In established primary hypertension cardiac output is normal, while peripheral vascular resistance is increased. Many factors may contribute to the elevated vascular resistance. Recently, it became obvious that the endothelium can affect vascular tone by releasing an endothelium-derived relaxing factor(s); endothelium-dependent relaxations appear to be reduced in arteries from rats with genetic hypertension. Under certain circumstances (e.g. anoxia) the endothelium can also release a constrictor substance(s). Preliminary experiments suggest that acetylcholine and serotonin can release a vasoconstrictor material from the aortic endothelium of genetically hypertensive rats (SHR) but not from normotensive controls (WKY). The major purpose of the present proposal is to explore the importance of the endothelium-derived contracting factor(s) in spontaneously hypertensive rats. Experiments will be performed on isolated aortas (and in some cases other arteries and veins), with and without endothelium, of SHR and WKY. Responses of vascular smooth muscle will be recorded as isometric tension. To demonstrate the release of the contracting factor(s) from the endothelium by acetylcholine and other potential releasers (neurohumoral mediators involved in hypertension, platelets, inhibitors of Na+,K+ ATPase, hypoxia, transmural pressure) we will use layered preparations (""""""""sandwich preparations"""""""") and a bioassay apparatus. To determine the nature of the endothelium-derived contracting factor(s) will require examination of the metabolism of arachidonic acid, of the involvement of other neurohumoral mediators, and of the role of oxygen-derived free radicals. To determine the cellular mechanism of action of the endothelium-derived contracting factor(s) on vascular smooth muscle will require measurement of membrane potential and pharmacological interference with Na+,K+ ATPase, the metabolism of arachidonic acid, and Ca2+ movements. The importance of chronic exposure to high blood pressure and of aging for the occurrence of endothelium-dependent contractions will be examined. Finally, we will determine whether endothelium-dependent contractions occur in blood vessels of rats and dogs with secondary hypertension. A disturbed endothelial function could contribute to the elevated peripheral resistance of hypertension and complications such as myocardial infarction and stroke. It is expected that the knowledge gained from the proposed research will provide new insight concerning the role of the endothelium as a source of vasoconstrictor signals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL035614-05
Application #
3349630
Study Section
(SRC)
Project Start
1989-09-30
Project End
1990-09-29
Budget Start
1989-09-30
Budget End
1990-09-29
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
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

Showing the most recent 10 out of 35 publications