Our long range goal is to understand the mechanisms which lead to hemorrhagic cerebral arterial vasospasm following aneurysmal rupture and to develop an effective treatment regimen for patients. Experimental investigation in this area proceeds on several fronts: (1) In vitro biochemical and biophysical analysis of activation processes and actomyosin coupling in normal and abnormal cerebral arteries; (2) in vivo animal protocols to test promising therapeutic strategies; and (3) Morphological studies of changes in the cerebrovascular wall after subarachnoid hemorrhage. Development in our laboratory of the """"""""two-hemmorrhage"""""""" canine model of cerebral vasospasm has answered the question of why so many promising agents used in experimental cerebral vasospasm have failed in patients. Previous animal models were """"""""acute"""""""" in design, thus appearing susceptible to vasodilators to which the human condition is not. The """"""""chronic"""""""" model now in use is resistant to these vasodilators and also displays the delayed onset and morphological changes characteristic of human cerebral vasospasm. This model is of central importance to the proposed work. The immediate goal is to complete three sets of experiments: (1) Experiments to evaluate fully the use of calmodulin antagonism to prevent the development of cerebral vasospasm after subarachnoid hemorrhage; (2) Examination of actin-myosin coupling mechanisms in normal and abnormal arteries in the hope that fruitful new avenues of attack can be discovered; and (3) Electrophysiological and biophysical studies of the spontaneous contractility noted in vitro in arteries excised while chronically constricted in situ. This last topic may be of importance in understanding the mechanisms of autoregulation in cerebral vessels. Further into the future, a characterization of vasoactive substances will be undertaken, not in in-vitro systems as has been the rule, but in in-vivo systems using the """"""""two-hemorrhage"""""""" rabbit model currently under development coupled with emplacement of an agar cast into the basal cistern from which specific substances are slowly released.
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