The development of hypertension is sexually dimorphic. Blood pressure rises more quickly and to a greater extent in males. While considerable research attention has been directed toward the arterial circulation, there has been relatively little investigation of venous changes in hypertension. Our previous work indicated that venous tone was elevated by neural mechanisms in the developmental stages of hypertension in the spontaneously hypertensive rat, an animal model of that resembles essential hypertension in humans. Recent data suggest that veins and arteries are affected differently by hypertension. Thus, this project will test the general hypothesis that androgens amplify adrenergic tone of the arterial and venous vascular compartments via different mechanisms.
Specific aim I will address the possibility that this effect occurs at the level of vascular smooth muscle.
Specific aim II will assess the role of changes in norepinephrine release mechanisms.
Specific aim III will investigate the effects of androgens on CNS mechanisms controlling sympathetic nervous system outflow from the hypothalamus. Functional studies will be conducted in vivo and in isolated perfused vascular beds. Androgen induced changes in protein and gene expression will be assessed with Western blot and real time RT-PCR approaches. Collectively we expect these studies to show that androgens amplify adrenergic tone in veins and arteries but that the underlying mechanisms are different in these two vascular compartments. These data will expand our understanding of sex steroid modulation of vascular function and of hypertension development. Hypertension is a significant public health problem that is a risk factor for many other cardiovascular diseases. In addition, in patients hypertension is poorly controlled. Moreover, postural hypotension is common adverse effect of antihypertensive therapy, implying dysregulation of venous function. A better understanding the factors that control arterial and venous tone in hypertension may lead to design antihypertensive drugs with fewer adverse effects

Public Health Relevance

Hypertension is a significant public health problem affecting between 10-20% of the US population. Hypertension is a major risk factor for heart attack, heart failure, renal failure, stroke and atherosclerosis. In addition, many patients with hypertension remain poorly controlled because we lack an understanding of the mechanisms causing hypertension. A better understanding the factors that control blood vessels such as arteries and veins in hypertension may lead to design antihypertensive drugs with fewer adverse effects

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063053-06
Application #
7864223
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2000-09-15
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$311,955
Indirect Cost
Name
University of South Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069
Li, Shuai; Wang, Xuejun; Li, Yifan et al. (2013) Bortezomib, a proteasome inhibitor, attenuates angiotensin II-induced hypertension and aortic remodeling in rats. PLoS One 8:e78564
Tatchum-Talom, Rabelais; Eyster, Kathleen M; Kost Jr, Curtis K et al. (2011) Blood pressure and mesenteric vascular reactivity in spontaneously hypertensive rats 7 months after gonadectomy. J Cardiovasc Pharmacol 57:357-64
Mark-Kappeler, Connie J; Martin, Douglas S; Eyster, Kathleen M (2011) Estrogens and selective estrogen receptor modulators regulate gene and protein expression in the mesenteric arteries. Vascul Pharmacol 55:42-9
Song, Jin; Eyster, Kathleen M; Kost Jr, Curtis K et al. (2010) Involvement of protein kinase C-CPI-17 in androgen modulation of angiotensin II-renal vasoconstriction. Cardiovasc Res 85:614-21
Eyster, Kathleen M; Mark, Connie J; Gayle, Richard et al. (2007) The effects of estrogen and testosterone on gene expression in the rat mesenteric arteries. Vascul Pharmacol 47:238-47
Mark, Connie J; Tatchum-Talom, Rabelais; Martin, Douglas S et al. (2007) Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed. Am J Physiol Regul Integr Comp Physiol 293:R1969-75
Song, Jin; Kost Jr, Curtis K; Martin, Douglas S (2006) Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway. Cardiovasc Res 72:456-63
Martin, Doug S; Biltoft, Scott; Redetzke, Rebecca et al. (2005) Castration reduces blood pressure and autonomic venous tone in male spontaneously hypertensive rats. J Hypertens 23:2229-36
Tatchum-Talom, R; Eyster, K M; Martin, D S (2005) Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations. Can J Physiol Pharmacol 83:413-22
Rodrigo, Manoj C; Martin, Douglas S; Eyster, Kathleen M (2003) Vascular ECE-1 mRNA expression decreases in response to estrogens. Life Sci 73:2973-83

Showing the most recent 10 out of 13 publications