The long-term objective of the applicant is to elucidate the humoral mechanisms important in the regulation of vascular function and blood pressure in normotension and in the development of hypertension. This proposal is based upon recent findings by the PI and others that: in normal rats, pressor responsiveness to vasopressin (VP) is higher in males than in females during most phases of the estrous cycle; deoxycorticosterone (DOCA)-salt hypertension (a VP-dependent form of hypertension), develops to a greater extent in male than in female rats; and there are marked sex differences in vascular reactivity to VP and phenylephrine (PE) and in vascular prostanoid (PG) and endothelium- derived relaxing factor (EDRF) production in normotension and DOCA-salt hypertension. The objectives of this research proposal are to elucidate the local (endothelial) and systemic (vasoconstrictor) humoral mechanisms in the vasculature underlying sex differences in vascular responsiveness to VP and alpha1-adrenergic agonists in the rat, and to elucidate the role of the gonadal steroids in the sexual dimorphism in these local and systemic humoral mechanisms, both in normotension and in the development of DOCA-salt hypertension.
The specific aims of the proposed research are to: 1) Characterize male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 2) Determine the role of systemic vasoconstrictor mechanisms (vascular smooth muscle receptors) in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 3) Determine the role of vascular prostanoids as local (endothelial) modulators of vascular function in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; 4) Determine the role of endothelium-derived relaxing factor as a local (endothelial) modulator of vascular function in male-female differences in vascular reactivity to VP and PE in the rat aorta and peripheral vasculature in vitro; and 5) Determine the role of the gonadal steroid hormones in the sexual dimorphism in these local and systemic vascular mechanisms in vitro. The proposed research will provide a unique examination of local and systemic vascular mechanisms underlying sexual dimorphism in the humoral regulation of the cardiovascular system, both in normotension and in the development of hypertension. It is well established that the incidence of hypertension (and other cardiovascular disease) is higher in men than in pre- menopausal women, thus the proposed research is directly relevant to human health and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29HL047432-06
Application #
2881400
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1993-09-01
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
2000-08-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047006379
City
College Station
State
TX
Country
United States
Zip Code
77845
Li, Min; Kuo, Lih; Stallone, John N (2008) Estrogen potentiates constrictor prostanoid function in female rat aorta by upregulation of cyclooxygenase-2 and thromboxane pathway expression. Am J Physiol Heart Circ Physiol 294:H2444-55
Sellers, Minga M; Stallone, John N (2008) Sympathy for the devil: the role of thromboxane in the regulation of vascular tone and blood pressure. Am J Physiol Heart Circ Physiol 294:H1978-86
Li, Min; Stallone, John N (2005) Estrogen potentiates vasopressin-induced contraction of female rat aorta by enhancing cyclooxygenase-2 and thromboxane function. Am J Physiol Heart Circ Physiol 289:H1542-50
Voss, M R; Stallone, J N; Li, Min et al. (2003) Gender differences in the expression of heat shock proteins: the effect of estrogen. Am J Physiol Heart Circ Physiol 285:H687-92
Fulton, Clifford T; Stallone, John N (2002) Sexual dimorphism in prostanoid-potentiated vascular contraction: roles of endothelium and ovarian steroids. Am J Physiol Heart Circ Physiol 283:H2062-73
Deenadayalu, V P; White, R E; Stallone, J N et al. (2001) Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel. Am J Physiol Heart Circ Physiol 281:H1720-7
Ding, A Q; Stallone, J N (2001) Testosterone-induced relaxation of rat aorta is androgen structure specific and involves K+ channel activation. J Appl Physiol 91:2742-50
Stallone, J N; Salisbury, R L; Fulton, C T (2001) Androgen-receptor defect abolishes sex differences in nitric oxide and reactivity to vasopressin in rat aorta. J Appl Physiol 91:2602-10
Chao, J; Stallone, J N; Liang, Y M et al. (1997) Kallistatin is a potent new vasodilator. J Clin Invest 100:11-7
Costarella, C E; Stallone, J N; Rutecki, G W et al. (1996) Testosterone causes direct relaxation of rat thoracic aorta. J Pharmacol Exp Ther 277:34-9

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