The purpose of these experiments is to examine mechanisms which regulate cerebral microvascular permeability under normal and pathological conditions. The site and mechanism of disruption of the blood-brain barrier during pathological conditions remain controversial. I have completed experiments which suggest that veins are the primary site of disruption of the blood-brain barrier during acute hypertension and hyperosmolar arabinose. During acute hypertension, disruption of the venous blood-brain barrier was associated with an increase in pial venous pressure. Experiments are proposed to determine whether 1) rate of rise in venous pressure affects disruption of the venous blood-brain barier, 2) disruption of the blood-brain barrier during hyperosmolar arabinose and seizures is associated with an increase in pial venous pressure, and 3) disruption of the venous blood-brain barrier is associated with an increase in vesicular transport or with separation of endothelial tight junctions. Disruption of the blood-brain barrier during acute hypertension is reduced in genetically hypertensive rats. The mechanism of this protective effect is assumed to be related to hypertrophy of large cerebral arteries, protecting downstream arterioles and capillaries from an increase in pressure. I propose to determine whether 1) increases in pial venous pressure are attenuated in chronic hypertension, and 2) cerebral veins undergo hypertrophy during chronic hypertension and protect the venous blood-brain barrier during elevation of pial venous pressure. Oxygen radicals increase permeability in many vascular beds. In cerebral vessels, oxygen radicals dilate arterioles and damage endothelial cells. This effect is inhibited by enzymatic inhibitors of oxygen radicals. Oxygen radicals also are implicated as mediators of endothelial damage during acute hypertension. The proposed studies will determine whether 1) oxygen radicals alter permeability of the blood-brain barrier, and 2) oxygen radicals mediate disruption of the blood-brain barrier during acute hypertension. These experiments will provide new information in three areas: 1) the role of veins and venous pressure in disruption of the blood-brain barrier, 2) the mechanism of blood-brain barrier protection in chronic hypertension, and 3) the role of oxygen radicals in disruption of the blood-brain barrier.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R23)
Project #
1R23HL035940-01
Application #
3449176
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1986-01-08
Project End
1988-12-31
Budget Start
1986-01-08
Budget End
1986-12-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mayhan, W G; Faraci, F M; Spector, R et al. (1989) Effect of leukotriene D4 on blood flow to cerebrum and choroid plexus. Am J Physiol 257:H834-8
Mayhan, W G; Faraci, F M; Siems, J L et al. (1989) Role of molecular charge in disruption of the blood-brain barrier during acute hypertension. Circ Res 64:658-64
Faraci, F M; Mayhan, W G; Schmid, P G et al. (1988) Effects of arginine vasopressin on cerebral microvascular pressure. Am J Physiol 255:H70-6
Mayhan, W G; Amundsen, S M; Faraci, F M et al. (1988) Responses of cerebral arteries after ischemia and reperfusion in cats. Am J Physiol 255:H879-84
Faraci, F M; Mayhan, W G; Williams, J K et al. (1988) Effects of vasoactive stimuli on blood flow to choroid plexus. Am J Physiol 254:H286-91
Faraci, F M; Mayhan, W G; Farrell, W J et al. (1988) Humoral regulation of blood flow to choroid plexus: role of arginine vasopressin. Circ Res 63:373-9
Mayhan, W G; Faraci, F M; Heistad, D D (1988) Effects of vasodilatation and acidosis on the blood-brain barrier. Microvasc Res 35:179-92
Faraci, F M; Mayhan, W G; Heistad, D D (1987) Segmental vascular responses to acute hypertension in cerebrum and brain stem. Am J Physiol 252:H738-42
Mayhan, W G; Faraci, F M; Heistad, D D (1987) Impairment of endothelium-dependent responses of cerebral arterioles in chronic hypertension. Am J Physiol 253:H1435-40
Faraci, F M; Heistad, D D; Mayhan, W G (1987) Role of large arteries in regulation of blood flow to brain stem in cats. J Physiol 387:115-23

Showing the most recent 10 out of 15 publications