Dilation to Tissue Plasminogen Activator of Middle Cerebral Arteries is Prevented by Actin Cytoskeletal Stabilization
Background: Tissue plasminogen activator (tPA) is the only FDA approved treatment for acute ischemic stroke, however, the effects of tPA on the cerebral circulation are unknown. We have previously shown that perfusion of isolated middle cerebral arteries (MCAs) with 400μg/mL tPA inhibits pressure-induced myogenic constriction (Stroke 2000;31:940–45). In the present study, we investigated the effect of increasing concentrations of tPA on myogenic tone and whether or not treatment of MCAs with jasplakinolide (JASP), a cell-permeable compound that stabilizes the actin cytoskeleton of smooth muscle, could prevent tPA-induced vasodilation. Methods: MCAs were isolated from male Wistar rats and mounted on two glass microcannulas in a specialized arteriograph chamber that allowed control of transmural pressure (TMP) and continuous measurement of lumen diameter. Arteries were pressurized to 75mmHg and tone allowed to develop. One group of MCAs (JSP, n=8) were treated with 10-7M JASP and the other group left untreated (CTL, n=6) as controls. Increasing concentrations of tPA (0.1, 1.0, 5.0mg/mL) were then added to the arteriograph bath and lumen diameter recorded at each concentration. Results: Addition of tPA caused a concentration-dependent dilation in CTL arteries, decreasing myogenic tone from 28.5±2.8% to 26.7±3.2% in 0.1mg/mL (p<0.05), 22.7±2.3% in 1.0mg/mL (p<0.01) and 20.4±2.3% in 5.0mg/mL (p<0.01) tPA. Treatment of MCAs with JASP significantly prevented this loss of tone, diminishing tone from 25.5±3.0% to only 23.3±3.9% in 0.1mg/mL, 23.3±4.1 in 1.0mg/mL and 22.3±4.3 in 5.0mg/mL tPA (p>0.05 for all). Conclusions: It appears that tPA has a direct effect on the arterial wall of MCAs that interferes with myogenic reactivity. Whether this effect is beneficial or not is unclear, however, treatment of arteries to stabilize smooth muscle contractile proteins may prevent this vasodilation and loss of myogenicity. Understanding how tPA affects the cells within the vascular wall is an important step that could lead to improved treatment and stroke outcome.