Cerebral arteriovenous malformation (AVMs) are a treatable cause of stroke that display many abnormalities in vascular biology. The processes by which AVMs grow in size and spontaneously hemorrhage are unknown and high. AVM shunt flow often induces profound but asymptomatic regional cerebral hypotension in large areas of adjacent functional brain. The long-term goals of this project are to use AVMs as a model for chronic cerebral hypotension that is well compensated, both clinically and physiologically. On the basis of our preliminary data and other reports, we hypothesize that the vascular adaptation to chronic hypotension consists of a tonic decrease in arteriolar resistance by pathways that are dependent on nitric oxide (NO)-mediated vascular relaxation. This tonic NO-medicated decrease in vascular resistance will result in an impaired relaxation in response to vasodilators that work through an NO pathway. Experiments will enrol a total of 80 AVM patients to study otherwise normal middle cerebral artery (MCA) territories rendered hypotensive by the AVM shunt flow and 40 non-AVM controls over 4 years. Our objective will be to answer the following questions. (Spec.
Aim I) In AVM patients, to agents that work through nitric oxide (NO) versus non-NO pathways have different effects on cerebrovascular relaxation? We will test this question by demonstrating that arteriolar relaxation by an NO-dependent vasodilator (nitroprusside) or an NO precursor (L-arginine) is more impaired than vasodilation by NO-independent vasodilators (verpamil and papaverine) compared to control groups receiving the same agents. As further test of a participation of NO-mediated pathways, we will measure cerebral venous cGMP concentration before and after vasodilator challenges. (Spec.
Aim II) Dose AVM treatment (i.e., re-pressurizing hypotensive vascular territories) affect this chronic reduction in cerebrovascular resistance? We will test this question by repeating the vasodilator challenges at the post-operative angiogram or last embolization before radiosurgery to demonstrate that increasing MCA pressure by partial or complete obliteration of the shunt will normalize vasoreactivity. (Spec.
Aim III) Does chronic cerebral hypotension cause a re-localization (transference) of cerebral function? We will test this question by superselective anaesthetic testing of the hypotensive arterial distribution studied with pharmacologic vasodilation. Methods for the proposed studies will include the use of distal cerebral pressure measurement, superselective 133Xe cerebral blood flow (CBF) and sensorimotor and neurobehavioral testing before and after amobarbital testing of the arterial pedicles studied. Elucidating the mechanisms of adaptation to chronic compensate regional hypotension will lead to insight into the pathophysiology of AVMs and their management. In addition, new insights into pharmacologic manipulation of cerebrovascular resistance in states of chronic cerebral hypotension will lead to the development of new strategies to prevent and treat brain injury in occlusive cerebrovascular disease and a better understanding of the regulation of the human cerebral circulation.
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