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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022573-09
Application #
3336977
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1978-12-01
Project End
1989-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Tummala, Ramachandra P; Sheth, Rishi N; Heros, Roberto C (2006) Hemodilution and fluid management in neurosurgery. Clin Neurosurg 53:238-51
Kawamata, T; Peterson, J W; Bun, T et al. (1997) Augmentation of both hemolysate-induced contraction and activation of protein kinase C by submaximum activation in canine cerebral arteries in vitro. J Neurosurg 87:908-15
Manno, E M; Gress, D R; Ogilvy, C S et al. (1997) The safety and efficacy of cyclosporine A in the prevention of vasospasm in patients with Fisher grade 3 subarachnoid hemorrhages: a pilot study. Neurosurgery 40:289-93
Vacanti, F X; Kwun, B D (1996) Vascular occlusion produced over 24 hours increases spinal cord tolerance to occlusion. J Surg Res 62:29-31
Bulter, W E; Peterson, J W; Zervas, N T et al. (1996) Intracellular calcium, myosin light chain phosphorylation, and contractile force in experimental cerebral vasospasm. Neurosurgery 38:781-7;discussion 787-8
Sakas, D E; Whittaker, K W; Crowell, R M et al. (1996) Perfluorocarbons: recent developments and implications for neurosurgery. J Neurosurg 85:248-54
Vacanti, F X; Kwun, B D (1996) Carbon dioxide at anesthetic levels protects against irreversible damage during spinal cord ischemia. J Surg Res 62:59-62
Kaoutzanis, M C; Peterson, J W; Anderson, R R et al. (1995) Basic mechanism of in vitro pulsed-dye laser-induced vasodilation. J Neurosurg 82:256-61
Kwun, B D; Vacanti, F X (1995) Mild hypothermia protects against irreversible damage during prolonged spinal cord ischemia. J Surg Res 59:780-2
Yokota, M; Peterson, J W; Kaoutzanis, M C et al. (1995) Protein kinase C and diacylglycerol content in basilar arteries during experimental cerebral vasospasm in the dog. J Neurosurg 82:834-40

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