NEW APPROACHES TO PREVENTION AND TREATMENT OF RADIAL ARTERY GRAFT VASOSPASM

Background-There has been renewed interest in radial artery (RA) condu its for coronary artery bypass because of the relative resistance of a rterial grafts to atherosclerosis compared with autogenous vein grafts . Although improved drug therapy for arterial spasm is now available, vasospasm still occurs in at least 5% to 10% of RA grafts. We systemat ically evaluated the effectiveness of calcium channel blockers and org anic nitrates for inhibition or reversal of RA contraction in vitro. A dditionally, we investigated the efficacy of novel gene therapy with e ndothelial nitric oxide synthase (eNOS) to inhibit RA contractions, Me thods and Results-Segments of RA from 28 patients undergoing coronary artery bypass grafting were mounted in organ chambers. In control expe riments, KCl (5 to 50 mmol/L) produced dose-dependent increases in ten sion (maximum tension, 14,3+/-3,0 g, n=7). Addition of diltiazem or ve rapamil had no significant effect on KCl contraction (128+/-36% and 88 +/-24% control, respectively); however, nifedipine markedly inhibited KCl contraction (27+/-4% control, P=0.005). Norepinephrine (NE, 10(-9) to 10(-4) M) produced dose-dependent increases in tension (maximum te nsion, 15.7+/-2.7 g in control rings, n=8), Diltiazem and verapamil pr etreatment had no significant effect on NE contraction (103+/-14% and; 90+/-14% control, respectively); nifedipine significantly inhibited N E contraction (70+/-11% control, P=0.02). Isosorbide dinitrate and nit roglycerin markedly inhibited KCl contractions (47+/-9% and 30+/-8% of controls, n=6) and NE contractions (42+/-10% and 31+/-9% of controls, n=6). Nifedipine, isosorbide, and nitroglycerin were further evaluate d for the ability to reverse an established contraction (KCl 40 mmol/L ); nitroglycerin was most effective in reversing RA contraction. In se parate experiments, RA underwent adenoviral-mediated gene transfer wit h vehicle, Escherichia coli beta-galactosidase, or eNOS (eNOS, 10(10) PFU/mLx1 hour). Transgene expression was confirmed by beta-galactosida se activity and eNOS immunohistochemistry after 40 hours of ex vivo in cubation. Immunohistochemistry demonstrated recombinant NOS in adenovi rus encoding bovine eNOS (Ad.CMVeNOS) RA only. Ad.CMVeNOS arteries con tracted only 46.6+/-13.7% of controls to KCl (n=5) and 48.2+/-11.4% of controls to prostaglandin F-2 alpha a (10(-9) to 10(-6) M, n=5). Conc lusions-Diltiazem, which is used empirically to prevent RA vasospasm, had little effect on human RA contractions (receptor-independent and r eceptor-dependent). Organic nitrates inhibited and reversed RA contrac tions. Adenoviral transfer of NOS suggests that future clinical applic ation of gene therapy may play an important role in prevention of RA v asospasm.