The candidate's long-term career objective is to understand the mechanisms that regulate pulmonary vascular tone in the expectation that this will eventually improve therapy for patients with pulmonary hypertension. His research has evolved from studies in patients and awake animals to the study of isolated vessels and cells. This change has been driven by the conviction that Current therapy for pulmonary hypertension is ineffective because of inadequate understanding of the basic mechanisms that regulate Pulmonary vascular tone. The scientific focus of this proposal is to understand vasoconstrictor and vasodilator mediated signal transduction in pulmonary vascular tissue. The investigator's research group is moving to the University of Utah to take advantage of colla ration with experts in cell biology (Dr. John R. Hoidal), intracellular Ca++ (Dr. William H. Barry), and signal transduction (Dr. Stephen M. Prescott and Dr. Guy A. Zimmerman). The proposed experiments combine biochemical and physiological measurements. The first specific aim will define the effects of pulmonary vasoconstrictors on 45 Ca++ entry in pulmonary vessels and the release of intracellular Ca++ in pulmonary artery endothelial and smooth muscle cells. The second specific aim will test the hypothesis that vasoconstrictors activate the phosphatidylinositol cycle and that these products contribute to vasoconstriction by increasing intracellular Ca +4 and activating protein kinase C.
This specific aim will determine whether vasoconstrictors stimulate the production of 1,2 diacylglycerols and hydrolysis of phosphoinositides in pulmonary artery endothelial and smooth muscle cells. The importance of these products will be tested by studying the effect of inhibitors of phospholipase C and protein kinase C on agonist-induced pulmonary vasoconstriction. The third specific alm will determine the ability of cyclic AMP or cyclic GMP to prevent agonist-induced vasoconstriction.
This specific aim will also determine the effects of cyclic AMP and cyclic GMP on agonist-induced Ca++ entry, intracellular Ca 4+ release, and the formation of 1,2 diacylglycerols or the hydrolysis of phosphoinositides. The fourth specific alm will investigate the mechanisms by which pulmonary vasoconstrictors inhibit the action of vasodilators. Possible mechanisms for this functional antagonism will be studied including the hypothesis that activation of protein kinase C inhibits the increase in cyclic AMP caused by isoproterenol by stimulating a pertussis toxin sensitive guanine nucleotide regulatory protein (Gi or Go). The proposed research will lead to a better understanding of the mechanisms by which vasoconstrictors and vasodilators act alone and in concert to control pulmonary vascular tone.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL002297-04
Application #
3074423
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Markewitz, B A; Michael, J R; Kohan, D E (1997) Endothelin-1 inhibits the expression of inducible nitric oxide synthase. Am J Physiol 272:L1078-83
Chang, J; Rao, N V; Markewitz, B A et al. (1996) Nitric oxide donor prevents hydrogen peroxide-mediated endothelial cell injury. Am J Physiol 270:L931-40
Markewitz, B A; Kohan, D E; Michael, J R (1995) Endothelin-1 synthesis, receptors, and signal transduction in alveolar epithelium: evidence for an autocrine role. Am J Physiol 268:L192-200
Poss, W B; Timmons, O D; Farrukh, I S et al. (1995) Inhaled nitric oxide prevents the increase in pulmonary vascular permeability caused by hydrogen peroxide. J Appl Physiol 79:886-91
Markewitz, B A; Kohan, D E; Michael, J R (1995) Hypoxia decreases endothelin-1 synthesis by rat lung endothelial cells. Am J Physiol 269:L215-20
Hughes, A K; Padilla, E; Kutchera, W A et al. (1995) Endothelin-1 induction of cyclooxygenase-2 expression in rat mesangial cells. Kidney Int 47:53-61
Michael, J R; Yang, J; Farrukh, I S et al. (1993) Protein kinase C-mediated pulmonary vasoconstriction in rabbit: role of Ca2+, AA metabolites, and vasodilators. J Appl Physiol 74:1310-9
Markewitz, B A; Michael, J R; Kohan, D E (1993) Cytokine-induced expression of a nitric oxide synthase in rat renal tubule cells. J Clin Invest 91:2138-43
Jacobson, J M; Michael, J R; Meyers, R A et al. (1992) Hyperbaric oxygen toxicity: role of thromboxane. J Appl Physiol 72:416-22
Dupont, G P; Huecksteadt, T P; Marshall, B C et al. (1992) Regulation of xanthine dehydrogenase and xanthine oxidase activity and gene expression in cultured rat pulmonary endothelial cells. J Clin Invest 89:197-202

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