New approaches to prevention and treatment of radial artery graft vasospasm

Background - There has been renewed interest in radial artery (RA) conduits for coronary artery bypass because of the relative resistance of arterial 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 systematically evaluated the effectiveness of calcium channel blockers and organic nitrates for inhibition or reversal of RA contraction in vitro. Additionally, we investigated the efficacy of novel gene therapy with endothelial nitric oxide synthase (eNOS) to inhibit RA contractions. Methods and Results - Segments of RA from 28 patients undergoing coronary artery bypass grafting were mounted in organ chambers. In control experiments, KCl (5 to 50 mmol/L) produced dose-dependent increases in tension (maximum tension, 14.3±3.0 g, n=7). Addition of diltiazem or verapamil 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 tension, 15.7±2.7 g in control rings, n=8). Diltiazem and verapamil pretreatment had no significant effect on NE contraction (103±14% and 90±14% control, respectively); nifedipine significantly inhibited NE contraction (70±11% control, P=0.02). Isosorbide dinitrate and nitroglycerin 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 evaluated for the ability to reverse an established contraction (KCl 40 mmol/L); nitroglycerin was most effective in reversing RA contraction. In separate experiments, RA underwent adenoviral-mediated gene transfer with vehicle, Escherichia coli β- galactosidase, or eNOS (eNOS, 10¹⁰ PFU/mLx1 hour). Transgene expression was confirmed by β-galactosidase activity and eNOS immunohistochemistry after 40 hours of ex vivo incubation. Immunohistochemistry demonstrated recombinant NOS in adenovirus encoding bovine eNOS (Ad.CMVeNOS) RA only. Ad.CMVeNOS arteries contracted only 46.6±13.7% of controls to KCl (n=5) and 48.2±11.4% of controls to prostaglandin F₂(αa) (10^-9 to 10^-6 M, n=5). Conclusions - Diltiazem, which is used empirically to prevent RA vasospasm, had little effect on human RA contractions (receptor-independent and receptor- dependent). Organic nitrates inhibited and reversed RA contractions. Adenoviral transfer of NOS suggests that future clinical application of gene therapy may play an important role in prevention of RA vasospasm.