The role of the endothelium has taken on increasing significance in vascular pharmacology and physiology in the past several years with the discovery that numerous endogenous and exogenous vasodilators exert their action on vascular smooth muscle by releasing from the endothelium a substance termed endothelium- dependent relaxing factor (EDRF). The production of EDRF is calcium dependent; it has a short biologic half-life; and its relaxing action on vascular smooth muscle correlates with an increase in muscle cyclic GMP concentration. Several studies have implicated the importance of oxygen tension in the stability of the relaxation responses induced by EDRF. The proposed research plan will investigate the inhibition of endothelium dependent relaxation by hypoxia. The oxygen sensitivity of these responses could be due to an effect on factor production, to the stability of EDRF once produced, to the reactivity of the vascular smooth muscle where it acts, or to some combination of these events. An experimental system will be used which allows transfer of EDRF from cultured pulmonary artery endothelial cells to one of three bioassays: relaxation of a de-endothelialized vascular ring, increase in cyclic GMP levels in cultured-vascular smooth muscle, or activation of guanylate cyclase. Separate manipulation of the oxygen tensions of the endothelial cells, of EDRF in solution, and of the bioassay preparations will allow us to investigate the sites and mechanisms of oxygen interactions with EDRF. The effects of varying oxygen tensions on the increase in endothelial cell cytoplasmic calcium concentration which normally accompanies EDRF release also will be determined. In addition to providing further insight into the nature of EDRF, these studies will increase our understanding of the potential role of EDRF in the normal and diseased pulmonary circulation including regulation of basal tone, hypoxic pulmonary vasoconstriction, pulmonary hypertension, and adult respiratory distress syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL039706-01
Application #
3471724
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kolosova, Irina A; Angelini, Daniel; Fan, Chunling et al. (2013) Resistin-like molecule ? stimulates proliferation of mesenchymal stem cells while maintaining their multipotency. Stem Cells Dev 22:239-47
Fan, Chunling; Su, Qingning; Li, Yun et al. (2009) Hypoxia-induced mitogenic factor/FIZZ1 induces intracellular calcium release through the PLC-IP(3) pathway. Am J Physiol Lung Cell Mol Physiol 297:L263-70
Zelenkov, P; McLoughlin, T; Johns, R A (1993) Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase. Am J Physiol 265:L346-54
Rengasamy, A; Johns, R A (1993) Regulation of nitric oxide synthase by nitric oxide. Mol Pharmacol 44:124-8
Johns, R A (1993) Endothelium, anesthetics, and vascular control. Anesthesiology 79:1381-91
Rengasamy, A; Johns, R A (1993) Inhibition of nitric oxide synthase by a superoxide generating system. J Pharmacol Exp Ther 267:1024-7
Brendel, J K; Johns, R A (1992) Isoflurane does not vasodilate rat thoracic aortic rings by endothelium-derived relaxing factor or other cyclic GMP-mediated mechanisms. Anesthesiology 77:126-31
Uggeri, M J; Proctor, G J; Johns, R A (1992) Halothane, enflurane, and isoflurane attenuate both receptor- and non-receptor-mediated EDRF production in rat thoracic aorta. Anesthesiology 76:1012-7
Siragy, H M; Johns, R A; Peach, M J et al. (1992) Nitric oxide alters renal function and guanosine 3',5'-cyclic monophosphate. Hypertension 19:775-9
Johns, R A (1991) Endothelium-derived relaxing factor: basic review and clinical implications. J Cardiothorac Vasc Anesth 5:69-79

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