NITRIC-OXIDE (NO) DONOR MOLECULES - EFFECT OF NO RELEASE RATE ON VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION IN-VITRO

Nitric oxide (NO) inhibits vascular smooth muscle cell (SMC) growth in vitro. To determine the effects of release rate and exposure time on SMC growth inhibition by NO, we compared the activities of five NO don ors that generate NO with half-lives of 2 min (DEA/NO, Et(2)N[N2O2]Na) , 15 min (PAPA/NO, CH3(CH2)(2)N[N2O2](-)(CH2)(3)NH3+), 39 min, (SPER/N O, H2N(CH2)(3)NH2+(CH2)(4)N[N2O2](-)(CH2)(3)NH2), 3 h (DPTA/NO, H2N(CH 2)(3)N[N2O2](-)(CH2)(3)NH3+), and 20 h (DETA/NO, H2N(CH2)(2)N[N2O2](-) (CH2)(2)NH3+). After 22-h treatment, rat aorta SMC (RA-SMC) DNA synthe sis was inhibited with IC,, values of 180, 60, and 40 mu M for SPER/NO , DPTA/NO, and DETA/NO, respectively. DEA/NO and PAPA/NO did not inhib it DNA synthesis significantly at any concentration tested (20-500 mu M). The inhibitory effect of NO on RA-SMC DNA synthesis was thus great est when a given molar dose of NO was delivered slowly throughout the 22-h period. The antiproliferative effect of DETA/NO was confirmed by measurement of cell numbers for 7 days. When RA-SMC were treated with 500 mu M DETA/NO on days 1, 3, and 5, growth was completely suppressed . Cell viability was >95%, confirming that DETA/NO was not cytotoxic. The results suggest that NO donors may be useful inhibitors of intimal hyperplasia and restenosis after vascular injury such as balloon angi oplasty.