Postischemic attenuation of cerebral artery reactivity is increased in thepresence of tissue plasminogen activator

Background and Purpose-We investigated the combined effect of tissue plasmi nogen activator and ischemia on middle cerebral artery (MCA) reactivity to determine whether abnormal MCA function after 2 hours of ischemia was worse in arteries perfused with recombinant tissue plasminogen activator (rtPA). Methods-The intraluminal suture model of focal cerebral ischemia was used t o induce 2 hours of ischemia in rats, after which occluded MCAs were remove d and studied in vitro with an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were either nonischemic (control; n=8), nonischemic and perfused with 400 mu g/m L rtPA (rtPA; n=5), ischemic (ISC; n=6), or ischemic and perfused with 400 mu g/mL rtPA (ISC-rtPA; n=6). After a 1-hour equilibration at 75 mm Hg, TMP was increased to 125 mm Hg and lumen diameter was recorded at each pressur e. Reactivity to acetylcholine (ACh 0.1 to 10.0 mu mol/L) and serotonin (0. 01 to 10 mu mol/L) was then determined. Results-Control arteries responded myogenically to pressure and increased t he amount of tone from 18.5+/-3.8% at 75 mm Hg to 24.8+/-3.0% at 125 mm Hg (P<0.05), which decreased diameter from 241+/-7 to 232+/-6 mu m. In contras t, all other groups decreased tone at 125 mm Hg, which demonstrated a loss of myogenicity. The percent tone in each group at 75 versus 125 mm Hg was r tPA, 16.0+/-4.5% versus 11.8+/-3.8%; ISC, 23.5+/-4.5% versus 13.5+/-3.1%; a nd ISC-rtPA, 23.5+/-4.2% versus 12.3+/-3.2% (P<0.05 for all). The percent i ncrease in lumen diameter at each concentration of ACh was diminished in ai l groups compared with control; ISC-rtPA arteries responded the least, whic h suggests an additive effect of rtPA in ischemic arteries. The percent inc rease in lumen diameter at 10(-5) mol/L ACh was 23+/-4% for control versus 15+/-2% for rtPA; 17+/-3% for ISC arteries (P<0.05), and 8+/-2% for ISC-rtP A arteries (P<0.01). Sensitivity to serotonin was equally diminished in all groups compared with control: EC50 (mu mol/L) was 0.06+/-0.01 for control, 0.17+/-0.02 for rtPA, 0.22+/-0.07 for ISC, and 0.16+/-0.04 for ISC-rtPA (P <0.05). Conclusions-These results demonstrate that both ischemia and rtPA perfusion diminish cerebral artery reactivity and that the combination may produce a n additive effect. This impaired reactivity may contribute to reperfusion-i nduced injury during or after thrombolysis by altering upstream cerebrovasc ular resistance.