Endothelial cells release relaxing factors (EDRF), of which nitric oxide (NO) appears to be the most important. Endothelium-dependent relaxations are reduced in arteries from hypertensive animals. In the spontaneously hypertensive rat (SHR) this has been attributed to the production of a yet unidentified endothelium-derived contracting factor (EDCF). The proposed research will determine the interactions between EDRF and EDCF, and determine whether or not the latter is an endoperoxide. We will also try to define whether or not platelet-derived products or endothelins can be regarded as (patho) physiological stimuli for the release of EDCF. We will begin to explore the molecular biological aspects that underlie the production of EDCF. We will explore whether or not endothelium-dependent contractions are prominent in another model of genetic hypertension, the New Zealand genetic hypertensive rat. We will examine the likelihood that the occurrence of endothelium-dependent contractions reflects premature aging of the blood vessel wall exposed to chronic hypertension. We will determine whether or not the occurrence of endothelium-dependent contractions can be induced by the cytokine interleukin-2. We hope to demonstrate that EDCF contributes to the abnormal responsiveness of hypertensive blood vessels not only by evoking vasoconstriction but also by facilitating the growth of vascular smooth muscle. We will use established techniques to bioassay the release of contracting and relaxing factors and to monitor cellular growth. We will use conventional chemical methods (gas chromatography-mass spectrometry, colorimetry) and radioimmunoassays to define the nature and the actions of EDCF and vascular smooth muscle. We will introduce molecular biological techniques to determine the degree of expression and/or of activity of the enzymes that leads to the production of EDCF. These studies will give insight into the chronic role of factors released by the endothelium and vascular .smooth muscle in the pathophysiology of hypertension, and may help to explain the transition from the vasoconstrictor stage in early hypertension to the morphological adaptation that perpetuates the hypertensive process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035614-08
Application #
2217865
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1989-09-30
Project End
1995-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Boulanger, C M; Heymes, C; Benessiano, J et al. (1998) Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: activation by angiotensin II in hypertension. Circ Res 83:1271-8
Ge, T; Hughes, H; Junquero, D C et al. (1995) Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res 76:1003-10
Desta, B; Vanhoutte, P M; Boulanger, C M (1995) Inhibition of the angiotensin converting enzyme by perindoprilat and release of nitric oxide. Am J Hypertens 8:1S-6S
Desta, B; Nakashima, M; Kirchengast, M et al. (1995) Previous exposure to bradykinin unmasks an endothelium-dependent relaxation to the converting enzyme inhibitor trandolaprilat in isolated canine coronary arteries. J Pharmacol Exp Ther 272:885-91
Boulanger, C M; Caputo, L; Levy, B I (1995) Endothelial AT1-mediated release of nitric oxide decreases angiotensin II contractions in rat carotid artery. Hypertension 26:752-7
Boulanger, C M; Morrison, K J; Vanhoutte, P M (1994) Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat. Br J Pharmacol 112:519-24
Boulanger, C M; Desta, B; Clozel, J P et al. (1994) Chronic treatment with the CA2+ channel inhibitor RO 40-5967 potentiates endothelium-dependent relaxations in the aorta of the hypertensive salt sensitive Dahl rat. Blood Press 3:193-6
Boulanger, C M; Nakashima, M; Olmos, L et al. (1994) Effects of the Ca2+ antagonist RO 40-5967 on endothelium-dependent responses of isolated arteries. J Cardiovasc Pharmacol 23:869-76
Boulanger, C M; Vanhoutte, P M (1993) Interleukin-2 causes endothelium-dependent contractions to arachidonic acid. Hypertension 21:289-93
Taddei, S; Vanhoutte, P M (1993) Endothelium-dependent contractions to endothelin in the rat aorta are mediated by thromboxane A2. J Cardiovasc Pharmacol 22 Suppl 8:S328-31

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