Marilyn J. Cipolla
>> tPA alone does appear to have an effect on diameter regulation of the arteries. Although it is not as pronounced as ischemia and reperfusion, the pressure at which forced dilatation occurs is significantly less. Also, the response to acetylcholine is diminished in both ischemic arteries and those perfused with tPA compared with control nonischemic arteries; arteries that were ischemic and in the presence of tPA responded significantly less than all the other groups, suggesting a combined effect of tPA in ischemic arteries. However, getting back to your original question regarding the effect of tPA on nonischemic vessels, the altered pressure-diameter curve in these arteries puts the pressure of forced dilatation in the normal myogenic range (i.e., arteries perfused with tPA lose their tone around 140mmHg, as opposed to 170mmHg in control arteries). This suggests that cerebrovascular resistance may be impaired in patients receiving tPA. As you can imagine, the consequences of this could be detrimental, especially during thrombolysis. Although we have not nailed down a mechanism, several could be involved, including those mentioned my presentation. We are currently persuing this area.
>I think this important work should be known by neurosurgeons and neurologists since they are the "block busters." I wonder if thrombin and ATP play a role too in the vascular response since lyse a thrombus will release them.
I have not looked at the interaction of a thrombus with tPA on cerebral artery myogenic activity, but plan to in the future. I think this would be very interesting given the vasoactive agents contained within a clot (such as ATP and thrombin as you mentioned). We started without a thrombus due to the complications associated with composition, placement, etc. Also, comparing the response of arteries in all these groups (nonischemic, ischemic, thrombus present, not present, with and without tPA, etc) is the goal that will provide a clearer picture of what is happening to these large arteries that have a role in overall cerebral hemostasis. I think that once we understand what is happening to the vascular components during stroke, including the large cerebral arteries and at the microcirculatory level (Kevin's study nicely addresses the importance of microcirulatory protection during reperfusion), then we can start to eliminate some of the detrimental side effects of stroke and stroke treatment, including edema and hemorrhage.