application) The aims of this proposal are to reveal some of the mechanisms of depolarization and constriction of cerebral artery smooth muscle to physiological stimuli. The central hypothesis is that vasoconstrictor stimuli inhibit K+ channels and activate Cl- channels, resulting in smooth muscle depolarization and contraction. The goals of the following 3 specific aims are to demonstrate the involvement of specific K+ and Cl- ion channels in cerebral artery constrictor responses and to define the cellular signaling pathways which regulate these ion channels.
Specific Aim #1, will test the hypothesis that inhibition of calcium activated K+ channels is a mechanism of cerebral artery constriction. Calcium-activated potassium channel activity is increased by calcium. One source of this calcium is the sarcoplasmic reticulum which via ryanodine-sensitive channels releases calcium to localized regions near the plasmalemma. The calcium release channels as well as the calcium-activated potassium channel itself are sites where vasoconstrictor generated second messengers could inhibit calcium-activated potassium channels. These possibilities will be examined using activators and inhibitors of established signal transduction pathways.
Specific Aim #2 will test the hypothesis that inhibition of voltage-dependent potassium channels is another mechanism of agonist-induced vasoconstriction. Pharmacological inhibition of voltage-dependent potassium channels depolarizes and constricts isolated cerebral arteries. Voltage-dependent potassium channel currents contribute to resting membrane potential in vascular smooth muscle. In this aim the direct and indirect effects of vasoconstrictors on voltage-dependent potassium channels will be determined.
Specific Aim #3 will test the hypothesis that chloride channels contribute to regulation of membrane potential in cerebral arteries. Chloride channels are present in vascular smooth muscle. Chloride channel blockers hyperpolarized and dilate cerebral arteries contracted by agonists or pressure. In this aim, the properties and mechanisms of regulation and functional roles of cerebrovascular smooth muscle chloride channels will be evaluated. These studies will employ state-of-the-art techniques to study: 1) localized and global changes in intracellular calcium using conventional digital fluorescence imaging and confocal microscopy, 2) ion channel activity using the patch-clamp technique and 3) correlated electrical and contractile responses of pressurized cerebral resistance arteries. A more complete understanding of the mechanisms of contraction and relaxation of vascular smooth muscle is essential to the development of new strategies for treatment of pathophysiological states that involve excessive vasoconstrictor (hypertension, vasospasm and ischemia). The proposed studies should provide essential new information relevant to these issues.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058231-02
Application #
2685534
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Jacobs, Tom P
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Dabertrand, Fabrice; Nelson, Mark T; Brayden, Joseph E (2013) Ryanodine receptors, calcium signaling, and regulation of vascular tone in the cerebral parenchymal microcirculation. Microcirculation 20:307-16
Dabertrand, Fabrice; Hannah, Rachael M; Pearson, Jessica M et al. (2013) Prostaglandin E2, a postulated astrocyte-derived neurovascular coupling agent, constricts rather than dilates parenchymal arterioles. J Cereb Blood Flow Metab 33:479-82
Dabertrand, Fabrice; Nelson, Mark T; Brayden, Joseph E (2012) Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels. Circ Res 110:285-94
Baylie, R L; Brayden, J E (2011) TRPV channels and vascular function. Acta Physiol (Oxf) 203:99-116
Nystoriak, Matthew A; O'Connor, Kevin P; Sonkusare, Swapnil K et al. (2011) Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol 300:H803-12
Earley, Scott; Brayden, Joseph E (2010) Transient receptor potential channels and vascular function. Clin Sci (Lond) 119:19-36
Earley, Scott; Pauyo, Thierry; Drapp, Rebecca et al. (2009) TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol 297:H1096-102
Brayden, Joseph E; Earley, Scott; Nelson, Mark T et al. (2008) Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin Exp Pharmacol Physiol 35:1116-20
Earley, Scott; Straub, Stephen V; Brayden, Joseph E (2007) Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Am J Physiol Heart Circ Physiol 292:H2613-22
Reading, Stacey A; Brayden, Joseph E (2007) Central role of TRPM4 channels in cerebral blood flow regulation. Stroke 38:2322-8

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