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Inhibition of integrin alphavbeta3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia.

Author(s): Kiessling JW, Cines DB, Higazi AA, Armstead WM

Affiliation(s): Dept. of Anesthesiology and Critical Care, 3620 Hamilton Walk, JM3, Univ. of Pennsylvania, Philadelphia, PA l9l04, USA.

Publication date & source: 2009-03, Am J Physiol Heart Circ Physiol., 296(3):H862-7. Epub 2009 Jan 23.

Publication type: Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Cerebral hypoxia (10 min) followed immediately by ischemia (20 min) (H/I) impairs cerebrovasodilation in response to hypercapnia and hypotension in the newborn pig; exogenous urokinase plasminogen activator (uPA) potentiates this effect, whereas the blockade of endogenous uPA-mediated vasoactivity prevents it completely. This study investigated the role of integrin alpha(V)beta(3) in the uPA-mediated impairment of cerebrovasodilation after H/I in piglets equipped with a closed cranial window. Pial artery dilation induced by hypercapnia (Pco(2), 75 mmHg) and hypotension (mean arterial blood pressure, decreased by 45%) was blunted after H/I, reversed to vasconstriction in piglets treated with uPA (10(-7) M), a concentration observed in cerebrospinal fluid after H/I, but reverted to a dilation no different than preinsult in piglets administered an anti-alpha(V)beta(3) antibody (10 ng/ml) in addition to uPA (26 +/- 1, 9 +/- 1, -10 +/- 3, and 22 +/- 3% for hypercapnia before H/I, after H/I, after H/I with uPA, and after H/I with combined uPA and anti-alpha(V)beta(3) antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti-alpha(V)beta(3) antibody. Similar results were obtained for the combined administration of uPA with the alpha(V)beta(3) antagonist Arg-Gly-Asp-d-Phe-Val and Arg-Gly-Asp-Ser, but not for the inactive analog Arg-Gly-Asp-Glu-Ser acetate. These data show that the activation of the integrin alpha(V)beta(3) contributes to the uPA-mediated impairment of pial artery dilation after H/I. These data suggest that the inhibition of uPA and integrin signaling may preserve cerebrohemodynamic control after H/I.

Page last updated: 2009-10-20

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