The three to four fold greater incidence of primary pulmonary hypertension in women when compared with men indicates the possible existence of a prominent sexual dimorphism in the vascular tissue of the lung. Primary pulmonary hypertension is generally manifest after puberty which also indicates a possible hormonal basis for the disease. Insight into the disease can be obtained by determining the presence of sexual dimorphism in the sensitivity and contractility of the pulmonary vasculature and relating this to the role of the endothelium which is recognized to release both contractile and relaxing factors. Preliminary studies indicate that this is a practical approach and have yielded results which indicate marked sexual differences in the response of vascular segments of the main pulmonary artery of the rat which relate to both the endothelium and the vascular smooth muscle.
The specific aims of this proposal are to establish in immature, mature and older rats the degree of expression of this sexual dimorphism, to identify the contributions of the endothelium and the vascular smooth muscle to the tension generated and to determine the effect of endocrinological manipulation in order to identify the specific hormonal basis. This will be done by tension and sensitivity measurements of rat pulmonary artery vessel segments under isometric conditions in vascular preparations where the endothelium is intact and where it is removed. Pilot experiments indicate that the dimorphism is best expressed by oxidation products of arachidonate. This will be evaluated with selected eicosanoids and other spasmogens including leukotrienes which are found in large amounts in pulmonary vessels. These data will provide an endocrinological basis for studies in perfused lung models. The long-term objective is to provide endocrinological insight into possible causes of primary pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036802-05
Application #
3352085
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1987-09-01
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Georgetown University
Department
Type
Schools of Dentistry
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Vargas, R; Hewes, B; Rego, A et al. (1996) Estradiol effect on rate of proliferation of rat carotid segments: effect of gender and tamoxifen. J Cardiovasc Pharmacol 27:495-9
Vargas, R; Delaney, M; Farhat, M Y et al. (1995) Effect of estradiol 17 beta on pressor responses of rat mesenteric bed to norepinephrine, K+, and U-46619. J Cardiovasc Pharmacol 25:200-6
Farhat, M Y; Chen, M F; Bhatti, T et al. (1993) Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in rats. Br J Pharmacol 110:719-23
Santoian, E C; Thomas, G; Angerio, A D et al. (1993) Vasodilator effects of hydroxylamine in the isolated rodent lung. Angiology 44:897-901
Vargas, R; Wroblewska, B; Rego, A et al. (1993) Oestradiol inhibits smooth muscle cell proliferation of pig coronary artery. Br J Pharmacol 109:612-7
Thomas, G; Ramwell, P W (1992) Identification of guanidino succinate as a putative endogenous source of the endothelium derived relaxing factor. Biochem Biophys Res Commun 183:584-9
Farhat, M Y; Vargas, R; Dingaan, B et al. (1992) In vitro effect of oestradiol on thymidine uptake in pulmonary vascular smooth muscle cell: role of the endothelium. Br J Pharmacol 107:679-83
Santoian, E C; Angerio, A D; Schneidkraut, M J et al. (1992) Calcium utilization associated with U-46619 and PGF2a vascular responses in rat lungs. Angiology 43:163-8
Farhat, M Y; Ramwell, P W (1992) Estradiol potentiates the vasopressor response of the isolated perfused rat lung to the thromboxane mimic U-46619. J Pharmacol Exp Ther 261:686-91
Thomas, G; Myers, A; Farhat, M et al. (1992) Effect of N-substituted arginine compounds on blood pressure in anesthetized rats. J Pharmacol Exp Ther 261:875-8

Showing the most recent 10 out of 27 publications