NS). -7.20 ± 0.15 (p < 0.05) and -6.99 ± 0.25 Log Mol NTG (p < 0.01) with increasing concentrations of ADR. Similar results were observed with two other endothelium-independent vasodilators, SIN-l (which activates guanylate cyclase) and isoproterenol (which activates adenylate cyclase). However, the inhibitory effect of ADR on NTG relaxation was much less pronounced if endothelium was absent. In fact, in denuded rings control maximal relaxation to NTG was 101 ± 3% and after 150 μM ADR it was 89 ± 4% (n = 6; P = NS). with no significant changes in ED 50 . Furthermore, when nitric oxide synthesis in rings with endothelium was inhibited by 300 μM L-NAME, maximal relaxation to NTG was not significantly affected, being 100 ± 42% before and 85 ± 44% after 150 μM ADR incubation (n = 6; p = NS). Thus, ADR may acutely impair smooth muscle relaxation. This impairment is dependent on the presence of normal endothelium. Formation of toxic peroxynitrite, via interaction of nitric oxide with ADR-formed free radicals, might mediate this phenomenon.