The long term goal of this project is to gain a more complete understanding of the role of ion transport pathways in the regulation of pulmonary and renal arterial tone. This renewal application is based upon several advances made during the previous funding period and focuses on characterization of the role of intracellular Ca2+ stores and selected sarcolemmal ion channels in excitation-contraction coupling of isolated pulmonary and renal arterial smooth muscle cells (PASMC and RASMC). A combination of experimental approaches will be utilized to obtain cellular and molecular information which will be related back to the physiology of intact pulmonary and renal arteries. We will specifically determine the physiological role, biophysical and pharmacological properties and the molecular identity of nonselective cation channels and volume-regulated chloride channels in these specialized vascular beds. We will also examine the properties of ryanodine- and inositol triphosphate (IP3)-sensitive Ca2+i stores in RASMC and PASMC and identify any physiologically relevant interactions which may occur between these two stores and possible effects of Ca2+ released from these stores on sarcolemmal ion channels. Finally, we will test the hypotheses that alterations of Ca2+i stores, pHi, sarcolemmal K+, Ca2+ and/or CI- channels represent critical early events in the initiation of hypoxic pulmonary vasoconstriction. Despite the clinical relevance of these two vascular beds to a number of important disease processes, relatively little information is presently available on the role of ion channels and Ca2+i stores in the control of pulmonary and renal vascular tone. This study will help fill the existing gap of knowledge regarding the role of ion channels and Ca2+i stores in vascular reactivity of the renal and pulmonary circulation. The medical significance of this project is that the results obtained have significant potential of revealing new, important cellular mechanisms responsible for pulmonary and systemic hypertension and could lead to the development of new drugs and therapeutic strategies to treat or prevent these conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL049254-07
Application #
6043795
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1993-08-01
Project End
2003-07-30
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Pharmacology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Xiong, Dazhi; Heyman, Nathanael S; Airey, Judith et al. (2010) Cardiac-specific, inducible ClC-3 gene deletion eliminates native volume-sensitive chloride channels and produces myocardial hypertrophy in adult mice. J Mol Cell Cardiol 48:211-9
Ng, Lih Chyuan; Ramduny, Deepa; Airey, Judith A et al. (2010) Orai1 interacts with STIM1 and mediates capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 299:C1079-90
Hume, Joseph R; Wang, Ge-Xin; Yamazaki, Jun et al. (2010) CLC-3 chloride channels in the pulmonary vasculature. Adv Exp Med Biol 661:237-47
Ng, Lih Chyuan; Airey, Judith A; Hume, Joseph R (2010) The contribution of TRPC1 and STIM1 to capacitative Ca(2+) entry in pulmonary artery. Adv Exp Med Biol 661:123-35
Xiong, Dazhi; Wang, Ge-Xin; Burkin, Dean J et al. (2009) Cardiac-specific overexpression of the human short CLC-3 chloride channel isoform in mice. Clin Exp Pharmacol Physiol 36:386-93
Hume, Joseph R; McAllister, Claire E; Wilson, Sean M (2009) Caffeine inhibits InsP3 responses and capacitative calcium entry in canine pulmonary arterial smooth muscle cells. Vascul Pharmacol 50:89-97
Ng, Lih Chyuan; McCormack, Mary D; Airey, Judith A et al. (2009) TRPC1 and STIM1 mediate capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells. J Physiol 587:2429-42
Ng, Lih Chyuan; Kyle, Barry D; Lennox, Alison R et al. (2008) Cell culture alters Ca2+ entry pathways activated by store-depletion or hypoxia in canine pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 294:C313-23
Ng, L C; Wilson, S M; McAllister, C E et al. (2007) Role of InsP3 and ryanodine receptors in the activation of capacitative Ca2+ entry by store depletion or hypoxia in canine pulmonary arterial smooth muscle cells. Br J Pharmacol 152:101-11
Ohya, Susumu; Horowitz, Burton; Greenwood, Iain A (2002) Functional and molecular identification of ERG channels in murine portal vein myocytes. Am J Physiol Cell Physiol 283:C866-77

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